Clinical trial NCT04940390
Conditions: Migraine Migraine With Aura Migraine Without Aura
Keywords: dihydroergotamine dihydroergotamine mesylate migraine
Sponsor: Satsuma Pharmaceuticals, Inc.
Start date: 2021-06-30; Completion date: 2022-10-26
Enrollment: 1591 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Study STS101-007 is a randomized, double-blind, parallel group, placebo-controlled, multicenter study to evaluate the efficacy, safety, and tolerability of single doses of STS101 (dihydroergotamine nasal powder) in the acute treatment of migraine.

Detailed description:
Study STS101-007 is a multi-center, single-dose, randomized, double-blind, placebo-controlled, parallel group study in subjects with acute migraine (ages 18 to 65 years).

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

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: 
A Randomized, Double-Blind, Parallel Group, Placebo-Controlled, 
Multicenter Study to Evaluate the Efficacy, Safety, and Tolerability of 
STS101 (Dihydroergotamine Nasal Powder) in the Acute Treatment of 
Migraine 
Study Number: 
STS101-007 
Investigational Drug: STS101 (Dihydroergotamine Nasal Powder) 
IND Number: 
136585 
Sponsor: 
Satsuma Pharmaceuticals, Inc. 
400 Oyster Point Boulevard, Suite 221 
South San Francisco, CA 94080 
Tel. No.: 408-857-5248 
Medical Monitor: 
Detlef Albrecht, MD 
Tel. No.: 408-857-5248 
Version History: 
Original 
 
Version 2 
March 8, 2021 
 
May 20, 2021 


STS101 (Dihydroergotamine Nasal Powder) 
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Clinical Trial Protocol: STS101-007 Version #2, May 20, 2021
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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 
Detlef Albrecht 
Digitally signed 
by Detlef 
Albrecht 
Date: 
2021.05.27 
14:45:58 -07'00' 


STS101 (Dihydroergotamine Nasal Powder) 
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Clinical Trial Protocol: STS101-007 Version #2, May 20, 2021
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PRINCIPAL INVESTIGATOR AGREEMENT 
I have carefully read this study protocol and agree that it contains all necessary information 
required to conduct this study. I agree to conduct the study according to this protocol (including 
any amendments) and in accordance with ICH Good Clinical Practices (GCP) and all other 
applicable regulations. I will inform all who assist me in the conduct of this study of their 
responsibilities and obligations. Furthermore, I understand that the Sponsor and the Institutional 
Review Board/Ethics Committee (IRB/EC) must approve any changes to the protocol in writing 
before implementation, unless a deviation is required to eliminate an immediate safety hazard to a 
subject. In such cases the Sponsor and the IRB/EC will be notified as soon as possible. 
 
 
 
Principal Investigator Signature 
 
Date 
 
 
 
Principal Investigator Name (print) 
 
 
 
Site Name 


STS101 (Dihydroergotamine Nasal Powder) 
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Clinical Trial Protocol: STS101-007 Version #2, May 20, 2021
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PROTOCOL SYNOPSIS 
Sponsor/Company Satsuma Pharmaceuticals, Inc.
Investigational 
Product 
STS101 (Dihydroergotamine Nasal Powder)
Active Ingredient
Dihydroergotamine mesylate
Protocol Number
STS101-007
Title of Study
A Randomized, Double-Blind, Parallel Group, Placebo-Controlled, 
Multicenter Study to Evaluate the Efficacy, Safety, and Tolerability of 
STS101 (Dihydroergotamine Nasal Powder) in the Acute Treatment of 
Migraine
Study center
Approximately 130 in the United States
Objectives 
Primary 
 To evaluate the efficacy of a single dose of 5.2 mg STS101 to achieve 
freedom from pain at 2 hours after dosing 
 To evaluate the efficacy of a single dose of 5.2 mg STS101 to achieve 
freedom from most bothersome symptom at 2 hours after dosing 
Secondary 
 To evaluate the efficacy of a single dose of 5.2 mg STS101 to achieve 
pain relief at 2 hours after dosing 
 To evaluate the efficacy of a single dose of 5.2 mg STS101 to avoid the 
use of rescue medication within 24 hours after dosing 
 To evaluate the efficacy of a single dose of 5.2 mg STS101 to achieve 
normal function at 2 hours after dosing  
 To evaluate the efficacy of a single dose of 5.2 mg STS101 to achieve 
2 to 24 hour sustained pain free status 
 To evaluate the efficacy of a single dose of 5.2 mg STS101 to achieve 
2 to 48 hour sustained pain free status 
 To evaluate the efficacy of a single dose of 5.2 mg STS101 to achieve 
2 to 24 hour sustained freedom from most bothersome symptom status 
 To evaluate the efficacy of a single dose of 5.2 mg STS101 to achieve 
2 to 48 hour sustained freedom from most bothersome symptom status 
 To evaluate the efficacy of a single dose of 5.2 mg STS101 to avoid the 
use of rescue medication within 48 hours after dosing 
 To evaluate the efficacy of a single dose of 5.2 mg STS101 to avoid 
headache pain relapse within 24 hours after dosing 
 To evaluate the efficacy of a single dose of 5.2 mg STS101 to avoid 
headache pain relapse within 48 hours after dosing 
 To evaluate the efficacy of a single dose of 5.2 mg STS101 to achieve 
freedom from pain at various timepoints after dosing 
 To evaluate the efficacy of a single dose of 5.2 mg STS101 to achieve 
freedom from most bothersome symptom at various timepoints after 
dosing
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Clinical Trial Protocol: STS101-007 Version #2, May 20, 2021
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 To evaluate the efficacy of a single dose of 5.2 mg STS101 to achieve 
pain relief at various timepoints after dosing 
 To estimate the probability of a subject to achieve freedom from pain 
during the 24-hour post dose period 
 To estimate the probability of a subject to achieve freedom from the 
most bothersome symptom during the 24-hour post dose period 
 To estimate the probability of a subject to achieve pain relief during 
the 24-hour post dose period 
 To estimate the probability of a subject requiring rescue medication 
during the 24-hour post dose period 
 To evaluate the efficacy of a single dose of 5.2 mg STS101 to achieve 
freedom from photophobia at 2 hours after dosing 
 To evaluate the efficacy of a single dose of 5.2 mg STS101 to achieve 
freedom from phonophobia at 2 hours after dosing 
 To evaluate the efficacy of a single dose of 5.2 mg STS101 to achieve 
freedom from nausea at 2 hours after dosing 
 To evaluate the efficacy of a single dose of 5.2 mg STS101 to achieve 
freedom from photophobia at various timepoints after dosing 
 To evaluate the efficacy of a single dose of 5.2 mg STS101 to achieve 
freedom from phonophobia at various timepoints after dosing 
 To evaluate the efficacy of a single dose of 5.2 mg STS101 to achieve 
freedom from nausea at various timepoints after dosing 
 
 of the study treatment 
 To assess the safety and tolerability of a single dose of 5.2 mg STS101 
in the treatment of acute migraine attacks 
Exploratory 
 To evaluate the efficacy of a single dose of 5.2 mg STS101 to achieve 
freedom from pain and most bothersome symptom by allodynia status 
at time of dosing 
 To evaluate the efficacy of a single dose of 5.2 mg STS101 to achieve 
freedom from pain and most bothersome symptom at 2 hours after 
dosing in subjects who wake up with acute migraine attacks 
 To evaluate the efficacy of a single dose of 5.2 mg STS101 to achieve 
freedom from pain and most bothersome symptom at 2 hours after 
dosing in subjects with acute menstrual related migraine attacks 
 To evaluate the efficacy of a single dose of 5.2 mg STS101 to achieve 
pain relief at 2 hours after dosing in subjects with acute migraine 
attacks by allodynia status at time of treatment 
 To evaluate the efficacy of a single dose of 5.2 mg STS101 to achieve 
pain relief at 2 hours after dosing in subjects who wake up with acute 
migraine attacks
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To evaluate the study subject's global impression 
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 To evaluate the efficacy of a single dose of 5.2 mg STS101 to achieve 
pain relief at 2 hours after dosing in subjects with acute menstrual 
related migraine attacks 
 To evaluate the efficacy of a single dose of 5.2 mg STS101 to achieve 
both, freedom from pain and most bothersome symptom at 2 hours 
after dosing 
 To evaluate the efficacy of a single dose of 5.2 mg STS101 to achieve 
both, freedom from pain and most bothersome symptom at various 
timepoints after dosing 
 To evaluate the efficacy of a single dose of 5.2 mg STS101 to achieve 
freedom from headache pain and most bothersome symptom (MBS) at 
2 hours after dosing by baseline (Visit 2) HIT-6 score 
 To evaluate the effects of a single dose of 5.2 mg STS101 on the 
24-hour Migraine Quality of Life Questionnaire (24-MQoLQ) 
Methodology 
This is a multi-center, single-dose, randomized, double-blind, placebo-
controlled, parallel group study in approximately 1400 subjects with acute 
migraine (ages 18 to 65 years). 
Study participants must have 2 to 8 migraine attacks, and fewer than 15 
headache days during each of the three months before the screening visit. 
At Visits 1 and 2, all study participants will be trained in the use of the 
STS101 device, the use of the electronic diary (e-diary) and undergo 
Placebo Response Reduction training, designed to improve discrimination 
between placebo and drug effects in clinical trials. 
After establishing eligibility, the study participants will be randomized 
(1:1) to receive one of two treatments: 
 5.2 mg STS101 (equivalent to  6.0 mg of DHE mesylate USP) 
 Placebo (matching nasal powder) 
The randomization will be stratified by the use of migraine prevention 
medication. After the randomization, the study participants will treat their 
next qualifying migraine attack of at least moderate pain severity with the 
allocated blinded study medication within 4 hours of the onset of the 
attack. 
The study participants will document the following symptoms of their 
treated migraine before and over 48 hours after study drug administration 
in an electronic diary (e-diary): migraine headache pain severity, presence 
of symptoms (photophobia, phonophobia, nausea), presence of allodynia 
and functionality status. Headache pain severity and symptom data will be 
documented immediately before drug administration (time 0), at 15, 30, 45 
minutes and 1, 1.5, 2, 3, 4, 6, 12, 24, and 48 hours after study drug 
administration. The subjects must select a most bothersome symptom 
among photophobia, phonophobia, and nausea immediately before study 
drug administration. 
If subjects require rescue medication, they will be encouraged to wait until
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the 2-hour post study drug administration data collection timepoint. The 
use of triptans or other DHE mesylate products as rescue medications 
should be avoided for 24 hours after study drug administration. The study 
participants will return to the study site within approximately one week of 
the treated migraine attack. 
Adverse events, objective nasal evaluation data, safety laboratory data, 
vital sign data and ECGs will be recorded before and after treatment to 
evaluate the tolerability and safety of STS101. 
Number of 
subjects (planned) 
A total of approximately 1400 adult male and female subjects aged 18 to 
65 years with acute migraine headaches. 
Inclusion criteria 
1. English speaking males or females, 18-65 years of age at the time of 
Screening Visit 
2. Signed Informed Consent Form 
3. Subject has at least 1-year history of migraines (with or without aura), 
according to the International Classification of Headache Disorder, 3rd 
Edition (ICHD3), including the following: 
a. Migraine onset before the age of 50 years 
b. Migraine attacks, on average, lasting 4-72 hours if untreated 
c. Migraine headache frequency of 2 to 8 attacks of moderate or 
severe pain intensity per month in each of the 3 months prior to the 
Screening Visit 
d. Fewer than 15 days with headache (migraine or non-migraine) per 
month in each of the 3 months prior to the Screening Visit 
e. Individual migraine attacks separated by at least 2 days of no headache 
pain 
f. Subject is able to distinguish migraines from other headache types, 
e.g., tension-type or cluster headache. 
4. Subjects on preventive migraine medication are permitted to remain on 
therapy provided they have been on a stable dose for at least 3 months 
prior to study entry and have no plans to change the dose during the study
5. Female subjects will be included if they are post-menopausal (at least 
1 year since last menses 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 


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Clinical Trial Protocol: STS101-007 Version #2, May 20, 2021
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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) 
6. 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), and no other nasal conditions 
that may interfere with intranasal dosing at randomization (Visit 2) 
7. Willing and able to comply with the requirements of the protocol and 
follow directions from the clinic staff 
8. Adequate compliance 
in the completion of the e-diary during 
the Screening Period 
Exclusion criteria 1. Pregnant or breast-feeding women 
2. Women of child-bearing potential not using or not willing to use 
highly effective contraception 
3. Diagnosis of headache conditions other than migraine with or without 
aura, including diagnosis of basilar or hemiplegic migraines, 
medication overuse headache or cluster headache 
4. Abnormal physical findings of clinical significance which would 
interfere with the objectives of the study at the screening or 
randomization visit examination 
5. History of coronary artery disease, coronary artery vasospasm (including 
Printz-
vascular disease, ischemic disease (e.g., 
, 
ischemic bowel syndrome, angina pectoris, myocardial infarction, or 
documented silent ischemia); percutaneous coronary intervention, or 
cardiac surgery 
6. History of cerebrovascular disease, including but not limited to stroke, 
transient ischemic attack, cerebral hemorrhage, subarachnoid 
hemorrhage 
7. Presence of two or more of the following cardiovascular risk factors: 
a. Previous diagnosis of hypertension or currently taking 
antihypertensive medication 
b. Previous diagnosis of hypercholesteremia, or currently taking 
cholesterol lowering treatment or LDL >159 mg/dL at screening 
(Visit 1; note: re-draws prior to Visit 2 may be permitted) 
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
(~80%) 
metals' angina), clinically significant arrhythmia or, peripheral 
Raynaud' s syndrome 


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g. Males 46 years and older  
8. Clinically significant abnormal laboratory values (as determined by the 
Principal Investigator) at the screening (Visit 1; note: re-draws prior to
Visit 2 may be permitted) 
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; note: re-draws prior to Visit 2 may be permitted) 
10. Screening 12-lead ECG showing any clinically significant abnormalities 
at screening (Visit 1) 
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) 
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 or within less than 5 half-lives of tested drug 
(whichever is longer) 
15. Concomitant use of potent CYP3A4 inhibiting medications, for 
example protease inhibitors (e.g., ritonavir, nelfinavir, indinavir, 
saquinavir, tipranavir, lopinavir, atazanavir, darunavir), macrolide 
antibiotics (e.g., erythromycin, clarithromycin, troleandomycin), or 
strong imidazole antifungals (e.g., ketoconazole, and itraconazole) 
16. Previously shown hypersensitivity to ergot alkaloids or the inactive 
ingredients of STS101 (microcrystalline cellulose, hydroxypropyl 
methylcellulose, mannitol) 
17. Concomitant use of more than one preventive migraine medication. 
18. Current use of opioids, cannabis or cannabinoid containing products 
19. Concomitant use of peripheral and central vasoconstrictors including 
but not limited to amphetamines, phenylephrine, pseudoephedrine, 
propranolol and nicotine (from smoking, vaping or smokeless products) 
20. Score of >0 on any of the questions 1-14 of the Sheehan Suicidality 
Tracking Scale


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Clinical Trial Protocol: STS101-007 Version #2, May 20, 2021
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Investigational 
product, dosage 
and mode of 
administration 
 5.2 mg STS101 dose strength (equivalent to 6.0 mg of DHE mesylate 
USP; nasal powder) 
 Placebo (matching nasal powder) 
For subject training 
 STS101 Empty Training Devices 
 STS101 Filled Training Devices (microcrystalline cellulose powder) 
Duration of study 
 Screening period: Up to 30 days 
 Treatment & follow up period: Up to 66 days 
Criteria for 
Evaluation 
Efficacy 
Primary Efficacy: 
 Proportion of subjects free from headache pain at 2 hours after dosing 
(defined as moderate or severe headache pain [2 or 3 on a 4-point scale] 
at baseline [time 0] becoming none [0] on a 4-point scale) 
 Proportion of subjects free from most bothersome symptom (MBS) 
among photophobia, phonophobia and nausea at 2 hours after dosing 
(defined as the MBS selected at baseline [time 0] being absent) 
Secondary Efficacy: 
 Proportion of subjects with relief from headache pain at 2 hours after 
dosing (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 who use rescue medication within 24 hours after 
dosing 
 Proportion of subjects who achieve normal function at 2 hours after 
dosing (defined as score of 0 on the 4-point functional impairment scale)
 Proportion of subjects free from headache pain at 2 hours after dosing 
and remaining headache free at 24 hours after dosing with no use of 
rescue medication and no relapse of any headache pain (defined as 
score of 0 on a 4-point scale from 2-24 hours) 
 Proportion of subjects free from headache pain at 2 hours after dosing 
and remaining headache free at 48 hours after dosing with no use of 
rescue medication and no relapse of any headache pain (defined as 
score of 0 on a 4-point scale from 2-48 hours) 
 Proportion of subjects free from most bothersome symptom (MBS) at 
2 hours after dosing and remaining MBS free at 24 hours after dosing 
with no use of rescue medication and no relapse of any MBS (defined 
as MBS selected at baseline [time 0] absent from 2-24 hours) 
 Proportion of subjects free from most bothersome symptom (MBS) at 
2 hours after dosing and remaining MBS free at 48 hours after dosing 
with no use of rescue medication and no relapse of any MBS (defined 
as MBS selected at baseline [time 0] absent from 2-48 hours)
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 Proportion of subjects who use rescue medication within 48 hours after 
dosing 
 Proportion of subjects with headache relapse within 24 hours after 
dosing (defined as the return of headache of any severity within 24 
hours post dosing of the investigational drug, when the subject was 
pain-free at 2 hours after dosing) 
 Proportion of subjects with headache relapse within 48 hours after 
dosing (defined as the return of headache of any severity within 48 
hours post dosing of the investigational drug, when the subject was 
pain-free at 2 hours after dosing) 
 Proportion of subjects free from headache pain at various time points 
after dosing 
 Proportion of subjects free from most bothersome symptom at various 
time points after dosing 
 Proportion of subjects achieving pain relief at various time points after 
dosing 
 Proportion of subjects who achieve normal function at various 
timepoints after dosing 
 Proportion of subjects free from photophobia (defined as photophobia 
being absent at 2 hours after dosing if present at baseline [time 0]) 
 Proportion of subjects free from phonophobia (defined as phonophobia 
being absent at 2 hours after dosing if present at baseline [time 0]) 
 Proportion of subjects free from nausea (defined as nausea being 
absent at 2 hours after dosing if present at baseline [time 0]) 
 Proportion of subjects free from photophobia at various timepoints 
after dosing 
 Proportion of subjects free from phonophobia at various timepoints 
after dosing 
 Proportion of subjects free from nausea at various timepoints after dosing 
 Patient Global Impression ratings 
Exploratory 
 Proportion of subjects free from headache pain at 2 hours after dosing 
by allodynia status at baseline (allodynia status will be defined as 
-question allodynia 
questionnaire [Ashkenazi 2007; Tepper 2011]) 
 Proportion of subjects free from headache pain and free from most 
bothersome symptom (MBS) at 2 hours after dosing in subjects who 
wake up with migraine headache 
 Proportion of subjects free from headache pain and free from most 
bothersome symptom (MBS) at 2 hours after dosing in subjects with 
menstrual related migraine attack
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 Proportion of subjects with relief from headache pain at various 
timepoints after dosing by allodynia status at baseline (time 0) 
(allodynia s
responses to the 6-question allodynia questionnaire [Ashkenazi 2007; 
Tepper 2011]) 
 Proportion of subjects free from headache pain and free from most 
bothersome symptom (MBS) at various timepoints after dosing in 
subjects who wake up with migraine headache 
 Proportion of subjects free from headache pain and free from most 
bothersome symptom (MBS) at various timepoints after dosing in 
subjects with menstrual related migraine attack 
 Proportion of subjects free from both, headache pain and most 
bothersome symptom (MBS) at 2 hours after dosing 
 Proportion of subjects free from both, headache pain and most 
bothersome symptom (MBS) at various time points after dosing 
 Proportion of subjects free from headache pain and free from most 
bothersome symptom (MBS) at 2 hours after dosing by baseline 
(Visit 2) HIT-6 score 
 24-hour Migraine Quality of Life Questionnaire summary scores 
Safety 
The following assessment and measurements will be conducted at 
screening, before randomization and at the final visit: 
 Physical examination 
 Vitals signs and body weight 
 Objective nasal symptom assessment 
 12-lead ECG 
 Blood tests for hematology and biochemistry analysis (including liver 
function, renal function, thyroid function, electrolytes) 
 Urinalysis 
 Adverse events (AEs) 
 Documentation of concomitant medications 
Statistical methods Sample Size Determination 
A total of approximately 1400 evaluable subjects is planned for the study. 
Given the 1:1 randomization ratio, approximately 700 subjects will be 
randomized to each treatment group. For the co-primary endpoint of pain 
freedom at 2 hours post dosing of investigational drug, a therapeutic gain 
of 10%, assuming a 25% responder rate for STS101 and 15% for the 
placebo is targeted. Based on these assumptions, 700 subjects per 
treatment group can provide 99% power to detect the target treatment 
difference. For the co-primary endpoint of MBS freedom at 2 hours post 
investigational drug, a therapeutic gain of 10%, assuming a 45% responder 
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rate for STS101 and 35% for the placebo is targeted. Based on these 
assumptions, 700 subjects per treatment group can provide 95% power to 
detect the target treatment difference. The sample size calculation is based 
on a chi-square test with a significance level of 0.05 and a 2-sided test. 
The primary efficacy objective will be addressed by simultaneously testing 
the 2 co-primary endpoints of pain freedom and MBS freedom at 2 hours 
after drug administration at a significance level of 0.05. This sample size 
will provide an overall power of at least 94%. 
Efficacy 
A detailed Statistical Analysis Plan (SAP) including the final hierarchy of 
testing of primary and secondary endpoints will be created before data base 
lock and study unblinding. 
All study data will be summarized by treatment using descriptive statistics. 
Unless otherwise specified, for numeric data (e.g., age, weight), descriptive 
statistics will include the number of subjects with data to be summarized 
(n), mean, standard deviation (SD), median, minimum (min) and maximum 
(max). All categorical/qualitative data (e.g., gender, race) will be presented 
using absolute and relative frequency counts and percentage. 
Data from all investigational centers will be pooled for analysis. For the 
primary analysis of the co-primary endpoints, missing data will be imputed 
based on a single-imputation method. Subjects who do not have evaluable 
assessments at the 2-hour time point, or who received rescue medications 
prior to the 2-hour time point will be considered as non-responders. The 
impact of missing data will be further investigated in a number of 
sensitivity analyses with other single and multiple-imputation approaches. 
A study-wise Type I error of 0.05 will be used for this study. A fixed-
sequence testing method with a pre-defined hierarchical order will be 
employed to control for the study-wise Type I error rate. 
For both co-primary endpoints, the Chi-square test will be used to 
compare the active treatment groups and placebo. Chi-square test will also 
be used to test secondary endpoints consisting of proportion of responders. 
For analyses stratified by allodynia status, timing of treatment, the 
Cochran-Mantel-Haenszel test will be used. The Kaplan-Meier method 
will be used for time to use of rescue medications. The 24-hour Migraine 
Quality of Life Questionnaire assessments will be analyzed with the 
Analysis of Variance (ANOVA) models. The Chi-Square test will be used 
to analyze the Patient Global Impression ratings. 
Subgroup analyses of the key efficacy endpoints will be conducted to gain 
insight of the nature and consistency of the treatment effect. 


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Safety 
Safety analyses will include all subjects who received at least one dose of 
study medication. 
All adverse events reported or observed will be listed, documenting 
severity, start and stop date and time, possible relationship to study 
medication, action taken, and outcome. Treatment emergent adverse 
events (TEAE) are defined as adverse events recorded after dosing of the 
investigational product. Verbatim terms will be classified to preferred 
terms (PT) and related system organ class (SOC) using the MedDRA 
dictionary. The preferred terms and system organ classes will be tabulated 
by treatment group. All reported adverse events will be summarized by the 
number of subjects reporting adverse events, system organ class, preferred 
term, severity and relationship to study drug. 
Safety labs including complete blood count (CBC), chemistry and 
urinalysis will be tabulated using descriptive statistics. A tabulation of 
by-subject abnormal/out-of-range findings and changes from pre-dose 
(Visit 1) to post-dose in all laboratory variables will be provided. 
Vital signs, objective and subjective evaluations of nasal symptom and 
standard 12-lead ECGs will be tabulated using descriptive statistics. A 
tabulation of by-subject abnormal/out-of-range findings and changes from 
pre-dose (Visit 1) to post-dose variables will be provided. 
 


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TABLE OF CONTENTS 
Signature Page (Sponsor) ................................................................................................................ 2 
Principal Investigator Agreement ................................................................................................... 3 
Protocol Synopsis............................................................................................................................ 4 
List of Tables ................................................................................................................................ 19 
List of Figures ............................................................................................................................... 19 
List of Appendices ........................................................................................................................ 19 
List of Abbreviations and Definitions of Terms ........................................................................... 20 
Study Protocol Revision History .................................................................................................. 22 
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 ................................................................................. 28 
1.2.6. DHE Mesylate Pregnancy Category................................................................. 28 
1.3. Summary of Nonclinical Data ...................................................................................... 28 
1.4. Summary of Clinical Data for STS101 ........................................................................ 28 
1.5. Rationale for the study ................................................................................................. 29 
2. STUDY OBJECTIVES AND PURPOSE ..............................................................................30 
3. STUDY DESIGN....................................................................................................................32 
3.1. Overall Study Design and Plan .................................................................................... 32 
3.2. Study Procedures Descriptions ..................................................................................... 33 
3.2.1. Informed Consent ............................................................................................. 33 
3.2.2. Assignment of Subject Identification Number ................................................. 33 
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) ..................................................................... 34 
3.2.6. Physical Examination ....................................................................................... 34 
3.2.7. Vital Signs ........................................................................................................ 34 


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3.2.8. Weight, Height and Body Mass Index (BMI) .................................................. 34 
3.2.9. Evaluations of Effects in the Nose ................................................................... 35 
3.2.9.1. Objective Assessment of Nasal Symptoms ....................................... 35 
3.2.10. Clinical Laboratory Tests ................................................................................. 35 
3.2.10.1. Lab Testing for Chest Related Symptoms or Adverse Events .......... 36 
3.2.11. Electrocardiogram ............................................................................................ 36 
3.2.12. Adverse Events Recording ............................................................................... 37 
3.2.13. Electronic Headache Diary ............................................................................... 37 
3.2.14. Placebo Response Reduction Training ............................................................. 37 
3.2.15. Sheehan Suicidality Tracking Scale (S-STS) ................................................... 37 
3.3. Schedule of Observations and Procedures ................................................................... 37 
3.3.1. Screening Procedures ....................................................................................... 37 
3.3.2. Screening Visit & Period (Day-30 to Day -1) .................................................. 38 
3.3.3. Randomization Visit (Visit 2; Day1)................................................................ 38 
3.3.4. Final Visit/Early Termination (Visit 3) ............................................................ 39 
4. SELECTION AND WITHDRAWAL OF SUBJECTS ..........................................................40 
4.1. Subject Inclusion Criteria ............................................................................................. 40 
4.2. Subject Exclusion Criteria ............................................................................................ 41 
4.3. Subject Withdrawal Criteria ......................................................................................... 42 
5. TREATMENT OF SUBJECTS ..............................................................................................44 
5.1. Description of Investigational Product and Packaging ................................................ 44 
5.2. Investigational Product Labeling.................................................................................. 44 
5.3. Investigational Product Storage.................................................................................... 45 
5.4. Investigational Product Administration & Training ..................................................... 45 
5.5. Investigational Product Accountability ........................................................................ 45 
5.6. Investigational Product Handling and Disposal ........................................................... 46 
5.7. Concomitant Medications & Migraine Treatments ...................................................... 46 
5.8. Treatment Compliance ................................................................................................. 47 
5.9. Randomization and Blinding ........................................................................................ 47 
5.9.1. Subject Randomization..................................................................................... 47 
5.9.2. Blinding ............................................................................................................ 47 
5.9.3. Unblinding Procedures ..................................................................................... 47 
6. ASSESSMENT OF EFFICACY ............................................................................................48 


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6.1. Efficacy Evaluation Parameters (e-Diary) ................................................................... 48 
6.1.1. Migraine Headache Pain Severity .................................................................... 48 
6.1.2. Most Bothersome Symptom ............................................................................. 48 
6.1.3. Evaluation of Allodynia ................................................................................... 48 
6.1.4. Use of Rescue Medication ................................................................................ 49 
6.1.5. Evaluation of Function ..................................................................................... 49 
6.1.5.1. Functional Impairment Scale ............................................................ 49 
6.1.5.2. 24-hour Migraine Quality of Life Questionnaire .............................. 49 
6.2. Patient Subjective Impression Questions (Office; Visit 3) .......................................... 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 . 50 
7. ASSESSMENT OF SAFETY .................................................................................................51 
7.1. Safety Parameters ......................................................................................................... 51 
7.1.1. Examinations .................................................................................................... 51 
7.1.1.1. Physical Examinations ...................................................................... 51 
7.1.1.2. Height, Weight, and BMI .................................................................. 51 
7.1.1.3. Vital Signs ......................................................................................... 51 
7.1.1.4. Objective Nasal Symptom Assessments ........................................... 51 
7.1.1.5. Electrocardiogram (ECG) ................................................................. 51 
7.1.2. Laboratory Assessments ................................................................................... 52 
7.1.2.1. Hematology ....................................................................................... 52 
7.1.2.2. Serum Chemistry ............................................................................... 52 
7.1.2.3. Urinalysis .......................................................................................... 52 
7.1.2.4. Urine Drug Screen ............................................................................. 52 
7.1.2.5. Serum & Urine Pregnancy Test ........................................................ 52 
7.1.2.6. Serum FSH test.................................................................................. 52 
7.1.2.7. Lab testing for chest related symptoms or adverse events ................ 52 
7.1.2.8. Sheehan Suicidality Tracking Scale .................................................. 53 
7.2. Adverse Events ............................................................................................................. 53 
7.2.1. AE Relationship to Study Drug ........................................................................ 54 
7.2.2. Assessment of Adverse Event Severity ............................................................ 54 


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7.2.3. Serious Adverse Events (SAEs) Recording and Reporting.............................. 54 
8. STATISTICS ..........................................................................................................................57 
8.1. Sample Size Determination .......................................................................................... 57 
8.2. Subject Populations ...................................................................................................... 57 
8.2.1 Intent-to-Treat Population ................................................................................ 57 
8.2.2 Modified Intent-to-Treat Population ................................................................ 57 
8.2.3 Per-Protocol Population ................................................................................... 57 
8.2.1. Safety Population ............................................................................................. 58 
8.3. Statistical Analysis ....................................................................................................... 58 
8.3.1. Demographic and Baseline Variables .............................................................. 58 
8.3.2. Efficacy Analysis ............................................................................................. 58 
8.3.2.1. Primary Efficacy Endpoints .............................................................. 58 
8.3.2.2. Secondary Efficacy Endpoints .......................................................... 58 
8.3.2.3. Exploratory Endpoints....................................................................... 59 
8.3.3. Hypotheses Testing and Significance Level .................................................... 60 
8.3.4. Handling of Missing Data ................................................................................ 60 
8.3.5. Pooling of Centers ............................................................................................ 60 
8.3.6. Analysis Methods for Efficacy Endpoints........................................................ 61 
8.3.7. Subgroup Analysis of Efficacy Endpoints ....................................................... 61 
8.3.8. Safety Analysis ................................................................................................. 61 
8.3.8.1. Extent of Exposure ............................................................................ 62 
8.3.8.2. Adverse Events .................................................................................. 62 
8.3.8.3. Assessment of Nasal Symptoms ....................................................... 62 
8.3.8.4. Laboratory Evaluations ..................................................................... 62 
8.3.8.5. Vital Signs ......................................................................................... 63 
8.3.8.6. ECG Evaluations ............................................................................... 63 
8.3.8.7. Concomitant Medications ................................................................. 63 
8.3.8.8. Sheehan Suicidality Tracking Scale .................................................. 63 
8.3.9. Interim analysis ................................................................................................ 63 
9. DATA HANDLING AND RECORDKEEPING ...................................................................64 
9.1. Case Report Forms (CRFs) .......................................................................................... 64 
9.2. Retention of Records .................................................................................................... 64 
10. QUALITY CONTROL AND QUALITY ASSURANCE ......................................................65 


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10.1. Study Monitoring ......................................................................................................... 65 
10.2. Audits and Inspections ................................................................................................. 65 
11. ETHICS...................................................................................................................................66 
11.1. Ethics Review ............................................................................................................... 66 
11.2. Ethical Conduct of the Study........................................................................................ 66 
11.3. Written Informed Consent ............................................................................................ 66 
11.4. Disclosure of Data ........................................................................................................ 67 
12. REFERENCES .......................................................................................................................68 
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. Laboratory Tests ........................................................................................................... 36 
Table 4. Adverse Event Relationship to Study Drug ................................................................. 54 
Table 5. Assessment of Adverse Event Severity ........................................................................ 54 
List of Figures 
Figure 1. STS101 Device ............................................................................................................. 25 
Figure 2. Dihydroergotamine mesylate chemical structure ......................................................... 26 
Figure 3. Study Schematic ........................................................................................................... 33 
List of Appendices 
Appendix A. Schedule of Assessments ...................................................................................... 71 
Appendix B. List of Allowed and Disallowed Other Headache Types ...................................... 72 
Appendix C. Objective Assessment of Nasal Symptoms........................................................... 73 
Appendix D. STS101 Instructions for Use ................................................................................. 75 
Appendix E. 24-Hour Migraine Quality of Life Questionnaire ................................................. 76 
Appendix F. Headache Impact Test (HIT-
 ......................................................................... 78 
Appendix G. Sheehan Suicidality Tracking Scale (S-STS) ....................................................... 79 
 
 
6™) 


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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 
ANOVA 
Analysis of variance 
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Concentration-Time Curve 
BMI 
Body Mass Index 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CGRP 
Calcitonin Gene-Related Peptide 
CM 
Concomitant Medication 
Cmax 
Maximum Observed Plasma Concentration 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
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
GCP 
Good Clinical Practice 
hCG 
Human Chorionic Gonadotropin 
HPMC
Hydroxypropyl Methylcellulose
ICF
Informed Consent Form
ICHD3 
International Classification of Headache Disorder, 3rd Edition 
IM 
Intramuscular 
IN
Intranasal
IRB
Institutional Review Board
ITT
intent-to-treat
IV 
Intravenous 
max
maximum
MBS
bothersome symptom
MCC
Microcrystalline Cellulose


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Abbreviation or specialist term 
Explanation 
MedDRA 
Medical Dictionary for Regulatory Activities 
min 
minimum 
mITT 
modified intent-to-treat 
NOAEL 
No Observed Adverse Effect Level 
PK 
Pharmacokinetic 
PP 
per protocol 
PT 
Preferred Term (in MedDRA dictionary) 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
SD 
Standard Deviation 
SOC 
System Organ Class (in MedDRA dictionary) 
T1/2 
Terminal Elimination Half-Life 
TEAE 
Treatment Emergent Adverse Events 
 
 
 


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STUDY PROTOCOL REVISION HISTORY 
Changes in Version 1 (May 17, 2021) 
Investigational product dose strength: The sponsor decided to conduct this Phase 3 study with the 
5.2 mg STS101 dose strength (equivalent to 6.0 mg of DHE mesylate USP) instead of the 8.6 mg 
dose strength. In all protocol sections all references to the 8.6 mg dose strength have been 
replaced with the 5.2 mg dose strength. 
 
The sponsor decided to increase the number of study sites to 130. In all protocol sections all 
references to the number of sites has been updated to 130 
 
Synopsis (page 9) and Section 4.2 Subject Exclusion Criteria (page 42) 
 
Added Exclusion Criteria #20: 
0 on any of the questions 1-14 of the Sheehan Suicidality Tracking Scale 
 
Rationale: 
FDA requirement to explore treatment emergent suicidal ideation and behavior for drugs in 
neurological indications. 
 
 
Section 1.2.1 STS101 Device (page 25) 
 
New image of STS101 device without cap was added since the device used in this study will not 
have a cap. 
 
 
Section 1.3 Summary of Nonclinical Data (page 28) 
 
Minor changes in the text to address higher margins of safety for 5.2 dose strength. 
 
 
Section 1.5 Rationale for Study (page 29) 
 
Minor changes in the text to delete references to 8.6 mg dose strength. 
 
 
Section 3.2.10 Clinical Laboratory Tests (Table 3, page 36); Section 3.3.3 Randomization 
Visit (page 38); Section 7.1.2.5 Serum & Urine Pregnancy Test (page 52); Appendix A 
Schedule of Assessments (page 71) 
 
Added urine pregnancy test conducted at Visit 2. 
 
 
Score of2:: 


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Section 3.2.10.1 (page 36) & 7.1.2.7 (page 52) Lab testing for chest related symptoms or 
adverse events 
 
Added sections to describe additional lab tests for subjects who report chest related symptoms or 
adverse events. 
 
 
Section 3.2.11 Electrocardiogram (page 36) 
 
Added sections to describe additional ECGs for subjects who report chest related symptoms or 
adverse events. 
 
 
Section 3.2.15 Sheehan Suicidality Tracking Scale (page 37); Section 3.3.2 Screening Visit 
& Period (page 38); Section 3.3.3 Randomization Visit (page 38); Section 3.3.4 Final Visit/ 
Early termination (Visit 3), (page 39); Section 7.1.2.8 Safety Evaluation (page 53); Section 
8.3.8.8 Safety Analysis - Sheehan Suicidality Tracking Scale (page 63); Appendix A Schedule 
of Assessments (page 71); Appendix G Sheehan Suicidality Tracking Scale (page 79) 
 
Added completion of Sheehan Suicidality Tracking Scale at Visits 1, 2 and 3 and analysis of data 
in safety analysis. 
 
 
Section 4.2 Subject Exclusion Criteria (page 41) 
 
Added missing words 
 to Exclusion criteria #3 
 
 
Section 5.6 Investigative Product Handling & Disposal (page 46) 
 
Minor text edits. 
 
 
Section 8.3.6 Analysis Methods for Efficacy Endpoints (page 61) 
 
Minor text changes. 
 
 
Appendix A Schedule of Assessments (page 71) 
 
Minor text change reg. follow up visit window 
 
 
Appendix D_STS101 Instructions for Use (page 75) 
 
New instructions for use illustration added. 
"medication overuse headache" 


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


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o Low and variable bioavailability (
; 
Migranal® Prescribing Information 2017) 
o Slow onset of action (
) 
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 
 
• 
• 
• 
Tfelt-Hansen 2013 
Tfelt-Hansen 2013 
Tab 
Nozzle 
Pump 
Medication 
Nozzle Base 


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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)-
-
,monomethanesulfonate. Its molecular weight is 679.80 and its empirical formula is 
C34H41N5O8S. The chemical structure is shown in Figure 2. 
Figure 2. Dihydroergotamine mesylate chemical structure 
 
1.2.3. 
DHE Mechanism of Action in the Treatment of Migraine 
The antimigraine activity of DHE is likely related to the agonist activity at 5-HT1B, 5-HT1D, and 
5-HT1F receptors (Dahlöf 2012). Additionally, DHE can cause vasoconstriction via CGRP release 
2A/2c and 5-HT2A receptors and may inhibit neurogenic inflammation 
in peripheral meningeal tissues and nociceptive neuronal transmission centrally in the trigeminal 
nucleus caudalis (Hoskin 1996; Burstein 2004; Silberstein 2003; Dahlöf 2012; González-
Hernández 2018). The DHE mesylate-related side effects of nausea and vomiting are likely 
related to activation of central 5-HTlA receptors and dopamine D2 receptors (Silberstein 2003). 
Because of slow diffusion from the receptor biophase, the effects of DHE mesylate last far 
longer than can be expected from plasma concentrations (Dahlöf 2012; 
). 
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. 
,(5'a) 
CH, o 
.... ot fl 
N···· .. 
---rl',,1,,,,J 
_H 
N H 
N 
0 
~ 
H 
·. 
0 
0 
by stimulating adrenergic a 
Tfelt-Hansen 2013 


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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 
 
 
 
Additional information including may be found in the STS101 Investigator's Brochure. 


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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 
 Brochure. 
1.2.6. 
DHE Mesylate Pregnancy Category 
DHE mesylate may cause fetal harm when administered to a pregnant woman. There are no 
adequate studies of DHE mesylate in human pregnancy, but developmental toxicity has been 
demonstrated in experimental animals. DHE mesylate possesses oxytocic properties and, 
therefore, should not be administered during pregnancy. If this drug is used during pregnancy, or 
if the patient becomes pregnant while taking this drug, the patient should be apprised of the 
potential hazard to the fetus. DHE mesylate is designated Pregnancy Category X in the U.S 
(D H E  45® Prescribing Information 2017; Migranal® Prescribing Information 2017). 
1.3. Summary of Nonclinical Data 
The nonclinical toxicology program for STS101 was designed to supplement the known 
nonclinical studies in support of the general safe use of DHE mesylate. In a GLP 14-day 
intranasal toxicology study with a 14-day recovery period conducted in dog, the presumed 
No Observed Adverse Effect Level (NOAEL) of DHE mesylate dose given to dogs (the most 
sensitive species) was approximately 49-fold more than the planned highest clinical dose of 
STS101 on a dose/weight (mg/kg) basis and 5-fold more based on a normalized nasal cavity 
surface area comparison. The results of the dog 14-day study support the presumption that the 
STS101 DHE mesylate formulation yields no new or unexpected significant toxicity at the 
highest feasible concentrations possible. The large safety multiples based on the NOAEL provide 
reassurance that the proposed human clinical dosing is reasonable and safe. The study is 
 
1.4. Summary of Clinical Data for STS101 
In the Phase 1 Study STS101-001 (up to 5.2 mg STS101) no serious adverse events occurred and 
no adverse event led to study or treatment discontinuation. All treatment emergent adverse events 
recorded were graded as mild, clinically not significant and resolved by the end of the study. As 
expected, most of the adverse events were local in the nose and described as mild nasal discomfort 
and taste disturbances usually described as sour or bitter taste. In the Phase 3 Study STS101-002, 
up to 5.2 mg STS101 showed a favorable safety and tolerability profile. No drug related serious 
adverse events or deaths occurred during the study. The most common TEAEs were nasal 
discomfort, dysgeusia, and rhinorrhea. For more details see 
 
Investigator's 
summarized in detail in the STSlOl Investigator's Brochure. 
the STS101 Investigator's Brochure. 


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1.5. Rationale for the study 
In the Phase 3 Study STS101-002, STS101 narrowly missed to achieve statistically significant 
efficacy for the two co-primary endpoints, freedom from pain and most bothersome symptom at 
2 hours after use of study medication (Data on file). The main reasons for this were: 
 A high rate of severe migraine attacks during the treatment period. Severe migraine 
attacks are more difficult to treat and tend to have lower response rates for acute migraine 
treatments (Aurora 2011; Diener 2004). Consistent with the literature severe attacks less 
response to the study medication. 
 The mean delivered dose of study medication was approximately 30% below the label 
claim because of a combination of suboptimal administration by the study subjects, 
thicker walls of the pump of the device making it harder to adequately squeeze and some 
powder loss within the device (Satsuma; Data on file). 
 A high placebo response rate in relation to the reported pain and symptom severity of the 
treated attacks (Aurora 2011; Diener 2004; Dodick 2019; Goadsby 2019; Kuca 2018; 
Lipton 2019; Tepper 2011) 
Satsuma has corrected the device and administration related drug delivery issues, and with these 
corrections and an increase in sample size, this study is expected to achieve statistically 
significant efficacy at 2 hours after use of study medication and to demonstrate the clinical 
benefits of STS101 in the acute treatment of migraine. 
This study follows the FDA Guidance1 and the Guidelines of the International Headache Society 
for acute migraine studies (Diener 2019) and is being conducted as part of the clinical 
development program for STS101 to demonstrate the efficacy, safety and tolerability of STS101 
in the treatment of acute migraine attacks with or without aura. 
 
1 FDA Guidance for Industry. Migraine: Developing Drugs for Acute Treatment. February 2018. 
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2. 
STUDY OBJECTIVES AND PURPOSE 
The objectives of this study are: 
Primary 
 To evaluate the efficacy of a single dose of 5.2 mg STS101 to achieve freedom from pain at 
2 hours after dosing 
 To evaluate the efficacy of a single dose of 5.2 mg STS101 to achieve freedom from most 
bothersome symptom at 2 hours after dosing 
Secondary 
 To evaluate the efficacy of a single dose of 5.2 mg STS101 to achieve pain relief at 2 hours 
after dosing 
 To evaluate the efficacy of a single dose of 5.2 mg STS101 to avoid the use of rescue 
medication within 24 hours after dosing 
 To evaluate the efficacy of a single dose of 5.2 mg STS101 to achieve normal function at 
2 hours after dosing  
 To evaluate the efficacy of a single dose of 5.2 mg STS101 to achieve 2 to 24 hour sustained 
pain free status 
 To evaluate the efficacy of a single dose of 5.2 mg STS101 to achieve 2 to 48 hour sustained 
pain free status 
 To evaluate the efficacy of a single dose of 5.2 mg STS101 to achieve 2 to 24 hour sustained 
freedom from most bothersome symptom status 
 To evaluate the efficacy of a single dose of 5.2 mg STS101 to achieve 2 to 48 hour sustained 
freedom from most bothersome symptom status 
 To evaluate the efficacy of a single dose of 5.2 mg STS101 to avoid the use of rescue 
medication within 48 hours after dosing 
 To evaluate the efficacy of a single dose of 5.2 mg STS101 to avoid headache pain relapse 
within 24 hours after dosing 
 To evaluate the efficacy of a single dose of 5.2 mg STS101 to avoid headache pain relapse 
within 48 hours after dosing 
 To evaluate the efficacy of a single dose of 5.2 mg STS101 to achieve freedom from pain at 
various timepoints after dosing 
 To evaluate the efficacy of a single dose of 5.2 mg STS101 to achieve freedom from most 
bothersome symptom at various timepoints after dosing 
 To evaluate the efficacy of a single dose of 5.2 mg STS101 to achieve pain relief at various 
timepoints after dosing 
 To estimate the probability of a subject to achieve freedom from pain during the 24-hour post 
dose period 
 To estimate the probability of a subject to achieve freedom from the most bothersome 
symptom during the 24-hour post dose period 
 To estimate the probability of a subject to achieve pain relief during the 24-hour post dose 
period 
 To estimate the probability of a subject requiring rescue medication during the 24-hour post 
dose period 
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 To evaluate the efficacy of a single dose of 5.2 mg STS101 to achieve freedom from 
photophobia at 2 hours after dosing 
 To evaluate the efficacy of a single dose of 5.2 mg STS101 to achieve freedom from 
phonophobia at 2 hours after dosing 
 To evaluate the efficacy of a single dose of 5.2 mg STS101 to achieve freedom from nausea 
at 2 hours after dosing 
 To evaluate the efficacy of a single dose of 5.2 mg STS101 to achieve freedom from 
photophobia at various timepoints after dosing 
 To evaluate the efficacy of a single dose of 5.2 mg STS101 to achieve freedom from 
phonophobia at various timepoints after dosing 
 To evaluate the efficacy of a single dose of 5.2 mg STS101 to achieve freedom from nausea 
at various timepoints after dosing 
 
 
 To assess the safety and tolerability of a single dose of 5.2 mg STS101 in the treatment of 
acute migraine attacks 
 
Exploratory 
 To evaluate the efficacy of a single dose of 5.2 mg STS101 to achieve freedom from pain and 
most bothersome symptom by allodynia status at time of dosing 
 To evaluate the efficacy of a single dose of 5.2 mg STS101 to achieve freedom from pain and 
most bothersome symptom at 2 hours after dosing in subjects who wake up with acute 
migraine attacks 
 To evaluate the efficacy of a single dose of 5.2 mg STS101 to achieve freedom from pain and 
most bothersome symptom at 2 hours after dosing in subjects with acute menstrual related 
migraine attacks 
 To evaluate the efficacy of a single dose of 5.2 mg STS101 to achieve pain relief at 2 hours 
after dosing in subjects with acute migraine attacks by allodynia status at time of treatment 
 To evaluate the efficacy of a single dose of 5.2 mg STS101 to achieve pain relief at 2 hours 
after dosing in subjects who wake up with acute migraine attacks 
 To evaluate the efficacy of a single dose of 5.2 mg STS101 to achieve pain relief at 2 hours 
after dosing in subjects with acute menstrual related migraine attacks 
 To evaluate the efficacy of a single dose of 5.2 mg STS101 to achieve both, freedom from 
pain and most bothersome symptom at 2 hours after dosing 
 To evaluate the efficacy of a single dose of 5.2 mg STS101 to achieve both, freedom from 
pain and most bothersome symptom at various timepoints after dosing 
 To evaluate the efficacy of a single dose of 5.2 mg STS101 to achieve freedom from 
headache pain and most bothersome symptom (MBS) at 2 hours after dosing by baseline 
(Visit 2) HIT-6 score 
 To evaluate the effects of a single dose of 5.2 mg STS101 on the 24-hour Migraine Quality 
of Life Questionnaire (24-MQoLQ) 
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3. 
STUDY DESIGN 
3.1. Overall Study Design and Plan 
This is a multi-center, single-dose, randomized, double-blind, placebo-controlled, parallel group 
study in approximately 1400 subjects with acute migraine (ages 18 to 65 years). 
After establishing initial eligibility, the study participants will be trained in the use of the 
electronic diary (e-diary) to record their headache attacks for 15 days during the screening 
period. Attack pain severity, presence of symptoms (nausea; photophobia, phonophobia) and 
impact on functional status will be documented. 
The study subjects will also be trained in the administration of study medication and use of the 
STS101 device, and undergo Placebo Response Reduction training, designed to improve 
discrimination between placebo and drug effects in clinical trials. 
After establishing full eligibility, the study participants will be trained in the use of the STS101 
device and randomized (1:1) to receive: 
 5.2 mg STS101 (equivalent to 6.0 mg of DHE mesylate USP), or 
 Placebo (matching nasal powder) 
The randomization will be stratified by the use of migraine prevention medication. After the 
randomization, the study participants will treat a qualifying migraine attack of at least moderate 
pain severity with the allocated blinded study medication within 4 hours of the onset of the 
attack. 
The study participants will document the following symptoms of their treated migraine before 
and over 48 hours after study drug administration in an e-diary: migraine headache pain severity, 
presence of symptoms (photophobia, phonophobia, nausea), presence of allodynia and 
functionality status. Headache pain severity and symptom data will be documented immediately 
before drug administration (time 0), at 15, 30, 45 minutes and 1, 1.5, 2, 3, 4, 6, 12, 24, and 48 
hours after study drug administration. The subjects must select a most bothersome symptom 
among photophobia, phonophobia, and nausea immediately before study drug administration. 
If subjects require rescue medication, they will be encouraged to wait until the 2-hour post study 
drug administration data collection timepoint. The use of triptans, other ergot-containing products 
(including DHE mesylate and ergotamine), lasmiditan, ubrogepant and rimegepant as rescue 
medications should be avoided for 24 hours after study drug administration. The study participants 
will return to the study site within approximately one week of the treated migraine attack. 
Adverse events, objective nasal evaluation data, safety laboratory data, vital sign data and ECGs 
will be recorded before and after treatment to evaluate the tolerability and safety of STS101. 
Sufficient numbers of subjects will be screened to randomize approximately 1400 subjects in the 
study. The dropout rate is estimated to be less than 35%. Subjects who withdraw or are withdrawn 
from the study after dosing will not be replaced. However, in the event that the number of drop-
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outs or number of subjects with missing data exceeds initial expectations, subjects who withdraw 
or are withdrawn might be replaced. 
Figure 3 displays the study schematic design: 
Figure 3. Study Schematic 
 
3.2. Study Procedures Descriptions 
The following list is a description of the procedures to be completed at screening and during the 
study: 
3.2.1. 
Informed Consent 
An Ethics Committee (EC)/Investigational Review Board (IRB)-approved informed consent 
form (ICF) must be signed and dated by each study subject prior to any study procedures being 
performed and a copy must be given to the subject. 
3.2.2. 
Assignment of Subject Identification Number 
Each subject will be assigned an individual subject identification number. The first three digits 
will identify the study site (ranging from 001 to 999) and last three digits will identify the subject 
as a running number starting with 001. As an example, the first subject entering screening at site 
001 would receive the subject identification number 001-001, the second subject 001-002 etc. 
3.2.3. 
Inclusion and Exclusion Criteria Assessment 
All subjects must qualify for the study based on the inclusion and exclusion criteria specified in 
Section 4.1 and Section 4.2, respectively. 
3.2.4. 
Medical History, Demographics, Concomitant and Prior Medications 
A complete medical history will be obtained including a review of all major organ systems, and 
a history of alcohol, tobacco and caffeine use. Demographics will include gender, date of birth 
 
 
 
 
30 Day Screening 
Period 
STS101 
5.2mg 
Placebo 


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race, ethnicity, relationship status, employment status and education level. Prior medications will 
include all medications taken for 28 days prior to Screening. The medical history, demographics 
and a list of concomitant and prior medications, concomitant procedures and non-drug therapies 
will be documented at the screening visit (Visit 1). 
In female subjects who menstruate the following additional information will be documented for 
the three months prior to the Screening Visit: 
 Timing and duration of menstruation in each month 
 Occurrence of migraine headaches on day 1 (± 2 days) of menstruation in each month 
Previous or current triptan use will be documented. Subjects who have previously 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 
Medical Records and source documentation to support important diagnoses, e.g., migraine 
history and inclusion/exclusion criteria must be provided or obtained whenever possible. 
3.2.5. 
Headache Impact Test (HIT-6TM) 
At the Randomization Visit (Visit 2), subjects will complete the 6-question Headache Impact 
Test (Appendix F), a tool for assessing the impact of headache on daily life in subjects with 
migraine (Yang 2010). 
3.2.6. 
Physical Examination 
A physical examination will be performed at Screening (Visit 1), Randomization (Visit 2) and at 
the Follow-up/early termination visit. The examination will include all major body systems with 
the exception of genitourinary. Site Personnel performing the physical exams must be qualified 
by training and licensure. 
3.2.7. 
Vital Signs 
Vital signs will be obtained at Screening (Visit 1), Randomization (Visit 2), and at the Follow-
up/early termination visit. Vital signs will include temperature, sitting blood pressure (to be 
taken after 5 minutes of sitting), and pulse rate. 
3.2.8. 
 Weight, Height and Body Mass Index (BMI) 
Subjects will be weighed in street clothes after removing shoes, coat or jacket. Weight will be 
measured at Screening, Randomization, and at the follow-up/early termination visit. Subject 
height will only be measured at screening, without shoes. Subjects will have their BMI calculated 
at the Screening visit (Visit 1) using the following formula: BMI = weight (kg)/height (m2). 
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3.2.9. 
Evaluations of Effects in the Nose 
3.2.9.1. Objective Assessment of Nasal Symptoms 
This is a 5-item assessment to be completed by a qualified physician, Nurse Practitioner, or 
physician assistant
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 during Screening (Visit 1), 
Randomization (Visit 2), and at the Follow-up/early termination Visit (Visit 3). Assessment 
sheets must be retained for all subjects. The person performing the assessments should be the 
same at all visits whenever possible. 
3.2.10. Clinical Laboratory Tests 
A designated central laboratory will perform the hematology, biochemistry, urinalysis and 
diagnostic tests as specified in Table 3. 
Samples for clinical laboratory tests will be taken at Screening (Visit 1) and at the Follow-
up/early termination visit (Visit 3). All samples will be collected in accordance with the Study 
Laboratory Manual and shipped to the designed central laboratory. 
Laboratory reports will be reviewed by the investigator and out of range values will be identified 
and may be repeated at the Investigator's discretion. The Investigator will determine if any out of 
range values are clinically-significant and require recording as adverse events (AEs) in the 
electronic Case Report Form (eCRF). All clinically-significant out of range laboratory values 
obtained at the Randomization Visit or Follow-up visit will be followed until they return to 
normal or become medically stable. 
Laboratory tests with exclusionary results at Visit 1, may be repeated with prior approval by the 
Medical Monitor. The repeat test should be done at an unscheduled visit (UV) before the subject 
returns for the randomization visit (Visit 2). 
. Using categorical scales ranging from "none" to "severe", the physician will 


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Table 3. Laboratory Tests 
Hematology 
Serum Chemistry 
Urinalysis 
Hematocrit
Hemoglobin 
MCV 
Red Blood Cell Count 
Platelet Count 
White Blood Cell Count (with Differential) 
Albumin
Alkaline Phosphatase 
Alanine Transaminase (ALT) 
Aspartate Transaminase (AST) 
Blood Urea Nitrogen (BUN) 
Calcium 
Chloride 
Cholesterol profile 
Creatine phosphokinase 
Creatinine 
Gamma Glutamyl Transferase 
Glucose  
Lactate Dehydrogenase 
Potassium 
Sodium 
Direct and Total Bilirubin 
Total Protein 
Thyroid function tests (TSH, 
total T3 & T4) 
FSH 
Serum pregnancy test 
Appearance
Color 
pH 
Specific Gravity 
Protein  
Glucose  
Ketones 
Occult Blood 
Nitrites 
Urobilinogen 
Leukocytes 
Bilirubin 
Urine microscopy, if necessary 
Diagnostic Screening 
Urine 
Alcohol & Drug Panel, including Amphetamines, Cannabinoids, Cocaine, Opiates, PCP and Methadone  
 
Urine Pregnancy test 
To be performed at Visit 2 on all females regardless of childbearing potential 
Test kits will be provided by central laboratory.
 
3.2.10.1. 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 
- 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. 
3.2.11. Electrocardiogram 
A 12-lead ECG will be performed at Screening (Visit 1) and at the Follow-up/early termination 
Visit (Visit 3). The investigator or a qualified delegate will review the ECG to assure subject 
eligibility. All ECGs will be done in triplicate approximately one minute apart. 
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. 
(CK), CK-myocardial band (CK 


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3.2.12. Adverse Events Recording 
Adverse events will be recorded and assessed as specified in Section 7. 
3.2.13. Electronic Headache Diary 
Study participants will receive a handheld device for collection of data in an electronic diary. At 
the Screening and Randomization Visits, study participants will receive training in the use of the 
device and completion of the diaries. During the screening period the study participants will 
document their headaches for 15 days. Headaches and migraine attacks (including information 
on pain severity and symptoms) will be documented. 
During the treatment period, the study participants will document sign and symptoms identifying 
a migraine headache, the pain severity of their treated migraine attack, presence and severity of 
symptoms (photophobia, phonophobia, nausea, allodynia) and functional status over the 48-hour 
period after study drug administration in the e-diary. 
The complete content and the training procedures for the electronic diary device will be 
described in separate documents. 
3.2.14. Placebo Response Reduction Training 
At Visit 1 and Visit 2, study participants will undergo a Placebo Response Reduction (PRR) 
Training that consists of a set of subject and staff educational materials for training on 
appropriate expectations of personal benefit while participating in a clinical trial and to 
neutralize excessive expectations that drive high placebo responses in clinical trials. 
The complete content and the PRR training procedures 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 G) 
at Visits 1, 2 and 3.  
3.3. Schedule of Observations and Procedures 
Appendix A shows the procedures for the study. The following assessments should be completed 
at the designated time period(s). 
3.3.1. 
Screening Procedures 
Initial screening will be performed at Study Entry, and it will determine whether subjects will 
qualify for the study. 


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3.3.2. 
Screening Visit & Period (Day-30 to Day -1) 
Subject screening procedures and study entry procedures include: 
a. Signing of informed consent 
b. Review of inclusion/exclusion criteria 
c. Recording of demographic data 
d. Medical history, including migraine history, concomitant medications, procedures and 
non-drug therapies 
e. Physical examination 
f. Vital signs (including pulse rate, sitting blood pressure and temperature) 
g. Body weight, height and BMI calculation 
h. Objective Assessment of Nasal Symptoms 
i. Completion of Sheehan Suicidality Tracking Scale 
j. STS101 device training  
k. Electronic device & diary use training 
l. Placebo response reduction training 
m. Clinical laboratory tests 
n. Urinalysis 
o. Serum pregnancy test (all female subjects) 
p. Urine drug and alcohol screen 
q. 12-lead ECG (in triplicate) 
r. Adverse event recording 
s. Completion of Headache Diary by subject (for 15 days within screening period) 
3.3.3. 
Randomization Visit (Visit 2; Day1) 
a. Review of Headache diary data 
b. Vital signs (including pulse rate, sitting blood pressure and temperature) 
c. Physical examination 
d. Weight 
e. Review of concomitant medications, procedures and non-drug therapies 
f. Serum pregnancy test (all female subjects) 
g. Urine pregnancy test (all female subjects) 
h. Objective Assessment of Nasal Symptoms 
i. Completion of Sheehan Suicidality Tracking Scale 
j. Completion of HIT-6 instrument 


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k. Review of eligibility criteria 
Any subject that no longer qualifies for study participation based on findings in any of the 
procedures will be withdrawn from the study as a screen failure and the reasons recorded on the 
screen failure log. 
If the subject still meets all eligibility criteria for study participation, the following procedures 
will be done: 
a. Randomization 
b. STS101 device and administration training 
c. Dispense Investigational Product 
d. Electronic device and diary use training 
e. Placebo response reduction training 
The subject has 56 days to treat a qualifying migraine attack in the Treatment Period. 
3.3.4. 
Final Visit/Early Termination (Visit 3) 
Subjects will undergo final safety assessment procedures within approximately one week (7 days 
± 3 days) after use of study medication. If a subject has not treated a qualifying migraine within 
56 days of randomization, the subject should return to the site and all final visit procedures 
should be performed. 
The follow-up visit/early termination procedures will comprise the following: 
a. Physical examination 
b. Vital signs (including pulse rate, sitting blood pressure and temperature) 
c. Review of concomitant medications, procedures and non-drug therapies 
d. Serum pregnancy test (all female subjects) 
e. Clinical laboratory tests  
f. Urinalysis 
g. 12-lead ECG (in triplicate) 
h. Completion of Sheehan Suicidality Tracking Scale 
i. Objective Assessment of Nasal Symptoms 
j. Patient Subjective Impression Questions (see Section 6.2) 
k. Adverse event recording 
l. Collect used Investigational Product (STS101 device) 
m. Collect electronic diary device 


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4. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
A total of approximately 1400 adult male and female subjects aged 18 to 65 years with acute 
migraine headaches will be randomized. 
4.1. Subject Inclusion Criteria 
A subject will be eligible for inclusion in this study only if all of the following criteria applied: 
1. English speaking males or females, 18-65 years of age at the time of Screening Visit 
2. Signed Informed Consent Form 
3. Subject has at least 1-year history of migraines (with or without aura), according to the 
International Classification of Headache Disorder, 3rd Edition (ICHD3), including the following: 
a. Migraine onset before the age of 50 years 
b. Migraine attacks, on average, lasting 4-72 hours if untreated 
c. Migraine headache frequency of 2 to 8 attacks of moderate or severe pain intensity per 
month in each of the 3 months prior to the Screening Visit 
d. Fewer than 15 days with headache (migraine or non-migraine) per month in each of the 
3 months prior to the Screening Visit 
e. Individual migraine attacks separated by at least 2 days of no headache pain 
f. Subject is able to distinguish migraines from other headache types, e.g., tension-type or 
cluster headache. 
4. Subjects on preventive migraine medication are permitted to remain on therapy provided they 
have been on a stable dose for at least 3 months prior to study entry and have no plans to 
change the dose during the study 
5. Female subjects will be included if they are post-menopausal (at least 1 year since last 
menses) or surgically sterilized; or if they are of childbearing potential, they are not 
breastfeeding, have a negative pregnancy test, have no intention of becoming pregnant during 
the course of the study, and are using adequate contraceptive drugs or devices during the 
course of this study. Medically acceptable methods of contraception that may be used by the 
subject and/or her partner are: 
a. Simultaneous use of male condom and intra-uterine contraceptive device placed at least 
4 weeks prior to screening (Visit 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) 


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6. 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), and no 
other nasal conditions that may interfere with intranasal dosing at randomization (Visit 2) 
7. Willing and able to comply with the requirements of the protocol and follow directions from 
the clinic staff 
8. Adequate compliance ( 80%) in the completion of the e-diary during the Screening Period 
4.2. Subject Exclusion Criteria 
1. Pregnant or breast-feeding women 
2. Women of child-bearing potential not using or not willing to use highly effective contraception 
3. Diagnosis of headache conditions other than migraine with or without aura, including 
diagnosis of basilar or hemiplegic migraines, medication overuse headache or cluster 
headache 
4. Abnormal physical findings of clinical significance which would interfere with the objectives 
of the study at the screening or randomization visit examination 
5. History of coronary artery disease, coronary artery vasospasm (including Printz-
angina), clinically significant arrhythmia or, peripheral vascular disease, ischemic disease 
(e.g., 
 
or documented silent ischemia); percutaneous coronary intervention, or cardiac surgery 
6. History of cerebrovascular disease, including but not limited to stroke, transient ischemic 
attack, cerebral hemorrhage, subarachnoid hemorrhage 
7. Presence of two or more of the following cardiovascular risk factors: 
a. Previous diagnosis of hypertension or currently taking antihypertensive medication 
b. Previous diagnosis of hypercholesteremia, or currently taking cholesterol lowering 
treatment or LDL >159 mg/dL at screening (Visit 1; note: re-draws prior to Visit 2 may 
be permitted) 
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 46 or older 
8. Clinically significant abnormal laboratory values (as determined by the Principal 
Investigator) at screening (Visit 1; note: re-draws prior to Visit 2 may be permitted) 
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; note: re-draws prior to Visit 2 may be permitted) 
> 
metals' 
Raynaud's syndrome, ischemic bowel syndrome, angina pectoris, myocardial infarction, 


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10. Screening 12-lead ECG showing any clinically significant abnormalities at screening (Visit 1) 
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) 
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 or within less 
than 5 half-lives of tested drug (whichever is longer) 
15. Concomitant use of potent CYP3A4 inhibiting medications, for example protease inhibitors 
(e.g., ritonavir, nelfinavir, indinavir, saquinavir, tipranavir, lopinavir, atazanavir, darunavir), 
macrolide antibiotics (e.g., erythromycin, clarithromycin, troleandomycin), or strong 
imidazole antifungals (e.g., ketoconazole, and itraconazole) 
16. Previously shown hypersensitivity to ergot alkaloids or the inactive ingredients of STS101 
(microcrystalline cellulose, hydroxypropyl methylcellulose, mannitol) 
17. Concomitant use of more than one preventive migraine medication 
18. Current use of opioids, or cannabis or cannabinoid containing products 
19. Concomitant use of peripheral and central vasoconstrictors including but not limited to 
amphetamines, phenylephrine, pseudoephedrine, propranolol and nicotine (from smoking, 
vaping or smokeless products) 
20. 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 ju
 
in the study due to compliance, medical or other reasons. All data normally collected at 
completion of the study (Visit 3) must be collected as soon as possible once a subject is withdrawn. 
The primary reason for discontinuation of treatment should be noted in the CRF and source data 
using the following categories: 
a. Adverse Event: The subject has experienced an AE that, in the opinion of the Investigator, 
requires early termination. If a subject is discontinued from the study due to an AE, the 
Investigator is required to follow the subject until the AE is resolved, or declared 
medically stable or the subject is lost to follow up. 
dgrnent to terminate a subject's participation 


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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: 
continued participation in the 
study would not be in the best interest of the subject or the study. 
f. Study Termination: The Sponsor, or IRB terminates the study. 
g. Lost to follow up. Every effort should be expended to contact the subject and have them 
return for follow up assessments and return of Investigational Product (used or unused) 
and the electronic diary device. 
h. Other: If subject is discontinued from the study for any reason not applicable to the 
reasons stated above, this category should be used. The specific reason should then 
be 
 
In the Investigator's judgment, 
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 
HPMC. STS101 Placebo consists of the same inactive ingredients but without DHE mesylate. 
DHE mesylate is a white or almost white to faintly red powder or colourless crystals. DHE 
mesylate is known chemically as ergotaman-3´,6´,18-trione,9,10-dihydro-12´-hydroxy-2´-
methyl-5´-(phenylmethyl)-
-,monomethanesulfonate. Its molecular weight is 679.80 and its 
empirical formula is C34H41N5O8S. 
 
The investigational product will be made available as: 
 5.2 mg STS101 dose strength (equivalent to 6.0 mg DHE mesylate USP) as unit dose in a 
labeled foil wrap. 
 Matching placebo as unit dose in a labeled foil wrap. 
The non-investigational product will be made available for training during the Screening and 
Randomization Visits: 
 STS101 Empty Training Devices (empty STS101 Device). 
 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 DHE, or placebo) 
 Protocol number 
 Lot number 
 Kit Number 
 Name and address of study sponsor 
 Recommended storage conditions 
 Investigational use only 
 Directions: Use as directed following the Instructions for Use  
 Warning: For nasal use only 
 Blank spaces for: Date dispensed & Subject Number (to be completed by site personnel 
at time of dispensing) 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
• 
,(5'a) 
Further information can be found in the Investigator's Brochure . 


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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 (2o  30o C or 36o  86oF). 
The study site pharmacist or designee will maintain an inventory and acknowledge receipt of all 
shipments of the Investigational Product. Accurate storage and dispensation records must be kept 
for drug accountability. Supplies of the investigational products will be checked and accountability 
records will be reviewed at each monitoring visit. A copy of all completed drug accountability 
forms will be collected by the monitor. 
5.4. Investigational Product Administration & Training 
STS101 will be self-administered by the subjects using the delivery device according to the 
Instructions for Use. 
At Screening (Visit 1) and Randomization (Visit 2), study personnel will train the subject in the 
study drug preparation and administration. Instructions for Use (Appendix D), an instructional 
video, STS101 Empty Training Devices and STS101 Filled Training Devices will be used for 
training of the study subject at both visits. 
When using the study medication at home, the study subject will record the following 
information in the electronic diary: 
 Time of dosing (defined as time of last intranasal delivery device actuation). 
 The nostril (right or left) into which study drug was administered. 
 Whether or not there was any sneezing and/or nose blowing, within 30 minutes after dosing. 
Subjects will be instructed to: 
 
 
 Place 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. 
• 
• 
• 
• 
Place clear Cap, Nozzle's Tab and Nasal Device into the plastic bag provided . 
• 
• 


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All Investigational Products designated for this clinical study must not be administered to any 
subjects other than those enrolled in this study and may not be utilized for any laboratory or 
animal research. 
5.6. Investigational Product Handling and Disposal 
Site study staff will retain used and unused Investigational Product at the study site. All used and 
unused Investigational Product 
All used and 
unused STS101 devices will be returned to the Sponsor or a designee 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 & Migraine Treatments 
Use of any concomitant medications will be documented and reported. 
Triptans, ergot alkaloids, Lasmiditan, ubrogepant and rimegepant are not allowed within 
48 hours before and for 24 hours after study drug administration.  
No other medication intended for treatment of the acute migraine attack should be taken 
within 24 hours before and for 2 hours after study drug administration. 
The concomitant use of more than one prevention medication for migraine is not allowed.  
The use of external neuromodulation devices for treatment of acute migraine (e.g., 
transcutaneous electrical nerve stimulation, transcranial magnetic stimulation) is not allowed for 
48 hours before and 24 hours after study drug administration. 
If a subject does not experience relief from migraine headache at 2 hours after study medication 
administration (and after the 2-hour assessments have been completed in the eDiary), the use of 
the following rescue medication is allowed: aspirin, acetaminophen, NSAIDs, neuroleptics, 
corticosteroids, antiemetics, muscle relaxants, sedatives, sleep medications, gabapentin. 
The concomitant use of potent CYP3A4 inhibiting medications, for example protease inhibitors 
(e.g., ritonavir, nelfinavir, indinavir, saquinavir, tipranavir, lopinavir, atazanavir, darunavir), 
macrolide antibiotics (e.g., erythromycin, clarithromycin, troleandomycin), or strong imidazole 
antifungals (e.g., ketoconazole, and itraconazole) is not allowed. 
The chronic daily concomitant use of a peripheral and central vasoconstrictive medication (e.g., 
amphetamine, methamphetamine, epinephrine) is not allowed. Subjects may use vasoconstrictive 
medication on a PRN basis, but the use of vasoconstrictive medication is not allowed within 48 
hours before and for 24 hours after study drug administration.  
The concomitant use of opioids, or cannabis or cannabinoid containing products is not allowed. 
will be reconciled by the Sponsor's designee. 


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The use of nasal preparations containing decongestants is not allowed within 12 hours before 
study drug administration. 
Further details of allowed and disallowed concomitant medications will be provided in a separate 
document. 
5.8. Treatment Compliance 
All used or unused Investigational Product will be returned to the site at Visit 3 at which time the 
dispensed Investigational Product will be reconciled in the drug accountability log. 
5.9. Randomization and Blinding 
5.9.1. 
Subject Randomization 
After evaluation of the subject eligibility and confirmation that subject meets the Inclusion and 
Exclusion criteria at the Randomization Visit, a study subject will be randomized in the IWRS 
system according to the pre-programmed randomization schedule. The randomization will be 
stratified for the use of migraine prevention medication. The randomization process will be 
described in a separate document. 
5.9.2. 
Blinding 
The study is a double-blind study of STS101 and matching placebo. No personnel directly 
involved with the conduct of the study will have knowledge of a subje
This includes all personnel at the study site, at the sponsor and any CRO involved in the conduct 
and monitoring of the study. A randomization code will be generated by a statistician independent 
of the study and not be available to the analysis team until the clinical and data collection, entry, 
and cleaning processes are complete and database is locked for unblinded analysis. 
5.9.3. 
Unblinding Procedures 
Unblinding procedures will be described in a separate document. 
ct' s treatment assignment. 


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


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


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6.2. Patient Subjective Impression Questions (Office; Visit 3) 
6.2.1. 
Patient Global Impression 
The study subjects will be asked to rate the global impression of the study treatment at Visit 3 
 
-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 3 with 
How easy was the administration of the study medication?  
-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 3 
months 
How likely is it that you would use the study medication to treat 
 
-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 at Visit 3 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. 
with this question: "What is your global impression of the study treatment?" 
The subject's rating will be documented on a five 
this question: " 
" 
The subject's rating will be documented on a five 
with this question: " 
your migraine if it were available?" 
The subject's rating will be documented on a five 


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


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7.1.2. 
Laboratory Assessments 
Central laboratory tests results will be reviewed for any clinically significant abnormalities by a 
qualified physician or physician assistant. If any clinically significant findings are present at 
screening, the subject will be considered a screen failure and ineligible for study participation. 
7.1.2.1. 
Hematology 
Complete blood count (CBC) with differential including: white blood cell count with differential, 
red blood cell count, hemoglobin, hematocrit, MCV, and platelet count. 
7.1.2.2. 
Serum Chemistry 
Serum chemistry including: albumin, alkaline phosphatase, alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), bilirubin (direct and total), blood urea nitrogen (BUN), calcium, 
chloride, cholesterol profile, creatine phosphokinase, creatinine, gamma glutamyl transferase, 
glucose, lactate dehydrogenase, potassium, sodium, thyroid function tests (TSH, total T3 & T4), 
and total protein. 
7.1.2.3. 
Urinalysis 
Urinalysis examination including: Appearance, color, pH, specific gravity, protein, glucose, 
ketones, occult blood, nitrites, urobilinogen, leukocytes, bilirubin and if necessary, urine microscopy. 
7.1.2.4. 
Urine Drug Screen 
Alcohol & Drug Panel: Amphetamines, Barbiturates Benzodiazepines, Cannabinoids, Cocaine, 
Opiates, PCP and Methadone. 
7.1.2.5. 
Serum & Urine Pregnancy Test 
A serum HCG pregnancy test will be performed at screening, randomization and the follow-
up/early termination visits in all female subjects regardless of child bearing potential. A urine 
pregnancy test will be performed on all female subjects, regardless of child bearing potential at 
randomization (Visit 2). 
7.1.2.6. 
Serum FSH test 
A serum FSH test will be performed for any woman who is either surgically menopausal 
(absence of both ovaries) or physiologically menopausal.  
7.1.2.7. 
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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- 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. 
7.1.2.8. 
Sheehan Suicidality Tracking Scale 
The S-STS is a 16-item scale that assesses the seriousness of suicidality risk using a 5-point 
Likert sc
-STS wil be 
completed by all subjects at Visits 1, 2 and 3. 
7.2. Adverse Events 
investigation subject administered a pharmaceutical product that does not necessarily have to 
 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 
at the 
Screening Visit (Visit 1) and continue until the follow-up/early termination visit. AEs 
related to the administration of inactive powder during the administration training at Visit 1 and 
Visit 2 will also be recorded. 
AEs will be solicited at the times indicated in the schedule of assessments by asking a question 
 last seen
 
AEs may also be reported spontaneously. 
Each AE should be recorded to represent a single diagnosis. Accompanying signs (including 
abnormal laboratory values) or symptoms related to a single diagnosis 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. 
(CK), CK-myocardial band (CK 
ale from "not at all" (0) to "extremely" (4) (Sheehan, 2014). The S 
An adverse event (AE) is defined as: "Any untoward medical occurrence in a subject or clinical 
have a causal relationship with this treatment." 
following the subject's signing the informed consent 
such as: "Since you were 
, have you felt unwell or different from usual in any way?" 


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All AEs must be recorded in the source data and the CRF. Any ongoing AE will be followed, 
whenever possible, until it resolves, or returns to the baseline condition, or is declared medically 
stable with no further change expected or the subject is lost to follow up. 
7.2.1. 
AE Relationship to Study Drug 
investigational product 
based on the criteria listed in Table 4. Assessment of the causal relationship between any Serious 
Adverse Event (SAE) and study drug administration will be performed by both the Investigator 
and the Sponsor. If at least one of the parties assesses the event as related, it will be reported 
expeditiously as required to the appropriate authorities. 
Table 4. Adverse Event Relationship to Study Drug 
Related: 
that the event may have been caused by the product under 
investigation (i.e., there are facts, evidence, or arguments to suggest possible causality). 
criteria are not met. 
Not 
Related: 
There is an unlikely 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., injury 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 5 shows the guidelines for rating severity of AEs may be used: 
Table 5. Assessment of Adverse Event Severity 
Mild: 
Awareness of signs or symptoms, but easily tolerated; are of minor irritant type; no loss of time from 
normal activities; symptoms would not require medication or a medical evaluation; signs and 
symptoms may be transient, disappearing during continued treatment with study medication.
Moderate:
Discomfort enough to cause interference with or modification of usual activities.
Severe: 
Incapacitating, with inability or notable impairment in work or usual activities; signs and symptoms 
may be of systemic nature or require medical evaluation; the study drug may be stopped, and 
treatment for the event may be required.
7.2.3. 
Serious Adverse Events (SAEs) Recording and Reporting 
The Investigator must decide whether each AE meets the definition of an SAE. An SAE is any 
untoward medical occurrence that at any dose: 
An AE will be considered 'related" or "not related" to the use of the 
There is "a reasonable possibility" 
Individual AE reports will be considered "related" to the use of the product if the ''not related" 


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1. Results in death. 
2. Is life-threatening. 
3. Requires inpatient hospitalization or prolongation of existing hospitalization. 
4. Results in persistent or significant disability/incapacity. 
5. Is a congenital anomaly/birth defect. 
6. Is considered medically significant by the Investigator or requires intervention to prevent 
any one of the outcomes above. 
For fatal events, the cause of death is reported whenever known. If an autopsy was performed, an 
autopsy report should be provided. Death should be reported as the outcome of a specific SAE. 
Life-threatening, in the definition of serious, refers to an event in which the subject was at risk of 
death at the time of the event; it does not refer to an event which hypothetically might have 
caused death if it were more severe. 
Reports for hospitalization of elective procedures do not need to be reported as SAEs if there are 
no precipitating signs/symptoms or worsening of the pre-existing condition that necessitated the 
procedure. However, SAEs must be reported for any medical complications that prolonged the 
hospitalization. 
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. 
Medically significant events are those events considered important in the Investigator's opinion 


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It is the responsibility of the Investigator to report to the relevant IRB/EC in accordance with the 
 
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 
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 the treatment 
period must immediately be withdrawn from the study (classified as ET). Subjects who become 
pregnant within 30 days following treatment must be reported to the sponsor. 
IRB/EC's reporting specific reporting requirements for SAEs. 
monitor. Pregnancies will be considered 'events of special interest' and will not be captured as 


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8. 
STATISTICS 
8.1. Sample Size Determination 
A total of approximately 1400 subjects (approximately 700 in each treatment group) will be 
randomized. 
For the co-primary endpoint of pain freedom at 2 hours post dosing of investigational drug, a 
therapeutic gain of 10%, assuming a 25% responder rate for STS101 and 15% for the placebo is 
targeted. Based on these assumptions, 700 subjects per arm can provide 99% power to detect the 
target treatment difference. For the co-primary endpoint of MBS freedom at 2 hours post 
investigational drug, a therapeutic gain of 10%, assuming a 45% responder rate for STS101 and 
35% for the placebo is targeted. Based on these assumptions, 700 subjects per treatment group 
can provide 95% power to detect the target treatment difference. The sample size calculation is 
based on a chi-square test with a significance level of 0.05 and a 2-sided test. 
The primary efficacy objective will be addressed by simultaneously testing the 2 co-primary 
endpoints of pain freedom and MBS freedom at 2 hours after drug administration at a 
significance level of 0.05. This sample size will provide an overall power of at least 94%. 
8.2. Subject Populations 
The analysis populations to be used in the study are defined below. 
8.2.1 Intent-to-Treat Population 
The intent-to-treat (ITT) population will include all randomized subjects who reported a qualifying 
migraine attack, received the study drug, and reported any post-treatment efficacy evaluation. 
Data will be analyzed according to the treatment group each subject is randomized to. 
8.2.2 Modified Intent-to-Treat Population 
For the purposes of efficacy data analysis, the modified intent-to-treat (mITT) population will be 
the primary analysis population. This population will include all randomized subjects who 
reported a qualifying migraine attack, received the study drug, and reported a post-treatment 
efficacy evaluation for at least 1 time point at or before the 2-hour time point. Data will be 
analyzed according to the treatment group each subject is randomized to. 
8.2.3 Per-Protocol Population 
The per protocol (PP) population will consist of all mITT subjects who do not have protocol 
deviations that could significantly affect the interpretation of the results for the primary 
 inclusion/exclusion from the PP population will be determined and 
documented prior to the database lock and unblinding. 
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8.2.1. 
Safety Population 
The safety population will include all subjects who are randomized and have received the study 
drug. Data will be analyzed according to the treatment each subject actually received. 
8.3. Statistical Analysis 
All study data will be summarized by treatment using descriptive statistics. Unless otherwise 
specified, for numeric data (e.g., age, weight), descriptive statistics will include the number of 
subjects with data to be summarized (n), mean, standard deviation (SD), median, minimum (min) 
and maximum (max). All categorical/qualitative data (e.g., gender, race) will be presented using 
absolute and relative frequency counts and percentage. 
All summaries, statistical analyses, and individual subject data listings described below will be 
completed using Version 9.3 or later of the SAS software (SAS Institute, Inc. Cary, NC). 
A detailed Statistical Analysis Plan (SAP) will be provided in a separate document. The SAP 
will include the final hierarchy for testing of the primary and secondary efficacy endpoints and 
will be finalized prior to database lock and unblinding of the study. 
8.3.1. 
Demographic and Baseline Variables 
Demographics and baseline characteristics (including migraine history, HIT-6 data and triptan 
response information) will be summarized descriptively by treatment group for the mITT 
Population, the ITT Population, the Per-Protocol Population, and the Safety Population. 
Exploratory hypotheses testing may be performed to assess the comparability of demographics 
and baseline characteristics among the treatment groups. No multiplicity adjustment will be 
applied to these tests. 
8.3.2. 
Efficacy Analysis 
8.3.2.1. 
Primary Efficacy Endpoints 
 Proportion of subjects free from headache pain at 2 hours after dosing (defined as moderate 
or severe headache pain [2 or 3 on a 4-point scale] at baseline [time 0] becoming none [0] 
on a 4-point scale) 
 Proportion of subjects free from most bothersome symptom (MBS) among photophobia, 
phonophobia and nausea at 2 hours after dosing (defined as the MBS identified at baseline 
[time 0] being absent) 
8.3.2.2. 
Secondary Efficacy Endpoints 
 Proportion of subjects with relief from headache pain at 2 hours after dosing (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]) 
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 Proportion of subjects who use rescue medication within 24 hours after dosing 
 Proportion of subjects who achieve normal function at 2 hours after dosing (defined as score 
of 0 on the 4-point functional impairment scale) 
 Proportion of subjects free from headache pain at 2 hours after dosing and remaining 
headache free at 24 hours after dosing with no use of rescue medication and no relapse of any 
headache pain (defined as score of 0 on a 4-point scale from 2-24 hours) 
 Proportion of subjects free from headache pain at 2 hours after dosing and remaining 
headache free at 48 hours after dosing with no use of rescue medication and no relapse of any 
headache pain (defined as score of 0 on a 4-point scale from 2-48 hours) 
 Proportion of subjects free from most bothersome symptom (MBS) at 2 hours after dosing 
and remaining MBS free at 24 hours after dosing with no use of rescue medication and no 
relapse of any MBS (defined as MBS selected at baseline [time 0] absent from 2-24 hours) 
 Proportion of subjects free from most bothersome symptom (MBS) at 2 hours after dosing 
and remaining MBS free at 48 hours after dosing with no use of rescue medication and no 
relapse of any MBS (defined as MBS selected at baseline [time 0] absent from 2-48 hours) 
 Proportion of subjects who use rescue medication within 48 hours after dosing 
 Proportion of subjects with headache relapse within 24 hours after dosing (defined as the 
return of headache of any severity within 24 hours post dosing of the investigational drug, 
when the subject was pain-free at 2 hours after dosing) 
 Proportion of subjects with headache relapse within 48 hours after dosing (defined as the 
return of headache of any severity within 48 hours post dosing of the investigational drug, 
when the subject was pain-free at 2 hours after dosing) 
 Proportion of subjects free from headache pain at various time points after dosing 
 Proportion of subjects free from most bothersome symptom at various time points after dosing 
 Proportion of subjects achieving pain relief at various time points after dosing 
 Proportion of subjects who achieve normal function at various timepoints after dosing 
 Proportion of subjects free from photophobia at 2 hours after dosing (defined as photophobia 
being absent at 2 hours after dosing if present at baseline [time 0]) 
 Proportion of subjects free from phonophobia at 2 hours after dosing (defined as 
phonophobia being absent at 2 hours after dosing if present at baseline [time 0]) 
 Proportion of subjects free from nausea at 2 hours after dosing (defined as nausea being 
absent at 2 hours after dosing if present at baseline [time 0]) 
 Proportion of subjects free from photophobia at various timepoints after dosing 
 Proportion of subjects free from phonophobia at various timepoints after dosing 
 Proportion of subjects free from nausea at various timepoints after dosing 
 Patient Global Impression ratings 
8.3.2.3. 
Exploratory Endpoints 
 Proportion of subjects free from headache pain at 2 hours after dosing by allodynia status at 
6-question allodynia questionnaire [Ashkenazi 2007; Tepper 2011]) 
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 Proportion of subjects free from headache pain and free from most bothersome symptom 
(MBS) at 2 hours after dosing in subjects who wake up with migraine headache 
 Proportion of subjects free from headache pain and free from most bothersome symptom 
(MBS) at 2 hours after dosing in subjects with menstrual related migraine attack 
 Proportion of subjects with relief from headache pain at various timepoints after dosing by 
-question allodynia questionnaire [Ashkenazi 2007; Tepper 2011]) 
 Proportion of subjects free from headache pain and free from most bothersome symptom 
(MBS) at various timepoints after dosing in subjects who wake up with migraine headache 
 Proportion of subjects free from headache pain and free from most bothersome symptom 
(MBS) at various timepoints after dosing in subjects with menstrual related migraine attack 
 Proportion of subjects free from both, headache pain and most bothersome symptom (MBS) 
at 2 hours after dosing 
 Proportion of subjects free from both, headache pain and most bothersome symptom (MBS) 
at various time points after dosing 
 Proportion of subjects free from headache pain and free from most bothersome symptom 
(MBS) at 2 hours after dosing by baseline (Visit 2) HIT-6 score 
 24-hour Migraine Quality of Life Questionnaire summary scores 
8.3.3. 
Hypotheses Testing and Significance Level 
A study-wise Type I error of 0.05 will be used for this study. A multiplicity strategy will be 
taken into account when interpreting the nominal 2-sided p-values. 
A fixed-sequence testing method which tests each endpoint individually in a pre-determined 
hierarchal order will be used for both primary and secondary endpoints. If the first endpoint is 
significant (<0.05), then you continue to the next endpoint. If an endpoint is not significant, then 
testing stops and all subsequent endpoints are considered non-significant. 
The order of the secondary endpoints to be tested will be described in detail in the SAP. 
8.3.4. 
Handling of Missing Data 
For the primary analysis of the co-primary endpoints, missing data will be imputed based on a 
single-imputation method. Subjects who do not have evaluable assessments at the 2-hour time 
point, or who received rescue medications prior to the 2-hour time point will be considered as 
non-responders. The impact of missing data will be further investigated in a number of sensitivity 
analyses with other single and multiple-imputation approaches. The details of the sensitivity 
analyses will be described in the SAP. 
8.3.5. 
Pooling of Centers 
Data from all investigational centers will be pooled for analysis. The analyses will not be 
performed by center and will not include adjustment for centers. 
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allodynia status at baseline (time 0) (allodynia status will be defined as "present" with at least 
2 "yes" responses to the 6 


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8.3.6. 
Analysis Methods for Efficacy Endpoints 
For both co-primary endpoints, the Chi-square test will be used to compare the active treatment 
group and placebo. The Chi-square test will also be used to test the secondary endpoints defined 
as a response variable. For analyses stratified by allodynia status, timing of treatment, or any 
other baseline characteristic the Cochran-Mantel-Haenszel test will be used. The Kaplan-Meier 
method will be used for time to use of rescue medications. The 24-hour Migraine Quality of Life 
Questionnaire assessments will be analyzed with the Analysis of Variance (ANOVA) models. 
The Chi-Square test will be used to analyze the Patient Global Impression ratings. 
To fully describe the treatment benefit of STS101, the proportion of subjects achieving 
 
treatment groups and placebo. The results will also be displayed graphically to show the time 
course of effect. To address the onset of efficacy, treatment difference vs. placebo will be 
examined from the 2 hour-timepoint towards the baseline in a sequential manner (i.e., 2 hours, 
1.5 hours, 1 hour, 45 minutes, 30 minutes, 15 minutes). A significance level of 0.05 will be used 
for this analysis. 
8.3.7. 
Subgroup Analysis of Efficacy Endpoints 
Subgroup analyses of the key efficacy endpoints will be conducted to gain insight of the nature 
and consistency of the treatment effect. Subgroups prospectively identified include: 
1. age group 
2. gender 
3. race 
4. baseline severity of attack (time 0) 
5. allodynia status 
6. menstrual related migraine attacks  
7. in subjects who wake up with migraine headache 
8. baseline (Visit 2) HIT-6 score 
Among these subgroup analyses, # 4, 5, 6, 7, and 8 are also included in the secondary or 
exploratory endpoints. Analysis by additional subgroups may be considered. They will be 
specified in the SAP before the study is unblinded for analysis. 
Because of the smaller sample sizes for each subgroup, the objective of the analysis is to evaluate 
the consistency of efficacy results across these factors. Statistical tests will be performed. 
However, the interpretation of the p-values will take into account sample size and multiplicity 
issues. Forest plots with estimates and 95% confidence intervals of the treatment effect across 
different subgroups will be presented. 
8.3.8. 
Safety Analysis 
Safety analyses will be conducted for the safety population, which will include all subjects who 
received at least one dose of study medication. All clinical safety and tolerability data will be 
summarized by treatment group and listed by treatment group and by subject. All reported 
"no headache pain" at various time points following treatment will be tested between the active 


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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. 
8.3.8.1. 
Extent of Exposure 
The number of subjects exposed to each treatment group will be summarized. Because this is a 
single-dose study, each subject is expected to receive one dose only. 
8.3.8.2. 
Adverse Events 
A TEAE is defined as an AE that begins after the dosing of study drug. 
An overview of adverse events will be presented by treatment group, which will include the number 
and percent of subjects who had at least one AE, TEAE, Serious TEAE, TEAE related to study 
drug, and 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 and treatment group: 
 Incidence of all TEAEs 
 Nasal TEAEs (including taste sensations coded as dysgeusia) 
 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 
All data collected in the AE case report form (CRF) will be listed in by-subject listings. 
8.3.8.3. 
Assessment of Nasal Symptoms 
The data from the Objective Assessment of Nasal Symptoms (Appendix C) will be summarized 
by treatment group. Exploratory hypothesis testing may be performed to compare treatment 
group by question. No multiplicity adjustment will be applied to these tests. 
8.3.8.4. 
Laboratory Evaluations 
The observed data at each time point and change from screening (Visit 1 or if re-draw: qualifying 
value) to the final study visit (Visit 3) in hematology, serum chemistry and quantitative 
urinalysis test results will be summarized by treatment group. 
For hematology and serum chemistry including calculated creatinine clearance, normal ranges 
for each parameter will be used to categorize the test result as low (value lower than the lower 
limit), normal (value within the normal range), or high (value higher than the upper limit). For 
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urinalysis, test results will be categorized as normal and abnormal. Frequency counts and 
percentages will be presented over time by treatment groups for these categorical data. In addition, 
shifts from baseline (shift to maximum value, shift to minimum value) to each post-baseline time 
point and to any post-baseline time point for each parameter will be summarized by treatment group. 
If a continuous laboratory value is reported as either below or above the limits of quantification, 
the qualifiers should be dropped and the nume
 
8.3.8.5. 
Vital Signs 
Observed data at each time point and the change from baseline (Visit 2) at each post-baseline 
time point for vital signs will be summarized by treatment group. 
Normal ranges for each vital sign parameter will be used to categorize the results as low (lower 
than the lower limit), normal (within the normal range), or high (higher than the upper limit). 
Frequency counts and percentages will be presented over time by treatment group for these 
categorical data. 
8.3.8.6. 
ECG Evaluations 
Observed data at each time point and the change at baseline (Visit 2) at each post-baseline time 
formula (QTcF), will be summarized by treatment groups. 
The number and percentage of subjects with other clinically significant ECG findings will also 
be summarized at each post baseline time point by treatment group. 
8.3.8.7. 
Concomitant Medications 
Concomitant medication usage will be summarized by the number and proportion of subjects in 
each treatment group. The World Health Organization Drug Dictionary (WHO Drug) will be 
used to classify prior and concomitant medications by therapeutic class and generic name based 
on ATC code level 3. Subjects will only be counted one time in each unique ATC Class and 
generic name if multiple drugs are used by a subject. 
8.3.8.8. 
Sheehan Suicidality Tracking Scale 
Reported data at each time point and the change from baseline (Visit 1) at Visit 3 will be 
summarized by treatment groups. 
8.3.9. 
Interim analysis 
No interim analysis is planned for this study. 
ric value used in the analysis ( e.g., "< 1" should be 
"1" and"> 100" should be "100"). 
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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 
representative and any subsequent data discrepancies identified will be recorded and 
communicated to the investigative site for resolution. 
 
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. 
will be monitored against source documents by the Sponsor's 
Completion of the electronic CRF should occur within 24 hours of a subject's visit. 


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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
records for verification of study-related procedures and data. 
, including the subject's original medical 


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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. 
this protocol. On the CRFs or other documents submitted to Satsuma, or its designee, subjects 
must be identified only by their initials and a subject number. Documents that are not for 
submission to Satsuma, and/or its designee, (i.e., signed ICFs) should be kept in strict confidence 
by the Investigator, in compliance with Federal regulations and ICH and GCP Guidelines. The 
Investigator is obligated to inform the subject in the ICF that his/her study-related records will be 
reviewed by the above-named study sponsor and representatives. 
11.3. Written Informed Consent 
Prior to any study procedures being performed, each study participant will be required to read, 
sign and date an EC/IRB -approved ICF, explaining the nature, purpose, possible risks and 
benefits, and the duration of the study. 
The ICF must be written in English or Spanish, and all subjects must be fluent in English or 
Spanish (speaking, writing, and reading). The Investigator or designee shall give the subject, 
adequate time to read the ICF and consider study participation and have all questions answered. 
They should also express understanding of the information presented regarding the trial before it 
is signed and dated. 
The ICF 
 In addition, a witness 
must also sign and date the ICF. The person who conducted the informed consent discussion will 
The Investigator must ensure that each subject's anonymity is maintained as described within 
must contain the subject's dated signature confirming the consent. 


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


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12. REFERENCES 
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Cook RO, Shrewsbury SB, Ramadan NM. Reduced adverse event profile of orally inhaled DHE 
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Dahlöf C, Maassen Van Den Brink A. Dihydroergotamine, ergotamine, methysergide and 
sumatriptan - 
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Ferrari MD, Goadsby PJ, Pozo-Rosich P, Wang SJ, Mandrekar J, International Headache Society 
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Djupesland PG, Messina JC, Mahmoud RA. Breath powered nasal delivery: a new route to rapid 
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doi: 10.1056/NEJMoa1813049. 
Edwards KR, Norton J, Behnke M. Comparison of intravenous valproate versus intramuscular 
dihydroergotamine and metoclopramide for acute treatment of migraine headache. Headache. 
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Gallagher RM. Acute treatment of migraine with dihydroergotamine nasal spray. 
Dihydroergotamine Working Group. Arch Neurol. 1996;53(12):1285-91. 
Goadsby PJ, Wietecha LA, Dennehy EB, Kuca B, Case MG, Aurora SK, Gaul C. Phase 3 
randomized, placebo-controlled, double-blind study of lasmiditan for acute treatment of 
migraine. Brain. 2019;142(7):1894-904. doi: 10.1093/brain/awz134. 
González-Hernández A, Lozano-Cuenca J, Marichal-Cancino BA, MaassenVanDenBrink A, 
Villalón CM. Dihydroergotamine inhibits the vasodepressor sensory CGRPergic outflow by 
prejunctional 
-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. 
Kuca B, Silberstein SD, Wietecha L, Berg PH, Dozier G, Lipton RB. Lasmiditan is an effective 
acute treatment for migraine: A phase 3 randomized study. Neurology. 2018;91(24):e2222-e32. 
doi: 10.1212/wnl.0000000000006641. 
Lipton RB, Dodick DW, Ailani J, Lu K, Finnegan M, Szegedi A, Trugman JM. Effect of 
Ubrogepant vs Placebo on Pain and the Most Bothersome Associated Symptom in the Acute 
Treatment of Migraine: The ACHIEVE II Randomized Clinical Trial. JAMA. 
2019;322(19):1887-98. doi: 10.1001/jama.2019.16711. 
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. 
Silberstein SD, McCrory DC. Ergotamine and dihydroergotamine: history, pharmacology, and 
efficacy. Headache. 2003;43(2):144-66. 
Tepper SJ, Kori SH, Goadsby PJ, Winner PK, Wang MH, Silberstein SD, Cutrer FM. MAP0004, 
orally inhaled dihydroergotamine for acute treatment of migraine: efficacy of early and late 
treatments. Mayo Clin Proc. 2011;86(10):948-55. doi: 10.4065/mcp.2011.0093. 
-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. 
activation of a2 
Tfelt-Hansen PC. Relatively slow and long 


STS101 (Dihydroergotamine Nasal Powder) 
Satsuma Pharmaceuticals, Inc. 
Clinical Trial Protocol: STS101-007 Version #2, May 20, 2021
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Confidential 
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 
-67. 
doi: 10.1177/0333102410379890. 
 
(HIT-6) across episodic and chronic migraine. Cephalalgia. 2010;31(3):357 


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Clinical Trial Protocol: STS101-007 Version #2, May 20, 2021 
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Confidential 
Appendix A. Schedule of Assessments 
 
Visit 1 
Visit 2 
Visit 3 
Screening 
Randomization 
Follow-up / Early Termination 
Timing of Visit 
Day -30 to -1 
Day 1 
Within one week (±3 days) of use of study medication 
(no later than Study Day 66) 
Informed consent 
X 
 
 
Demographic data / Medical history 
X 
 
 
Physical examination 
X 
X 
X 
Vital signs 
X 
X 
X 
Body weight and height 
X 
Xa 
Xa 
BMI Calculation 
X 
 
 
Hematology, clinical chemistry, urinalysisf 
X 
 
X 
Serum & Urine pregnancy screen (All females) 
Xg 
X 
Xg 
Urine Drug and Alcohol Screen 
X 
 
 
12-lead ECG (in triplicate) 
X 
 
X 
Determine / review eligibility 
X 
X 
 
HIT-6 Instrument 
 
X 
 
Sheehan Suicidality Tracking Scale (S-STS) 
X 
X 
X 
Headache Diary use training & review 
X 
X 
Xd 
Headache Diary event recording 
Xb 
Xc 
 
Objective Assessment of Nasal Symptom  
X 
X 
X 
Placebo Response Reduction Training 
X 
X 
 
Patient Subjective Impression Questions (6.2) 
 
 
X 
Randomization 
 
X 
 
Concomitant medications 
X 
X 
X 
STS101 Administration Training 
X 
X 
 
Investigational Product supply 
 
X 
Xe 
Adverse events recording 
X 
X 
X 
a Weight only; b Recording of headaches for 15 days; c Recording of headache severity & symptoms of treated attack, d Collect e-diary device; e Collect STS101 device; f FSH in 
menopausal females (surgical or physiologically menopausal); g Serum only 
 


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Appendix B. 
List of Allowed and Disallowed Other Headache Types 
Note: Subjects may not have 15 or more headache days per month in the three months before 
screening (Visit 1)  
a) Allowed headache types 
Subjects may be included in the study if they have these types of headaches and if they can 
distinguish them from their migraines: 
 
Tension headache 
 
R
 
 
Sinus congestion related headache 
 
Headache related to temporomandibular joint dysfunction 
 
Temporary headaches, e.g., from spinal tap or dental conditions that are temporary and no 
longer present when subject starts treatment period 
Note: Subjects must be instructed not to treat any of the above listed headaches with study 
medication 
b) Disallowed headache types 
 
days/month for 
 
 Post traumatic headache, e.g., within post-concussion syndrome  
 Headache related to intracranial structures, e.g., intracranial neoplasm, aneurysm  
 Headache related to other conditions, e.g., subarachnoid hemorrhage, acute or chronic subdural 
hematoma, intracranial infections or meningitis  
 
 
 Hemiplegic migraine  
 Cluster headache  
 Trigeminal neuralgia, other cranial neuralgias  
 Temporal arteritis  
 Intracranial inflammatory conditions or autoimmune related headaches.  
 Chronic dental conditions that lead to headaches 
 Intracranial hypertension (pseudotumor cerebri) 
 Spinal headache (e.g., due to intracranial hypotension due to a CSF leak) 
• 
• 
" egular" headache 
• 
• 
• 
• 
Medication overuse headache ("Regular intake of ergotamine or triptan on ~10 
> 3 months") 
• 
• 
• 
• 
Basilar migraine, now called: "Migraine with Brainstem Aura" (MBA) 
• 
• 
• 
• 
• 
• 
• 
• 


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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 
= subject reports blowing nose < 3 times in 1 hour 
Moderate = subject reports blowing nose 4-7 times in 1 hour 
Severe
= subject reports blowing 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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Clinical Trial Protocol: STS101-007 Version #2, May 20, 2021
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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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Clinical Trial Protocol: STS101-007 Version #2, May 20, 2021
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Appendix D. STS101 Instructions for Use 
 
INll'RUC1IOltlS FOR UIE 
lffll10'I 
~---.,..., 
ForNIIIIU.Ody 
DIINl'MPowellllnlO ...... NDIIII 
.. 
, ....................... lnhalt.JIIUequalll. 
...... 
-- ,,. 
••1111• 
.... ===-- .... ===-- .... ===--
Loaldnald91ha lmtllllafll ID 
11tlql00Mpowdlr 
IJlffillnlll 1halXllclm; 
................. 
=--· 
,.. ...... 
---Round 
-----
pnwidlll. 
TIIIJ\---
1:111 ... lnlD .. 
.......... 
-. ..... 
----


Dihydroergotamine intranasal powder (STS101) 
Satsuma Pharmaceuticals, Inc. 
Clinical Trial Protocol: STS101-007 Version #2, May 20, 2021
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Appendix E. 
24-Hour Migraine Quality of Life Questionnaire 
 
24-HOUR MIGRAINE QUALITY OF LIFE QUESTIONNAIRE 
Only the patient (subject) should enter information onto this questionnaire. 
The following questions are to be completed 24 HOURS after you take your first dose of 
medication for your migraine headache, and ask how your quality of life was affected. 
In the past 24 HOURS after you took your first dose of medication for your 
migraine headache, how much of the time did you: 
(Please check one box for each question) 
All 
Most 
A good 
Some 
A little 
Hardly 
None 
of the 
of the 
bit of the 
of the 
of the 
any of the 
of the 
time 
time 
time 
time 
time 
time 
time 
1 
2 
3 
4 
5 
6 
7 
1. have increased sensitivity to light 
and/or noise .. .. .. . . .. .. . . . .. . .. .. .. . . .. . .. . . . D 
□ 
□ 
□ 
□ 
□ 
□ 
2. have nausea ................................. D 
□ 
□ 
□ 
□ 
□ 
□ 
3. have throbbing head pain .............. D 
□ 
□ 
□ 
□ 
□ 
□ 
4. feel upset about having migraine 
headaches .................................... D 
□ 
□ 
□ 
□ 
□ 
□ 
5. feel physically uncomfortable ......... D 
□ 
□ 
□ 
□ 
□ 
□ 
6. feel concerned that your migraine 
medication wouldn't relieve your 
migraine headache symptoms ....... D 
□ 
□ 
□ 
□ 
□ 
□ 
Copyright © 1995 Merck & Co., Inc. 
Whitehouse Station, N.J., U.S.A. 
All Rights Reserved 


Dihydroergotamine intranasal powder (STS101) 
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Clinical Trial Protocol: STS101-007 Version #2, May 20, 2021
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Confidential 
 
Reference: Hartmaier 1995 
24-HOUR MIGRAINE QUALITY OF LIFE QUESTIONNAIRE 
In the past 24 HOURS after you took your first dose of medication, how much of the 
time did your migraine headache and accompanying symptoms limit your ability to: 
(Please check one box for each question) 
All 
Most 
Agood 
Some 
A little 
Hardly 
None 
of the 
of the 
bit of the 
of the 
of the 
any of the 
of the 
time 
time 
time 
time 
time 
time 
time 
1 
2 
3 
4 
5 
6 
7 
7. do normal everyday work Uob 
outside the home, schoolwork, 
□ 
□ 
□ 
□ 
□ 
□ 
□ 
housework) ....................... ........... 
8. stay alert ...................................... □ 
□ 
□ 
□ 
□ 
□ 
□ 
9. operate machinery or a motor 
vehicle (including home appliances 
and office equipment) .... ............... □ 
□ 
□ 
□ 
□ 
□ 
□ 
10. enjoy life ...................................... □ 
□ 
□ 
□ 
□ 
□ 
□ 
In the past 24 HOURS after you took your first dose of medication, how much did 
your migraine headache and accompanying symptoms negatively affect your: 
(Please check one box for each question) 
A very 
A 
great 
A great 
A good 
moderate 
Very 
deal 
deal 
deal 
amount 
Some 
little 
None 
1 
2 
3 
4 
5 
6 
7 
11 . interactions with people who 
□ 
□ 
□ 
□ 
□ 
□ 
□ 
are close to you ........... ................. 
12. interactions with other 
people ......................................... □ 
□ 
□ 
□ 
□ 
□ 
□ 
13. energy level ................................. □ 
□ 
□ 
□ 
□ 
□ 
□ 
14. ability to have a good night's 
sleep ........................... .......... ....... □ 
□ 
□ 
□ 
□ 
□ 
□ 
15. mood .... ....................................... □ 
□ 
□ 
□ 
□ 
□ 
□ 
Copyright © 1995 Merck & Co., Inc. 
Whitehouse Station, N.J., U.S.A . 
All Rights Reserved 


Dihydroergotamine intranasal powder (STS101) 
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Clinical Trial Protocol: STS101-007 Version #2, May 20, 2021
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Appendix F. 
Headache Impact Test (HIT-6
) 
HIT-6TM 
HEADACHE IMPACT TEST 
 
This questionnaire was designed to help you describe and communicate the way you feel and what 
you cannot do because of headaches. 
 
To complete, please check one box for each question. 
 
 
1. When you have headaches, how often is the pain severe? 
 
 
 Never 
 Rarely 
 Sometimes 
 Very Often 
 Always 
 
 
2. How often do headaches limit your ability to do usual daily activities including household 
work, work, school, or social activities? 
 
 
 Never 
 Rarely 
 Sometimes 
 Very Often 
 Always 
 
 
3. When you have a headache, how often do you wish you could lie down? 
 
 
 Never 
 Rarely 
 Sometimes 
 Very Often 
 Always 
 
 
4. In the past 4 weeks, how often have you felt too tired to do work or daily activities because of 
your headaches? 
 
 
 Never 
 Rarely 
 Sometimes 
 Very Often 
 Always 
 
 
5. In the past 4 weeks, how often have you felt fed up or irritated because of your headaches? 
 
 
 Never 
 Rarely 
 Sometimes 
 Very Often 
 Always 
 
 
6. In the past 4 weeks, how often did headaches limit your ability to concentrate on work or daily 
activities? 
 
 
 Never 
 Rarely 
 Sometimes 
 Very Often 
 Always 
 
 
 
 
 
 
 
 
-
 © 2001, 2015 Quality Metric Incorporated and the GlaxoSmithKline Group of Companies. All rights reserved. 
HIT-
United States (English) Version 
 
 
□ 
□ 
□ 
□ 
□ 
□ 
Headache Impact Test™ (HIT 6™) 
6™ 
□ 
□ 
□ 
□ 
□ 
□ 
□ 
□ 
□ 
□ 
□ 
□ 
TM 
□ 
□ 
□ 
□ 
□ 
□ 
□ 
□ 
□ 
□ 
□ 
□ 


Dihydroergotamine intranasal powder (STS101) 
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Clinical Trial Protocol: STS101-007 Version #2, May 20, 2021
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Confidential 
Appendix G. Sheehan Suicidality Tracking Scale (S-STS) 
 
SHEEHAN-SUICIDAUTY TRACKING SCALE: ,(~TS) 
'IIISTIIUCTIOHS: PLEAS:E USE DATA FROM All SOURCES. ANI), ,CONSIDER SE'!JE"lllTY, FREQUE C't. 
r. E S!Jl',EN A D 
J~ E: Fll:AME IN YOU-A B:ES:POI SH,. ffiE ~ES!PONSE 
-NOT ,U ALL• J,O AN'I' Q:UESTION 
EANS "NO' E" ANO ' EANS THAT THE fflOUGtfT, EXPEIINE~ CE OIR l!EflAVIO'R "DID ftOT OCCUII Ai All"_ TIUOUGHOUT lliE 
5,C_.!.l[, l1HE' WORDS r,•trfNT t 11,'TEr-lD ME"!.N A~lY I TfN G []I.RP.1R.!. ·z,ERO,. $CORE TttE ',10S SE IOU5 EVEtHTHAT OCCURRED FOIi E~Ctt 
EM ilE o w 
:In the past [timeframe); 
L 
clicl you nave :any accident? 
b . 
(this i 
udes taking too mu"h of your medicati.on :accicfent:a lly) 
[F NO, Sl(IP1O QUESTION 2. IF YES, GOTO QUESTION fa: 
now sieriously d'"Jd you :p!an ar intend to hurt you=lf in. any accident, either 
by oo,t :avoiding a ruk or by causing the :accident o.n ,purpose? 
IF THE A S.W E,RT,O O,U!ESTION b ISO!= Not at a I, S: P l'O QUESTION 2-
IF TI! E S:OOIIE tcS 1 OR HIGHER, •GIO TO Q,UESTIO' I l b: 
l b_ did you inteoo to di,;, acS a, result of :any accident? 
NO 0 
YES 0 
A littf., 
[I] 
Modenitely 
[I] 
NO 0 
YES □ 
11n the past {timeframe), hew serious!Jy did you: 
o-tstlll 
Modeir&lt.ely 
Ve.ry 
all'emely 
2_ 
t hink {even mornentarflyj that you would be better off dead, need to !be dead 
C)f wish you were dea,cl? 
How many times? __ 
3_ 
t'hink{even momentanly) ,aoout lila:rm[ngorhurting or injuri ng'f[IUrse 
iN~h a leacSt Sl[Jffle intent or :a:w:areness that you might die :as a, result-
or thin~ about suicide [l'i:i ling 1our5e,lf}? 
How many time-s? __ 
~. 
have avoioe or -.roices «.lling you ~o k' I yourse or have ctraams with :any 
suicidal oontent? 
J_ 
;;:,rk either or bot ; 
D 
.i vo5ce or 
C·~ · 
have any suicide me-tnod in mind (i.e. trow)?# 
have a ny s;uicide means in mlnd {Le_ with what}?# 
have :any !P ce in mind' to a,tterng,t suicide {i.e_ wlitere)? • ft 
have any date / timeframe in.m'"nd to :atte~ ptsuicicfe (Le_ Wh:enj?•# 
in«.nd to act on hou,ghts of kfll in-,g yourseLf? 
10_ jn end to die as :a, result of a s,uicid:al a:ct? 
•rk' eitliuar.bot :dJ 'fOU 
el\' 
':.o cfie.: D 
iiltthe ·time D iit~ametime i ~ e 
,e 
11. feel the ~ed o~ impulse to ki I yourse!f or to plan to kill yoursel • SOllfiler ,rather 
than laler? 
m;-rk eith e,r or lbo.1: 
•w ;as 
""; 
D t o kill ~r!r-elf 
.:rk eithe· air bot 
W iilS 1n· , 
D I.iii 
el'f 
prov-o ecd' 
D pror.·oked 
12_ ta~ :art1ve ste?S to prepare fot· a suldde attempt in which you expected or 
intended to die [lndude all'(thi ng dor,;e or pu~pose-ly not done that put you 
d oserto making a suici-de attempt)? 
fl_ injure V<JUrs f on p,rr,pose without 1ntending to l<iD yourself? 
How many times? __ 
u _ attempt .suicide (try to lciD yourself!? 
m 
m 
m 
m 
m 
[TI 
[I] 
[TI 
[I] 
[TI 
[I] 
Q 
[TI 
[TI 
[TI 
[TI 
[TI 
m 
IT] 
[I] 
m 
[I] 
m 
0 
[TI 
m 
m 
m 
m 
m 
[I] 
IT] 
m 
IT] 
[TI 
0 
0 
m 
m 
[TI 
m 
IT] 
m 
.. ,Jj ~uicid_. .a--rn. r,:ii"t ,is a; pati:,n ·D'_ay 5"11f injurio1J.!.· bha1,1i~r. allDcia~i.d Mlit1t .at kart .sa-m" int"Q'nt" l> OJ ta d(Q ,GS o n.-s.u-Jt aj th" cct. c ~;dMCQ that tfta indJiljdu 
int..nd"d to tilt him- or llwN, J,t. alt 
a~t t.o .s.om..- d.ggl"'i' lii1,. C&m bi.- - pJi.cit o,: J°r"ljQ>UQd from t.r.;Q b . ..-J,;;011ior·O"rdrcum.rt,a.rrci.·. 
Asuicid~ OttQmpt moy or """l" nor , .. ,vrtin,~cto,al lDjvry,.· (FDA 2021' d~- i6on'-'/. ' 
o.t"' =• 
&.8 o S-STS r- pion fo, s icide "] 
ea nsnot E,Oi 
~ beyond 
· e.~~ ort-.lki11i; ,iilbou 
iii pl• 
for s:u· i e. ff a.ctual 
1:,-
im-soccorr,ec:li. t'.he e--."ent !ihould not 
,c,ot!etd en · em 7 or -It :b t ; is ""pre:p.i_r.,teary behiiilYior•· (rtem 1 2.~ 
1Bothi e ,.ierlt!i c.in ,occ.ur;- sep.tr.,ite! y O\'e 
· .e siilm e · 
efr.ame. # r4o~: clia i. ·• a :sho 
~ k m det.iils. 
1/ 9/ 19 
1 


Dihydroergotamine intranasal powder (STS101) 
Satsuma Pharmaceuticals, Inc. 
Clinical Trial Protocol: STS101-007 Version #2, May 20, 2021
Page 80 of 81
Confidential 
 
SHEEHAN-SUICIDALITY TRACKING SCALE (S-STSJ - EVENTS REPORT 
15. If ANSWER 14 IS, POSffiVE ASK: 
:In the p,ast {li mefra me),. how man.y times did you attempts icicle? 
'Wh,en? 
How? 
How serious was each ainempt? 
dd/M MM.fll'fl'Y 
flot at ■II 
1.-----L--r-l ~~L.LL......r----------,1 CQJ 
2. 
3. 
4 . 
5. 
Add rows as needed. 
[QJ 
[QJ 
[I] 
m 
Levels of Attemp-t (halted by ,elf, by anot her person. ar event, or not at a II) 
A little 
[TI 
[TI 
Cu 
OJ 
[TI 
[I] 
OJ 
[I] m OJ 
[I] m [TI 
Level 1: You started the suictde attempt, but then ya111 decided 10 stop ,and did not finish the m empt. 
Level 2:: You started the suicide atternp , but then yo111 were 1intem1p,ted a,nd did not finish the ,attempt 
Level 3,: You went thrmi,g;h the s.uioid'.e attempt oom,pletely as you m ea1nl to,_ 
16. If ANSWfR 12 IS, POSffiVE ASK: 
CTI D 
CTI D 
[I] 
[TI 
D 
D 
/ 
.In the p-ast: (timefra.me),. h:0w many times did you take active Sljeps to prepare fur a suicide attempt in 'lo'thich you experted 
or intend.ed to die j iru:'I ude a nytflin:g done or pur posely not done tha,t put you doser o, making a suicide anem pt)i? __ 
[lntlu:de on!ythe times wtl.en ','OIJ stopped short of mating an actu,al suicid:e attempt.) 
When? 
How? 
How serious was each preparation? 
,i!~M . MJnw 
Ho:l.at:all 
A little 
Mod..,,lely 
v·.,'1' 
0:1,,.,,,,ely 
l~I 
1. 
m IT] m OJ m D 
2. 
[I] 
DJ 
[I] 
[I] IT] D 
3 . 
[I] 
DJ 
[I] 
[I] [TI D 
4. 
[I] 
DJ 
[I] 
[I] [TI D 
5. 
[QJ 
[TI 
0 
[TI CTI D 
Add rows as n.eieded. 
/ 
levels of Preparation 
Level 1: You took active Slieps to prepare to km yourself, but you did not start the suicide anempt. 
Level 2: You were abouito tty to kiri yourself, but then yo11 stopped'yourself j~t before harming yourself. 
Level 3.: You were aboUil: to try to ,kiri yourself, but tilen som,ec111e ar somethingstop;ped yo111just befor,e harmin,g yourself. 
Tl ME SPENT PER DAY WITH AN'rl' SUICIDAL IMPULSES, THOUGHIS OR .ACHONS OVER THE PAST ,[TIM E RAM'E): 
Usua11 time spent per day: 
hours 
minutes, 
Least amount of time spent in any day: __ hours __ mimllies. 
Most amount of time S'pent in any da~r: __ hours, __ minutes. 
l / 9/ 19 


Dihydroergotamine intranasal powder (STS101) 
Satsuma Pharmaceuticals, Inc. 
Clinical Trial Protocol: STS101-007 Version #2, May 20, 2021
Page 81 of 81
Confidential 
SHEEHAN-SUICIDALITV TRACKING SCALE (S-STS) - CLINICIAN SE ONLY 
Comp I ete tfl is s.ection only ijtbe: patient" doc?S not .return for the .scheduled follow up vis.it and is not a~raila ble 
to permit completion of .pages 1 and 2. Oruly one resporn.e ca.n be selected trom 17 through 22_ 
FOR CLINICIAN USE ONLY 
NO 
YES 
17. M issed appointment - reason,: s.ubj.e,a: died from a, completed suicide? 
m 1100 I 
18. M issed appointment - reason: :subj-ea: died but not enough information t o code as a suicide? 
0 E] 
19_ li;ilissed appointment - reason,: s.ubj.e,a: died from causets} otherthan suicide? 
CI] E] 
20. M issed appointment - reason,: s.ubj.e,CI: al'ive, but not avai!a.tlle because of a suicide attempt?' 
[TI I}[] 
l . M issed appointment- reason: subj&!: alive, but not a\rai[able for known reia50ll5 other t han suicide:? 
[TI E] 
22. M issec! appointment- reason: subject alive, but not a~Hab le, for uncertain r,e-asons, or "'tost to follow up"? 0 G 
Total Sca'le Score 
Add sc:ores from Questiol'lS la (onl;• if lb is roded YES),. + 2 thmu1¥1 ll + 
[the highest of 12 or any row of16] + [the highest of :J!.4 or any row of 
15] or (only if appricable 17 or 18 or 19 or 20 or 21 or 22 [page 3l]. ** = 
e:nte.r total S-STS S1Core 
m prior Yis-it onl~r if r~ response is a ;p lica b[e_ 
D 
I :have revie~\lled the answe,rs on P,ages 1 andi 2 ~vith t he patient. 
rnn·cian SfID'l-ature 
dd/ M MM/YVYY 
I have review-e,cl the answe.rs on P,a-ges 1 arid 2 with my doctor or di11ician,. 
Pat i·ent Signature 
dd/M MM/yyyy 
References. 
liOTAt 
□ 
1. 
Guio:anoe tor Industry Suicidal [deat ion and B,el:)a...,ior: ProspectM;! Asse:s.smentof (kcurreoce ln 
inkalTri-als... August 2012.. Revision 
1. U.S Department of Health and uman Se.rvice:s., Food and Drug Administfa · on, Center tor Drn;g Ev:a uation and Rese:arnh (CDERI, 
Sihrer Sprii;g, MD 20992-0002.. 'hn p;IJ'IVW,..,,.f,da,.goY/Drugs/GuidanceGompli anceRegu toryl nformatiion/G idances/defa u .. htm l 
Direct download from ,w,w.fda_go~/downloads/DrugsfGui d;mce.s.fUCM225130,"pdf 
2. 
Posner I(, Oquernlo MIA et: al. Columbia Classification 
~orithm of Suitide .Assessment (C,CASA): Classifica,tron of Suicidal E¥ ents in 
the· FDA' s: PedlialJ'ic Suicidal Risi A a.lysis of.Antidepressants. C-CASA Definitions. in Table 2, page 1.037. Am J Psy.chi!irtry 2!007; 
164:1035-1003 
line author is g;rateful toJM Gidde ns forveryvaluabl'e ad~ice in tne developmesnt ofthe S-STI.:and of 'liheS-STS CMCMve.rsions. 
1/.9/19 

SAP_001.pdf: 
ST·ATISTICAL ANALYSIS PLAN 
Satsuma Pharmaceuticals, Inc. 
400 Oyster Point Boulevard, Suite 221 
South San Francisco, CA 94080 
A Randomized, Double-Blind, Parallel Group, Placebo-Controlled, 
Multicenter Study to Evaluate the Efficacy, Safety, and Tolerability of 
Single Doses of STS101 (Dihydroergotamine Nasal Powder) in the 
Acute Treatment of Migraine 
Clinical Study Protocol No. STSl0l-007 
Final 17Oct2022 
Prepared by 
Brianne Gurney 
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 
A Randomized, Double-Blind, Parallel Group, Placebo-Controlled, 
Multicenter Study to Evaluate the Efficacy, Safety, and Tolerability of 
Single STS101 (Dihydroergotamine Nasal Powder) in the Acute 
Treatment of Migraine 
Clinical Study Protocol No. STSl0l-007 
..-,.,,..,...c 
Michelle Secic (Oct 18, 202214:34 EDT) 
Michelle Secic 
Secic Statistical Consulting, Inc. 
Detlef Albrecht (Oct 18, 202210:45 PDT) 
Detlef Albrecht, MD 
Satsuma Pharmaceuticals 
Jltet;a L{i(()z,/b 
Shelia Ligozio (O( 18, 202213:43 EDT) 
Shelia Ligozio 
Instat Clinical Research 
CONFIDENTIAL 
Oct 18, 2022 
Approval Date 
Oct 18, 2022 
Approval Date 
Oct 18, 2022 
Approval Date 
Final: October 17, 2022 


Satsuma Pharmaceuticals, Inc. - STSlOl-007 
Statistical Analysis Plan 
Page 1 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .................................................................... 2 
1. 
INTRODUCTION ............................................................................................................................. 3 
1.1 
Study Objectives .............................................................................................................................. 3 
1.2 
Study Design .................................................................................................................................... 6 
1.3 
Study Timepoints ............................................................................................................................. 7 
2. 
GENERAL ANALYSIS DEFINITIONS .......................................................................................... 9 
2.1 
Statistical Hypotheses ...................................................................................................................... 9 
2.2 
Determination of Sample Size .......................................................................................................... 9 
2.3 
Study Populations ............................................................................................................................. 9 
2.4 
Pooling of Investigator Sites .......................................................................................................... 10 
2.5 
General Handling of Missing Data ................................................................................................. 10 
3. 
SUBJECT CHARACTERISTICS ................................................................................................... 10 
3.1 
Subject Disposition ........................................................................................................................ 10 
3.2 
Protocol Deviations ........................................................................................................................ 11 
3.3 
Demographic and Baseline Characteristics .................................................................................... 11 
3.4 
Medical History .............................................................................................................................. 11 
3.5 
Migraine History ............................................................................................................................ 11 
3.6 
Headache Impact Test .................................................................................................................... 11 
3.7 
Treated Migraine Attack Baseline Symptoms ............................................................................... 11 
3.8 
Prior and Concomitant Medications and Therapies ....................................................................... 12 
4. 
EFFICACY ...................................................................................................................................... 12 
4.1 
Primary Efficacy Estimands ........................................................................................................... 12 
4.2 
Key Secondary Efficacy Estimands ............................................................................................... 13 
4.3 
Definitions and Derived Variables ................................................................................................. 16 
4.4 
Efficacy Variables .......................................................................................................................... 20 
4.5 
Efficacy Analysis Methods ............................................................................................................ 25 
4.5.1 
Multiplicity Strategy .......................................................................................................... 25 
4.5 .2 
Primary Endpoint Analysis Methods ................................................................................. 26 
4.5.3 
Key Secondary Endpoint Analysis Methods ...................................................................... 27 
4.5.4 
Additional Secondary Endpoint Analysis Methods ........................................................... 27 
4.5.5 
Exploratory Endpoint Analysis Methods ........................................................................... 28 
4.5.6 
Sensitivity Analyses ........................................................................................................... 29 
4.5.7 
Subgroup Analyses ............................................................................................................. 32 
5. 
SAFETY .......................................................................................................................................... 33 
5 .1 
Extent of Exposure ......................................................................................................................... 3 3 
5.2 
Adverse Events ............................................................................................................................... 33 
5.3 
Assessment of Nasal Irritation ....................................................................................................... 34 
5.4 
Physical Examination ..................................................................................................................... 34 
5.5 
Vital Signs ...................................................................................................................................... 34 
5.6 
Electrocardiogram .......................................................................................................................... 35 
5.7 
Laboratory Evaluations .................................................................................................................. 35 
5.8 
Sheehan Suicidality Tracking Scale ............................................................................................... 35 
6. 
Interim Analysis ............................................................................................................................... 35 
7. 
TABLES, LISTINGS, AND FIGURES .......................................................................................... 36 
8. 
REFERENCES ................................................................................................................................ 37 
CONFIDENTIAL 
Final: October 17, 2022 


Satsuma Pharmaceuticals, Inc. - STSlOl-007 
Statistical Analysis Plan 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Explanation 
AE 
adverse event 
ANOVA 
analysis of variance 
BMI 
body mass index 
CI 
confidence interval 
CRF 
case report form 
CSR 
clinical study report 
DHE 
dihvdroergotamine 
ECG 
electrocardiogram 
e-diary 
electronic diarv 
ET 
early termination 
FIS 
Functional Impairment Scale 
HIT-6 
Headache Impact Test 
HR 
heart rate 
LOCF 
last observation carried forward 
max 
maxnnum 
MBS 
most bothersome symptom 
MCMC 
Markov chain Monte Carlo 
MedDRA 
Medical Dictionarv for Refilllatorv Activities 
mm 
mmnnum 
MI 
multiple imputation 
mITT 
Modified Intent-to-Treat 
n 
number of subjects 
pp 
Per Protocol 
PT 
preferred term 
QTcF 
QT corrected with the Fridericia' s formula 
TEAE 
treatment emergent adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SI 
single imputation 
soc 
system organ class 
WHO Drug 
World Health Organization Drug Dictionarv 
24-MQoLQ 
24-hour Migraine Quality of Life Questionnaire 
CONFIDENTIAL 
Page2 
Final: October 17, 2022 


Satsuma Pharmaceuticals, Inc. - STSlOl-007 
Statistical Analysis Plan 
1. INTRODUCTION 
Page3 
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 Objectives of the study are: 
• 
To evaluate the efficacy of a single dose of 5.2 mg STS 101 to achieve freedom from pain 
at 2 hours after dosing 
• 
To evaluate the efficacy of a single dose of 5.2 mg STSlOl to achieve freedom from 
most bothersome symptom at 2 hours after dosing 
The Key Secondary Objectives of the study are: 
• 
To evaluate the efficacy of a single dose of 5.2 mg STS 101 to achieve pain relief at 2 
hours after dosing 
• 
To evaluate the efficacy of a single dose of 5.2 mg STS 101 to achieve pain relief at 1 
hour after dosing 
• 
To evaluate the efficacy of a single dose of 5.2 mg STSlOl to avoid the use ofrescue 
medication within 24 hours after dosing 
• 
To evaluate the efficacy of a single dose of 5.2 mg STSlOl to achieve normal function at 
2 hours after dosing 
• 
To evaluate the efficacy of a single dose of 5.2 mg STSlOl to achieve 2 to 48 hour 
sustained pain free status 
• 
To evaluate the efficacy of a single dose of 5.2 mg STSlOl to achieve 2 to 48 hour 
sustained freedom from most bothersome symptom status 
• 
To evaluate the efficacy of a single dose of 5.2 mg STSlOl to avoid the use ofrescue 
medication within 48 hours after dosing 
• 
To evaluate the efficacy of a single dose of 5.2 mg STSlOl to achieve 2 to 24 hour 
sustained pain free status 
• 
To evaluate the efficacy of a single dose of 5.2 mg STSlOl to achieve 2 to 24 hour 
sustained freedom from most bothersome symptom status 
• 
To evaluate the efficacy of a single dose of 5.2 mg STSlOl to achieve freedom from 
photophobia at 2 hours after dosing 
• 
To evaluate the efficacy of a single dose of 5.2 mg STS101 to achieve freedom from 
phonophobia at 2 hours after dosing 
• 
To evaluate the efficacy of a single dose of 5.2 mg STS101 to achieve freedom from 
nausea at 2 hours after dosing 
• 
To evaluate the efficacy of a single dose of 5.2 mg STS 101 to avoid headache pain 
relapse within 48 hours after dosing 
• 
To evaluate the efficacy of a single dose of 5.2 mg STS101 to achieve 2 to 24 hour 
sustained normal function status 
CONFIDENTIAL 
Final: October 17, 2022 


Satsuma Pharmaceuticals, Inc. - STSlOl-007 
Statistical Analysis Plan 
Page4 
• 
To evaluate the efficacy of a single dose of 5.2 mg STS 101 to achieve freedom from pain 
at the following timepoints after dosing: 3, 4, 6, 12, and 24 hours 
• 
To evaluate the efficacy of a single dose of 5.2 mg STS 101 to achieve freedom from pain 
at 2 hours after dosing by allodynia status at time of dosing 
• 
To evaluate the efficacy of a single dose of 5.2 mg STSlOl to achieve freedom from 
most bothersome symptom at 2 after dosing by allodynia status at time of dosing 
• 
To evaluate the efficacy of a single dose of 5.2 mg STSlOl to achieve freedom from pain 
at 2 hours after dosing in subjects with severe headache at baseline 
• 
To evaluate the efficacy of a single dose of 5.2 mg STSlOl to achieve freedom from 
most bothersome symptom at 2 hours after dosing in subjects with severe headache at 
baseline 
Additional Secondary Objectives of the study are: 
• 
To evaluate the efficacy of a single dose of 5.2 mg STSlOl to achieve freedom from 
headache pain at 48 hours after dosing 
• 
To evaluate the efficacy of a single dose of 5.2 mg STSlOl to achieve freedom from 
most bothersome symptom at various timepoints after dosing 
• 
To evaluate the efficacy of a single dose of 5.2 mg STS 101 to achieve pain relief at 
various timepoints after dosing 
• 
To evaluate the efficacy of a single dose of 5.2 mg STSlOl to achieve normal function at 
various timepoints after dosing 
• 
To evaluate the efficacy of a single dose of 5.2 mg STSlOl to avoid headache pain 
relapse within 24 hours after dosing 
• 
To estimate the probability of a subject to achieve freedom from pain during the 48-hour 
post dose period 
• 
To estimate the probability of a subject to achieve freedom from the most bothersome 
symptom during the 48-hour post dose period 
• 
To estimate the probability of a subject to achieve pain relief during the 48-hour post 
dose period 
• 
To estimate the probability of a subject to achieve pain relief during the 2-hour post dose 
period 
• 
To estimate the probability of a subject requiring rescue medication during the 48-hour 
post dose period 
• 
To evaluate the efficacy of a single dose of 5.2 mg STSlOl to achieve freedom from 
photophobia at various timepoints after dosing 
• 
To evaluate the efficacy of a single dose of 5.2 mg STS101 to achieve freedom from 
phonophobia at various timepoints after dosing 
• 
To evaluate the efficacy of a single dose of 5.2 mg STS101 to achieve freedom from 
nausea at various timepoints after dosing 
• 
To evaluate the frequency of each rescue medication 
• 
To evaluate the study subject's global impression of the study treatment as well as other 
subject impression responses 
CONFIDENTIAL 
Final: October 17, 2022 


Satsuma Pharmaceuticals, Inc. - STSlOl-007 
Statistical Analysis Plan 
Page 5 
• 
To evaluate the efficacy of a single dose of 5.2 mg STS 101 on Functional Impairment 
Scale scores 
• 
To evaluate the time to onset of efficacy in subjects achieving freedom from headache 
pam 
• 
To assess the safety and tolerability of a single dose of 5.2 mg STSlOl in the treatment of 
acute migraine attacks 
The Exploratory Objectives of the study are: 
• 
To evaluate the efficacy of a single dose of 5.2 mg STSlOl to achieve freedom from pain 
and most bothersome symptom at various timepoints after dosing by allodynia status at 
time of dosing 
• 
To evaluate the efficacy of a single dose of 5.2 mg STSlOl to achieve freedom from pain 
and most bothersome symptom at 2 hours and various timepoints after dosing in subjects 
who wake up with acute migraine attacks 
• 
To evaluate the efficacy of a single dose of 5.2 mg STSlOl to achieve freedom from pain 
and most bothersome symptom at 2 hours and various timepoints after dosing in subjects 
with acute menstrual related migraine attacks 
• 
To evaluate the efficacy of a single dose of 5.2 mg STSlOl to achieve pain relief at 2 
hours and various timepoints after dosing in subjects with acute migraine attacks by 
allodynia status at time of treatment 
• 
To evaluate the efficacy of a single dose of 5.2 mg STSlOl to achieve pain relief at 2 
hours and various timepoints after dosing in subjects who wake up with acute migraine 
attacks 
• 
To evaluate the efficacy of a single dose of 5.2 mg STSlOl to achieve pain relief at 2 
hours and various timepoints after dosing in subjects with acute menstrual related 
migraine attacks 
• 
To evaluate the efficacy of a single dose of 5.2 mg STSlOl to achieve both, freedom 
from pain and most bothersome symptom at 2 hours after dosing 
• 
To evaluate the efficacy of a single dose of 5.2 mg STSlOl to achieve both, freedom 
from pain and most bothersome symptom at various timepoints after dosing 
• 
To evaluate the efficacy of a single dose of 5.2 mg STSlOl to achieve freedom from 
headache pain and most bothersome symptom (MBS) at 2 hours after dosing by baseline 
(Visit 2) HIT-6 score 
• 
To evaluate the effects of a single dose of 5.2 mg STSlOl on the 24-hour Migraine 
Quality of Life Questionnaire (24-MQoLQ) 
• 
To evaluate the efficacy of a single dose of 5.2 mg STS101 to achieve freedom from pain 
and most bothersome symptom at 2 hours after dosing by baseline aura symptoms 
• 
To evaluate the efficacy of a single dose of 5.2 mg STS101 to achieve freedom from pain 
and most bothersome symptom at 2 hours after dosing by preventative migraine 
medication use at screening 
• 
To evaluate the efficacy of a single dose of 5.2 mg STS101 to achieve relief from 
headache pain at 2 hours after dosing by preventative migraine medication use at 
screemng 
CONFIDENTIAL 
Final: October 17, 2022 


Satsuma Pharmaceuticals, Inc. - STSlOl-007 
Statistical Analysis Plan 
Page 6 
• 
To evaluate the efficacy of a single dose of 5.2 mg STSlOl to achieve freedom from pain 
and most bothersome symptom at 2 hours after dosing by anti-CGRP antibody use at 
screemng 
• 
To evaluate the efficacy of a single dose of 5.2 mg STSlOl to achieve relief from 
headache pain at 2 hours after dosing by anti-CGRP antibody use at screening 
• 
To evaluate the efficacy of a single dose of 5.2 mg STSlOl to achieve freedom from pain 
and most bothersome symptom at 2 hours after dosing by inadequate response to triptan 
medication before screening 
• 
To evaluate the efficacy of a single dose of 5.2 mg STSlOl to achieve relief from 
headache pain at 2 hours after dosing by inadequate response to triptan medication use 
before screening 
• 
To evaluate the efficacy of a single dose of 5.2 mg STSlOl to achieve freedom from pain 
and most bothersome symptom at 2 hours after dosing by inadequate response to gepant 
medication before screening 
• 
To evaluate the efficacy of a single dose of 5.2 mg STSlOl to achieve relief from 
headache pain at 2 hours after dosing by inadequate response to gepant medication use 
before screening 
• 
To evaluate the efficacy of a single dose of 5.2 mg STSlOl to achieve freedom from pain 
and most bothersome symptom at 2 hours after dosing by baseline headache severity 
• 
To evaluate the efficacy of a single dose of 5.2 mg STSlOl on the 24-MQoLQ scores on 
subjects with freedom from headache pain, freedom from MBS, and relief from headache 
pain at 2 and 24 hours post dose 
• 
To evaluate the efficacy of a single dose of 5.2 mg STSlOl to achieve freedom from pain 
and most bothersome symptom at 2 hours after dosing by duration of migraine onset to 
study medication dosing 
• 
To evaluate the efficacy of a single dose of 5.2 mg STSlOl to achieve freedom from 
pain, freedom from most bothersome symptom, and relief from headache pain at 2 hours 
after dosing by various subgroups 
1.2 Study Design 
This is a multi-center, single-dose, randomized, double-blind, placebo-controlled, parallel group 
study in approximately 1400 subjects with acute migraines (ages 18 to 65 years). 
After establishing initial eligibility, the study participants will be trained in the use of the 
electronic diary (e-diary) to record their headache attacks for 15 days during the screening 
period. Attack pain severity, presence of symptoms (nausea, photophobia, or phonophobia) and 
impact on function status will be documented. 
The study subjects will also be trained in the administration of study medication and use of the 
STS101 device, and undergo Placebo Response Reduction training, designed to improve 
discrimination between placebo and drug effects in clinical trials. 
CONFIDENTIAL 
Final: October 17, 2022 


Satsuma Pharmaceuticals, Inc. - STSlOl-007 
Statistical Analysis Plan 
Page 7 
After establishing eligibility, the study participants will be randomized ( 1 : 1) to receive one of 
two treatments: 
• 
5.2 mg STSlOl (equivalent to 6.0 mg of dihydroergotamine (DHE) mesylate 
USP) 
• 
Placebo (matching nasal powder) 
The randomization will be stratified by the use of migraine prevention medication. After the 
randomization, the study participants will treat their next qualifying migraine attack of at least 
moderate pain severity with the allocated blinded study medication within 4 hours of the onset of 
the attack. 
The study participants will document the following symptoms of their treated migraine before 
and over 48 hours after study drug administration inane-diary: migraine headache pain severity, 
presence of symptoms (photophobia, phonophobia, nausea), presence of allodynia and 
functionality status. Headache pain severity and symptom data will be documented immediately 
before drug administration (time 0), at 15, 30, 45 minutes and 1, 1.5, 2, 3, 4, 6, 12, 14, and 48 
hours after study drug administration. The subjects must select a most bothersome symptom 
from among photophobia, phonophobia, and nausea immediately before study drug 
administration. 
If subjects require rescue medication, they will be encouraged to wait until the 2-hour post study 
drug administration data collection timepoint. The use oftriptans or other DHE mesylate 
products as rescue medications should be avoided for 24 hours after study drug administration. 
The study participants will return to the study site within approximately one week of the treated 
migraine attack. 
Adverse events, objective nasal evaluation data, safety laboratory data, vital sign data and ECGs 
will be recorded before and after treatment to evaluate the tolerability and safety of STS101. 
A sufficient number of subjects will be screened to randomize approximately 1400 subjects in 
the study. The dropout rate is estimated to be less than 35%. Subjects who withdraw or are 
withdrawn from the study after dosing will not be replaced. However, in the event that the 
number of dropouts or number of subjects with missing data exceeds initial expectations, 
subjects who withdraw or are withdrawn may be replaced. 
1.3 Study Timepoints 
A complete description of procedures at each visit can be found in the protocol. The Schedule of 
Assessments is presented in Table 1 below. 
CONFIDENTIAL 
Final: October 17, 2022 


Satsuma Pharmaceuticals, Inc. - STSlOl-007 
Statistical Analysis Plan 
Table 1: Schedule of Assessments 
Visit 1 
Screening 
Timing of Visit 
Day-30 to -1 
Informed Consent 
X 
Demographic Data/Medical History 
X 
Physical Examination 
X 
Vital Signs 
X 
Body Weight and Height 
X 
BMI Calculation 
X 
Hematology, Clinical Chemistry, 
X 
Urinalysisf 
Serum & Urine Pregnancy Screen 
xg 
(All Females) 
Urine Drug and Alcohol Screen 
X 
12-Lead ECG (in triplicate) 
X 
Determine/Review Eligibility 
X 
HIT-6 Instrument 
Sheehan Suicidality Tracking Scale 
X 
(S-STS) 
Headache Diary Use Training & 
X 
Review 
Headache Diary Event Recording 
Xb 
Objective Assessment of Nasal 
X 
Symptom 
Placebo Response Reduction 
X 
Training 
Patient Subjective Impression 
Questions (6.2) 
Randomization 
Concomitant Medications 
X 
STS101 Administration Training 
X 
Investigational Product Supply 
Adverse Events Recording 
X 
a Weight only 
b Recording of headaches for 15 days 
c Recording of headache severity & symptoms of treated attack 
d Collect e-diary device 
e Collect STSIOI device 
Page 8 
Visit 2 
Visit 3 
Randomization 
Follow-up/Early 
Termination (ET) 
Within one week (±3 
Day 1 
days) of use of study 
medication (no later 
than Study Day 66) 
X 
X 
X 
X 
xa 
xa 
X 
X 
xg 
X 
X 
X 
X 
X 
X 
X 
Xd 
xc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
xe 
X 
X 
f FSH in menopausal females (surgical or physiologically menopausal) 
gSerum Onlv 
CONFIDENTIAL 
Final: October 17, 2022 


Satsuma Pharmaceuticals, Inc. - STSlOl-007 
Statistical Analysis Plan 
2. GENERAL ANALYSIS DEFINITIONS 
2.1 Statistical Hypotheses 
Page9 
The hypothesis for the study objectives is that a single dose of 5.2 mg of STS 101 is significantly 
superior to placebo in achieving freedom from headache pain and freedom from most 
bothersome symptom at 2 hours post dose. 
2.2 Determination of Sample Size 
A total of approximately 1400 subjects ( approximately 700 in each treatment group) will be 
randomized. 
For the co-primary endpoint of pain freedom at 2 hours post dosing of investigational drug, a 
therapeutic gain of 10%, assuming a 25% responder rate for STSlOl and 15% for the placebo is 
targeted. Based on these assumptions, 700 subjects per arm can provide 99% power to detect the 
target treatment difference. For the co-primary endpoint ofMBS freedom at 2 hours post 
investigational drug, a therapeutic gain of 10%, assuming a 45% responder rate for STSlOl and 
35% for the placebo is targeted. Based on these assumptions, 700 subjects per treatment group 
can provide 95% power to detect the target treatment difference. The sample size calculation is 
based on a chi-square test with a significance level of 0.05 and a 2-sided test. 
The primary efficacy objective will be addressed by simultaneously testing the 2 co-primary 
endpoints of pain freedom and MBS freedom at 2 hours after drug administration at a 
significance level of 0.05. This sample size will provide an overall power of at least 94%. 
All study data will be summarized by treatment using descriptive statistics. Unless otherwise 
specified, for numeric data (e.g., age, weight), descriptive statistics will include the number of 
subjects with data to be summarized (n), mean, standard deviation (SD), median, minimum (min) 
and maximum (max). All categorical/qualitative data (e.g., gender, race) will be presented using 
absolute and relative frequency counts and percentages. 
2.3 Study Populations 
The analysis populations to be used in the study are defined below. 
Modified Intent-to-Treat Population 
For the purposes of efficacy data analysis, the modified intent-to-treat (mITT) population will be 
the primary analysis population. This population will include all randomized subjects who 
reported a qualifying migraine attack, received the study drug, and reported efficacy data in at 
least one post-treatment e-Diary. Data will be analyzed according to the treatment group each 
subject was randomized to receive. 
Per-Protocol Population 
The per protocol (PP) population will consist of all mITT subjects who do not have protocol 
deviations that could significantly affect the interpretation of the results for the primary 
CONFIDENTIAL 
Final: October 17, 2022 


Satsuma Pharmaceuticals, Inc. - STSlOl-007 
Statistical Analysis Plan 
endpoints. Subjects' inclusion/exclusion from the PP population will be determined and 
documented prior to the database lock and unblinding. 
Intent-to-Treat Population 
Page 10 
The intent-to-treat (ITT) population will include all subjects who are randomized. Data will be 
analyzed according to the treatment each subject was randomized to receive. 
Safety Population 
The safety population will include all subjects who are randomized and have received the study 
drug. Data will be analyzed according to the treatment each subject actually received. 
2.4 Pooling of Investigator Sites 
Data for all sites will be pooled for analysis. The analyses will not be performed by sites and will 
not include adjustment for sites. 
2.5 General Handling of Missing Data 
For incomplete dates 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. 
(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. 
Dates that are completely missing will not be imputed. 
Baseline values that are missing will not be imputed. Subjects who have missing subgroup 
values will not be included in that particular subgroup analyses. 
Missing data related to an efficacy parameter will be discussed in Efficacy Section 4. 
3. SUBJECT CHARACTERISTICS 
3.1 Subject Disposition 
The number of randomized subjects and number/percentage of subjects in each analysis 
population, number of subjects who completed/discontinued the study, and reasons for 
discontinuations will be presented by treatment group for all subjects. In addition, this summary 
will also be presented by treatment group for each analysis population. 
CONFIDENTIAL 
Final: October 17, 2022 


Satsuma Pharmaceuticals, Inc. - STSlOl-007 
Statistical Analysis Plan 
Reasons for population exclusion will be displayed in a data listing. 
3.2 Protocol Deviations 
Page 11 
Protocol violations/deviations will be collected, including the deviation category, classification, 
and the start date if possible. The deviations will be presented in a data listing for all randomized 
subjects. 
3.3 Demographic and Baseline Characteristics 
Demographics and baseline characteristics (including social history) will be summarized 
descriptively by treatment group for the ITT Population, mITT Population, the Per-Protocol 
Population, and the Safety Population. See Section 4.3 for derived variable definitions. 
Exploratory hypotheses testing may be performed to assess the comparability of demographics 
and baseline characteristics among the treatment groups. No multiplicity adjustment will be 
applied to these tests. 
3.4 Medical History 
Medical history will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
version 24.0 and listed by System Organ Class (SOC), Preferred Term (PT), and verbatim term. 
Medical history will also be summarized by treatment group using frequencies and percentages 
according to the SOC and PT. 
3.5 Migraine History 
Migraine history, including the number of years experiencing migraine, average number of 
migraine attacks with moderate or severe pain and headache days for the 3 months prior to 
screening, average duration of in hours of untreated moderate/severe migraine attack, typical 
symptoms in migraines during screening (aura, nausea, photophobia, phonophobia, allodynia), 
triptan use, pain relief with triptan use, gepant use, and pain relief with gepant use will be 
summarized by treatment group and listed by treatment group and subject as well. The 
definitions of the derived variables can be found in Section 4.3. 
3.6 Headache Impact Test 
The Headache Impact Test will be scored and categorized according to the derivations in Section 
4.3. Descriptive statistics for the total score and frequency distributions for the total score and 
each question will be summarized by treatment group. 
3. 7 Treated Migraine Attack Baseline Symptoms 
Baseline summaries of key efficacy parameters and subgroups will be summarized using 
descriptive statistics or frequency distributions. These summaries include: the severity of the 
baseline migraine (mild, moderate, severe), allodynia status (yes, no), aura symptoms (yes, no), 
nausea (yes, no), photophobia (yes, no), phonophobia (yes, no), most bothersome symptom 
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(nausea, photophobia, phonophobia), Functional Impairment Scale (FIS) (none, mild, moderate, 
severe), subjects taking anti-CG RP Antibody at screening (yes, no), subjects taking preventative 
migraine medication at randomization (yes, no), subjects taking preventative migraine 
medication during screening (yes, no), subjects who woke with migraine (yes, no), subjects with 
menstrual related attacks (yes, no), onset of migraine attacks compared to study medication 
dosing (:530 minutes, >30 minutes - 1 hour,> 1 - 2 hours, >2 - 4, >4 hours). See Section 4.3 for 
derivations. 
3.8 Prior and Concomitant Medications and Therapies 
Concomitant medication usage will be summarized by the number and proportion of subjects in 
each treatment group. 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. The World Health Organization Drug Dictionary (WHO Drug) 
version B3 Mar 1, 2020, will be used to classify prior and concomitant medications by 
therapeutic class and generic name based on ATC code level 3. If preferred coding level is not 
available, the next lowest level will be used. Subjects will only be counted one time in each 
unique ATC Class and generic name if multiple drugs are used by a subject. Preventative 
migraine concomitant medications and acute migraine concomitant medications will also be 
summarized by treatment. Preventative migraine and acute migraine medications will be 
determined by the indication selected on the case report form (CRF). Concomitant procedures 
and non-drug therapies will be listed by treatment group and subject. 
4. EFFICACY 
All efficacy parameters, except the Patient Subjective Impression Questions, will be recorded in 
an e-diary by the subjects. The data recorded in the e-diary will not be altered. All data is 
summarized as recorded by the subject. Patient Subjective Impression Questions will be recorded 
on the case report form. 
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). 
Throughout this document, p-values refer to 2-sided nominal p-values. To simplify the 
presentation of results, the statistical tables will present only nominal 2-sided p-values and 
unadjusted confidence intervals (Cl). 
A study-wise Type I error of 0.05 will be used for the study. A multiplicity strategy (See Section 
4.5.1) will be taken into account when interpreting the nominal 2-sided p-values for the primary 
and key secondary endpoints. 
4.1 Primary Efficacy Estimands 
The primary efficacy objectives are to evaluate the efficacy of a single dose of 5.2 mg STS101 to 
achieve freedom from headache pain and most bothersome symptom at 2 hours after dosing. The 
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co-primary endpoints used to achieve this objective will be defined using composite estimands as 
follows: 
Freedom from headache pain at 2 hours 
• 
Population: Subjects in the m.ITT population who had moderate or severe headache pain 
at baseline. 
• 
Variable: Proportion of headache pain response 
• 
Intercurrent event: If a subject took rescue medication at any time within the first 2 hours 
of dosing, non-response will be assumed at 2 hours. If a subject has a missing response 
for any reason at the 2-hour timepoint, non-response will be assumed at 2 hours. 
• 
Population-level summary: Proportion of subjects achieving freedom from headache pain 
at 2 hours 
Freedom from MBS at 2 hours 
• 
Population: Subjects in them.ITT population who had a MBS at baseline. 
• 
Variable: Proportion ofMBS response 
• 
Intercurrent event: If a subject took rescue medication at any time within the first 2 hours 
of dosing, non-response will be assumed at 2 hours. If a subject has a missing response 
for any reason at the 2-hour timepoint, non-response will be assumed at 2 hours. 
• 
Population-level summary: Proportion of subjects achieving freedom from MBS at 2 
hours 
4.2 Key Secondary Efficacy Estimands 
The secondary efficacy objectives are listed in Section 1.1. The secondary endpoints used to 
achieve these objectives will be defined using composite estimands as follows: 
Achieving relief from headache pain at 2 hours 
• 
Population: Subjects in the m.ITT population who had moderate or severe headache pain 
at baseline. 
• 
Variable: Proportion of headache pain response 
• 
Intercurrent event: If a subject took rescue medication at any time within the first 2 hours 
of dosing, non-response will be assumed at 2 hours. If a subject has a missing response 
for any reason at the 2-hour timepoint, non-response will be assumed at 2 hours. 
• 
Population-level summary: Proportion of subjects achieving relief from headache pain at 
2 hours 
Relief from headache pain at 1 hour will follow the same estimand with the focus on the 1-hour 
timepoint. 
Rescue medication use within 24 hours 
• 
Population: Subjects in the m.ITT population. 
• 
Variable: Proportion of rescue medication use 
• 
Intercurrent event: If a subject has a missing response for any reason at the 24-hour 
timepoint, rescue medication use will be assumed at 24 hours. 
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• 
Population-level summary: Proportion of subjects using rescue medication within 24 
hours 
Rescue medication use within 48 hours will be defined using the same estimand above for rescue 
medication use within 24 hours but with the timepoint of interest being 48 hours post dose. 
Achieve normal function at 2 hours 
• 
Population: Subjects in the m.ITT population who had mild, moderate, or severe 
impairment in ability to function at baseline. 
• 
Variable: Proportion of ability to function (FIS) response 
• 
Intercurrent event: If a subject took rescue medication at any time within the first 2 hours 
of dosing, non-response will be assumed at 2 hours. If a subject has a missing response 
for any reason at the 2-hour timepoint, non-response will be assumed at 2 hours. 
• 
Population-level summary: Proportion of subjects achieving normal function at 2 hours 
Sustained freedom from headache pain for 2 to 24 hours 
• 
Population: Subjects in the m.ITT population who had moderate or severe headache pain 
at baseline. 
• 
Variable: Proportion of headache pain response 
• 
Intercurrent event: If a subject took rescue medication at any time within 24 hours of 
dosing, non-response will be assumed. If a subject has a missing response for any reason 
at the 24-hour timepoint, non-response will be assumed. If a subject is missing responses 
between 2 - 24 hours, exclusive, no imputation will be made. 
• 
Population-level summary: Proportion of subjects with freedom from headache pain at 2 
hours and sustained to 24 hours 
Sustained freedom from headache pain for 2 to 48 hours will follow the same estimand with the 
timepoint of interest at 48 hours. 
Sustained freedom from MBS for 2 to 24 hours 
• 
Population: Subjects in them.ITT population who had a MBS at baseline. 
• 
Variable: Proportion ofMBS response 
• 
Intercurrent event: If a subject took rescue medication at any time within 24 hours of 
dosing, non-response will be assumed. If a subject has a missing response for any reason 
at the 24-hour timepoint, non-response will be assumed. If a subject is missing responses 
between 2 - 24 hours, exclusive, no imputation will be made. 
• 
Population-level summary: Proportion of subjects with freedom from MBS at 2 hours and 
sustained to 24 hours 
Sustained freedom from MBS for 2 to 48 hours will follow the same estimand with the timepoint 
of interest at 48 hours. 
Free from photophobia at 2 hours 
• 
Population: Subjects in the m.ITT population who had photophobia at baseline. 
• 
Variable: Proportion of photophobia response 
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• 
Intercurrent event: If a subject took rescue medication at any time within the first 2 hours 
of dosing, non-response will be assumed at 2 hours. If a subject has a missing response 
for any reason at the 2-hour timepoint, non-response will be assumed at 2 hours. 
• 
Population-level summary: Proportion of subjects free from photophobia at 2 hours 
Free from phonophobia at 2 hours 
• 
Population: Subjects in the mITT population who had phonophobia at baseline. 
• 
Variable: Proportion of phonophobia response 
• 
Intercurrent event: If a subject took rescue medication at any time within the first 2 hours 
of dosing, non-response will be assumed at 2 hours. If a subject has a missing response 
for any reason at the 2-hour timepoint, non-response will be assumed at 2 hours. 
• 
Population-level summary: Proportion of subjects free from phonophobia at 2 hours 
Free from nausea at 2 hours 
• 
Population: Subjects in the mITT population who had nausea at baseline. 
• 
Variable: Proportion of nausea response 
• 
Intercurrent event: If a subject took rescue medication at any time within the first 2 hours 
of dosing, non-response will be assumed at 2 hours. If a subject has a missing response 
for any reason at the 2-hour timepoint, non-response will be assumed at 2 hours. 
• 
Population-level summary: Proportion of subjects free from nausea at 2 hours 
Headache relapse within 48 hours 
• 
Population: Subjects in the mITT population and free from headache pain at 2 hours. 
• 
Variable: Proportion of headache pain response 
• 
Intercurrent event: If a subject has a missing response at the 48-hour timepoint, relapse 
will be assumed. If a subject is missing responses between 2 - 48 hours, exclusive, no 
imputation will be made. No imputation will be made if the subject takes a rescue 
medication. 
• 
Population-level summary: Proportion of subjects with headache pain of any severity 
within 48 hours 
Sustained Normal Function for 2 to 24 hours 
• 
Population: Subjects in the mITT population who had mild, moderate, or severe 
impairment in ability to function at baseline. 
• 
Variable: Proportion of ability to function (FIS) response 
• 
Intercurrent event: If a subject took rescue medication at any time within 24 hours of 
dosing, non-response will be assumed. If a subject has a missing response for any reason 
at the 24-hour timepoint, non-response will be assumed. If a subject is missing responses 
between 2 - 24 hours, exclusive, no imputation will be made. 
• 
Population-level summary: Proportion of subjects achieving normal function at 2 hours 
and sustained to 24 hours 
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Other key secondary endpoints that are variations of the estimands already presented are: 
• 
Freedom from headache pain at 3-24 hours post dose 
o Follows the freedom from headache pain at 2 hours post dose estimand for each 
timepoint 
• 
Freedom from headache pain at 2 hours post dose in subjects with allodynia at baseline 
o Follows the freedom from headache pain at 2 hours post dose estimand with the 
exception of the population, which is the subjects in mITT population who had 
allodynia at baseline 
• 
Freedom from MBS at 2 hours post dose in subjects with allodynia at baseline 
o Follows the freedom from headache pain at 2 hours post dose estimand with the 
exception of the population, which is the subjects in mITT population who had 
allodynia at baseline 
• 
Freedom from headache pain at 2 hours post dose in subjects with severe headache at 
baseline 
o Follows the freedom from headache pain at 2 hours post dose estimand with the 
exception of the population, which is the subjects in mITT population who had 
severe pain severity at baseline 
• 
Freedom from MBs at 2 hours post dose in subjects with severe headache at baseline 
o Follows the freedom from MBS at 2 hours post dose estimand with the exception 
of the population, which is the subjects in mITT population who had a baseline 
MBS and had severe pain severity at baseline. 
4.3 Definitions and Derived Variables 
• 
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. The efficacy parameters ( all collected in the e-diary) are measured just prior to 
study dosing (considered time 0) in the migraine report of thee-diary. These values are 
considered the baseline values for efficacy. 
• 
Body mass index (BMI) will be derived from the recorded height and weight at the 
screening visit. 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. 
• 
The number of subjects with < 15 headache days per month for 3 months prior to 
screening will be derived by averaging the number of headache days over months 1-3 
from the Migraine History CRF and dichotomizing the averages into Yes if the average is 
<15 and No if the average is >=15. 
• 
The number of migraine attacks with moderate or severe pain for 3 months prior to 
screening will be derived by averaging over months 1-3, the number of migraine attacks 
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with moderate/severe pain prior to screening from the Migraine History CRF and 
dichotomizing the averages into Yes if the average is between 2-8 inclusive and No if the 
average does not fall in this range. 
• 
Allodynia status is defined as present if a subject has at least 2 'yes' responses to the 6-
question allodynia questionnaire [Ashkenazi 2007; Tepper, 2011]). 
• 
The 4-point headache pain severity scale is as follows: 0=None, 1 =Mild, 2=Moderate, 
and 3=Severe. Free from headache pain is defined as moderate or severe [ 2 or 3] 
headache pain at baseline [time 0] becoming none [0]. 
• 
Freedom from headache pain is defined as headache pain identified at baseline [time 0] 
being absent, or severity is none [0]. 
• 
Freedom from most bothersome symptom is defined as the MBS identified at baseline 
[time 0] being absent. 
• 
Sustained pain freedom or remaining headache free up to a time point (e.g,. 24, or 48 
hours) after investigational drug administration is defined as a score of 0 from the 2 hours 
post dose timepoint to the timepoint, e.g. 24 hours, with no use of rescue medication. The 
2 and 24 or 48 hour post dose timepoints score must be 0 and the scores in between 2 and 
24 or 48 hours must be 0 or missing. 
• 
Sustained freedom from MBS or remaining free up to a time point (e.g,. 24, or 48 hours) 
after investigational drug administration is defined as the absence of the MBS at baseline 
(time 0) from the 2 hours post dose timepoint to the timepoint, e.g. 24 hours, with no use 
of rescue medication. The 2 and 24 or 48 hour post dose timepoints response must be 
absent and the responses between 2 and 24 or 48 hours must be absent or missing. 
• 
Headache relapse is defined as the return of headache of any severity within the specified 
hours of the endpoint after administration of the investigational drug, when the patient 
was pain-free at 2 hours after investigational drug administration. 
• 
Proportion of subjects who achieve normal function is defined as a rating of '0' on the 
FIS. For the sustaining normal function for 2-24 hour and 2-48 hour endpoints, the 
subjects must have a rating of '0' at the 2 and 24/48 hour time points and no non-zero 
responses in between the time interval (i.e., the responses in between the time interval 
can be missing). 
• 
Relief from headache pain is defined as a reduction in headache pain from moderate or 
severe [2 or 3] to mild or none [1 or 0]. 
• 
Free from photophobia is defined as photophobia being absent post dose if present at 
baseline (time 0). 
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• 
Free from phonophobia is defined as phonophobia being absent post dose if present at 
baseline (time 0). 
• 
Free from nausea is defined as nausea being absent post dose if present at baseline (time 
0). 
• 
Rescue medication is defined as any medication taken to treat migraine headaches after 
dosing. This will be derived from the electronic diary. Rescue medication use within 24 
hours is defined as follows: a) the 24-hour response is missing, b) the 24-hour response is 
Yes, or c) any non-missing time points prior to 24 hours are Yes. No rescue medication 
use within 24 hours is defined as the 24-hour response is No and all non-missing time 
points prior to 24 hours are No. Rescue medication use within 48 hours is defined 
similarly. 
• 
The definition of migraine headache during their menstruation period is taken from the 
Drug Accountability case report form in which the menstruation information was also 
collected. If the subject treated a migraine within 1 (+/- 2) days of menstruation, then the 
subject will be considered as having a menstruation related acute migraine attack. 
• 
Prior or current triptan use and inadequate response to triptan medication will be derived 
from the Migraine History CRF where the response to pain relief with triptan use is 
reported as <=75% of the time. 
• 
Prior or current gepant use and inadequate response to gepant medications will be derived 
from the Migraine History CRF where the response to pain relief with gepant use is 
reported as <=75% of the time. 
• 
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). 
• 
Number of years experiencing a migraine will be defined as the date of informed consent 
minus the date of migraine onset plus 1. 
• 
Preventative migraine medication taken at screening is recorded in the Concomitant 
Medication CRF ("Migraine Prevention" checked as indication for concomitant 
medication use) and on the Randomization CRF (use of migraine prevention medication 
as stratification factor). The response on the Randomization CRF will be summarized 
along with the actual responses as provided in the Concomitant Medication CRF. All 
analyses of efficacy and tolerability and summaries by preventative migraine medication 
use will use the actual responses from the Concomitant Medication CRF. 
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• 
Subjects taking anti-CGRP antibody at screening will be derived from the concomitant 
medications using a list of searchable preferred terms. If the end date of the medication is 
greater than the informed consent date or reported as ongoing/missing and the start date is 
less than or equal to the first dose date, then the medication will be included. 
• 
Onset of migraine attacks is broken into 4 categories: ::S30 minutes, >30 minutes- I hour, 
> 1 - 2 hours, >2 - 4, and >4 hours as compared to time of dosing with study medication. 
• 
Time to event derivations will compare the first time of the event (i.e., freedom from 
headache pain) to the time of dosing in hours. Data will be censored at 48 hours for 
freedom from headache pain, freedom from MBS, and pain relief if the subject did not 
have an event or if the subject took rescue medication. Rescue medication use will be 
censored at the last available non-missing time in hours. 
• 
Subjects who woke up with migraine headaches will be defined as migraines that have a 
recorded onset time between midnight and 7:00am. 
• 
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 baseline HIT-6 overall score will be categorized into the following categories: 
Severe Impact, defined 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. 
• 
A responder on the Patient Global Impression Rating is defined as a good or very good 
response. 
• 
Proportion of subjects who sustained pain relief for 2-24 hour and 2-48 hour is defined as 
the subjects must have pain relief (as defined previously) at 2 hours and a rating of '0' or 
'1' at the 24/48 hour time points and no responses of '2' or '3' in between the time 
interval (i.e., the responses in between the time interval can be missing) and no rescue 
medication use during the time period of interest. 
• 
Non-response is defined as the unwanted response for a variable. For all endpoints except 
rescue medication use, it will be an imputed value of No or 0. For rescue medication use, 
the value will be Yes or 1. 
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4.4 Efficacy Variables 
Primary Efficacy Endpoints: 
Page 20 
• 
Proportion of subjects free from headache pain at 2 hours after dosing (defined as 
moderate or severe headache pain [2 or 3 on a 4-point scale] at baseline [time 0] 
becoming none [0] on a 4-point scale) 
Proportion of subjects free from most bothersome symptom among photophobia, 
phonophobia and nausea at 2 hours after dosing (defined as the MBS identified at 
baseline [time 0] being absent) 
Key Secondary Efficacy Endpoints: 
The key secondary efficacy parameters are listed below, but not in the statistical testing 
hierarchy that will be tested with the fixed-sequence method in order to protect the study-wise 
Type error under 0.05 (see Section 4.5.1 for the statistical testing hierarchy). 
• 
Proportion of subjects who use rescue medication within 24 hours after dosing 
• 
Proportion of subjects free from photophobia at 2 hours after dosing 
• 
Proportion of subjects with relief from headache pain at 1 hour after dosing 
• 
Proportion of subjects free from headache pain at 3, 4, 6, 12, and 24 hour time points 
after dosing 
• 
Proportion of subjects who use rescue medication within 48 hours after dosing 
• 
Proportion of subjects who achieve normal function at 2 hours after dosing 
• 
Proportion of subjects free from headache pain at 2 hours after dosing and remaining 
headache free at 24 hours after dosing with no use of rescue medication and no relapse of 
any headache pain ( defined as 2-24 hour sustained pain free) 
• 
Proportion of subjects free from headache pain at 2 hours after dosing and remaining 
headache free at 48 hours after dosing with no use of rescue medication and no relapse of 
any headache pain ( defined as 2-48 hour sustained pain free) 
• 
Proportion of subjects free from most bothersome symptom at 2 hours after dosing and 
remaining MBS free at 24 hours after dosing with no use of rescue medication and no 
relapse of any MBS (defined as 2-24 hour sustained MBS free) 
• 
Proportion of subjects free from most bothersome symptom at 2 hours after dosing and 
remaining MBS free at 48 hours after dosing with no use of rescue medication and no 
relapse of any MBS (defined as 2-48 hour sustained MBS free) 
• 
Proportion of subjects with headache relapse within 48 hours after dosing 
• 
Proportion of subjects free from phonophobia at 2 hours after dosing 
• 
Proportion of subjects free from nausea at 2 hours after dosing 
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• 
Proportion of subjects with Sustained Normal Function based on FIS from 2 to 24 hours 
• 
Proportion of subjects with baseline allodynia and free from headache pain at 2 hours 
post dose 
• 
Proportion of subjects with baseline allodynia and free from MBS at 2 hours post dose 
• 
Proportion of subjects with severe headache severity at baseline and free from headache 
pain at 2 hours post dose 
• 
Proportion of subjects with severe headache severity at baseline and free from MBS at 2 
hours post dose 
Additional Secondary Efficacy Endpoints: 
The secondary efficacy parameters will be analyzed but no formal hypotheses testing will be 
performed. 
• 
Proportion of subjects with freedom from headache pain at 15, 30, 45 minutes, 1, 1.5, and 
48 hours after dosing 
• 
Proportion of subjects with freedom from MBS at 15, 30, 45 minutes, 1, 1.5, 3, 4, 6, 12, 
24, and 48 hours after dosing 
• 
Proportion of subjects who achieve relief from headache pain at 15, 30, 45 minutes, 1.5, 
3, 4, 6, 12, 24, and 48 hours after dosing 
• 
Proportion of subjects who achieve normal function at 1, 4, 24, and 48 hours after dosing 
• 
Proportion of subjects with freedom from photophobia at 15, 30, 45 minutes, 1, 1.5, 3, 4, 
6, 12, 24, and 48 hours after dosing 
• 
Proportion of subjects with freedom from phonophobia at 15, 30, 45 minutes, 1, 1.5, 3, 4, 
6, 12, 24, and 48 hours after dosing 
• 
Proportion of subjects with freedom from nausea at 15, 30, 45 minutes, 1, 1.5, 3, 4, 6, 12, 
24, and 48 hours after dosing 
• 
Proportion of subjects with headache pain relapse within 24 hours after dosing 
• 
Shift from baseline in FIS response 
• 
Time to achieving headache relief 
• 
Time to freedom from headache pain 
• 
Time to freedom from MBS 
• 
Time to rescue medication use 
• 
Frequency of Rescue Medications 
• 
Frequency of Patient Global Impression (very good, good, no opinion, poor, very poor) 
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• 
Patient global response (very good/good) 
Page 22 
• 
Frequency of Ease of Use Impression (very easy, easy, no opinion, not easy, not easy at 
all) 
• 
Comparison of Study Medication with Previously Used Migraine Medication: 
o Frequency of Return to Normal Faster (strongly agree, agree, neutral, disagree, 
strongly disagree) 
o Frequency of Consistently Treats Migraine (strongly agree, agree, neutral, 
disagree, strongly disagree) 
o Frequency of Works Faster (strongly agree, agree, neutral, disagree, strongly 
disagree) 
o Frequency of Keeps Migraine from Coming Back (strongly agree, agree, neutral, 
disagree, strongly disagree) 
• 
Time to onset of freedom from headache pain as established by testing for statistical 
differences in descending order from 2 hours to 15 minutes 
Exploratory Efficacy Endpoints: 
The following exploratory endpoints will be analyzed if there are adequate number of subjects in 
the sub-population of interest. 
• 
Proportion of subjects free from headache pain at various timepoints after dosing by 
allodynia status at baseline 
• 
Proportion of subjects free from MBS at various timepoints after dosing by allodynia 
status at baseline 
• 
Proportion of subjects with relief from headache pain at 2 hours after dosing by allodynia 
status at baseline 
• 
Proportion of subjects with relief from headache pain at various timepoints after dosing 
by allodynia status at baseline 
• 
Proportion of subjects free from both, headache pain and most bothersome symptom at 2 
hours after dosing 
• 
Proportion of subjects free from both, headache pain and most bothersome symptom at 
various time points after dosing 
• 
Proportion of subjects free from headache pain at 2 hours after dosing in subjects who 
wake up with migraine headache 
• 
Proportion of subjects free from most bothersome symptom at 2 hours after dosing in 
subjects who wake up with migraine headache 
• 
Proportion of subjects free from headache pain at various timepoints after dosing in 
subjects who wake up with migraine headache 
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Page 23 
• 
Proportion of subjects free from most bothersome symptom at various timepoints after 
dosing in subjects who wake up with migraine headache 
• 
Proportion of subjects with relief from headache pain at 2 hours after dosing in subjects 
who wake up with migraine headache 
• 
Proportion of subjects with relief from headache pain at various timepoints after dosing 
in subjects who wake up with migraine headache 
• 
Proportion of subjects free from headache pain at 2 hours after dosing by baseline HIT-6 
score (severe, substantial, some, little/no impact) 
• 
Proportion of subjects free from MBS at 2 hours after dosing by baseline HIT-6 score 
(severe, substantial, some, little/no impact) 
• 
Proportion of subjects free from headache pain at 2 hours after dosing in subjects with 
menstrual related migraine attack 
• 
Proportion of subjects free from most bothersome symptom at 2 hours after dosing in 
subjects with menstrual related migraine attack 
• 
Proportion of subjects free from headache pain at various timepoints after dosing in 
subjects with menstrual related migraine attack 
• 
Proportion of subjects free from most bothersome symptom at various timepoints after 
dosing in subjects with menstrual related migraine attack 
• 
Proportion of subjects with relief from headache pain at 2 hours after dosing in subjects 
with menstrual related migraine attack 
• 
Proportion of subjects with relief from headache pain at various timepoints after dosing 
in subjects with menstrual related migraine attack 
• 
24-hour Migraine Quality of Life Questionnaire total and domain scores (migraine 
symptoms, work functioning, social functioning, energy/vitality, feelings/concerns) 
• 
Proportion of subjects free from headache pain at 2 hours post dose in subjects 
with/without aura symptoms 
• 
Proportion of subjects free from MBS at 2 hours post dose in subjects with/without aura 
symptoms 
• 
Proportion of subjects free from headache pain at 2 hours post dose for subjects who 
were taking a preventive migraine medication at Screening 
• 
Proportion of subjects free from MBS at 2 hours post dose for subjects who were taking a 
preventive migraine medication at Screening 
• 
Proportion of subjects with relief from headache pain at 2 hours post dose for subjects 
who were taking a preventive migraine medication at Screening 
• 
Proportion of subjects free from headache pain at 2 hours post dose for subjects who 
were taking an anti-CGRP antibody at Screening 
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• 
Proportion of subjects free from MBS at 2 hours post dose for subjects who were taking 
an anti-CGRP antibody at Screening 
• 
Proportion of subjects with relief from headache pain at 2 hours post dose for subjects 
who were taking an anti-CGRP antibody at Screening 
• 
Proportion of subjects free from headache pain at 2 hours post dose for subjects who had 
inadequate response to triptan medication(s) before Screening; inadequate response is 
defined as having pain relief for less than or equal to 75% of the time. 
• 
Proportion of subjects free from MBS at 2 hours post dose for subjects who had 
inadequate response to triptan medication(s) before Screening; inadequate response is 
defined as having pain relief for less than or equal to 75% of the time. 
• 
Proportion of subjects with relief from headache pain at 2 hours post dose for subjects 
who had inadequate response to triptan medication(s) before Screening; inadequate 
response is defined as having pain relief for less than or equal to 75% of the time. 
• 
Proportion of subjects free from headache pain at 2 hours post dose for subjects who had 
inadequate response to gepant medication(s) before Screening; inadequate response is 
defined as having pain relief for less than or equal to 75% of the time. 
• 
Proportion of subjects free from MBS at 2 hours post dose for subjects who had 
inadequate response to gepant medication(s) before Screening; inadequate response is 
defined as having pain relief for less than or equal to 75% of the time. 
• 
Proportion of subjects with relief from headache pain at 2 hours post dose for subjects 
who had inadequate response to gepant medication(s) before Screening; inadequate 
response is defined as having pain relief for less than or equal to 75% of the time. 
• 
Association between total score and individual domain scores of 24-hour Migraine 
Quality of Life Questionnaire at 24 hours post dose and 
o Freedom from pain at 2 hours post dose 
o Freedom from pain at 24 hours post dose 
o Freedom from MBS at 2 hours post dose 
o Freedom from MBS at 24 hours post dose 
o Relief from pain at 2 hours post dose 
o Relief from pain at 24 hours post dose 
• 
Proportion of subjects free from headache pain at 2 hours post dose in subjects by 
baseline headache severity 
• 
Proportion of subjects free from MBS at 2 hours post dose in subjects by baseline 
headache severity 
• 
Proportion of subjects free from headache pain at 2 hours post dose in subjects by 
migraine onset category 
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• 
Proportion of subjects free from MBS at 2 hours post dose in subjects by migraine onset 
category 
• 
Proportion of subjects free from headache pain by subgroups defined in Section 4.5.7 
• 
Proportion of subjects free from MBS by subgroups defined in Section 4.5.7 
• 
Proportion of subjects who achieve relief from headache pain by subgroups defined in 
Section 4.5.7 
4.5 Efficacy Analysis Methods 
4.5.1 Multiplicity Strategy 
A fixed-sequence method will be employed to control for the study-wise Type I error rate at 
alpha=0.05. The fixed-sequence method will test each endpoint at an alpha of 0.05 in the 
hierarchal order described below. The method is as follows: 
If the first hypothesis test is significant at the 0.05 significance level (i.e. p-value < 0.05), the 
next hypothesis will be tested at the same 0.05 level. This process will continue according to the 
hierarchy defined below. The testing will stop when the p-value of the test is greater than or 
equal to 0.05. At that point, further hypotheses testing will be considered exploratory and the 
Type I error is not controlled under the study-wise 0.05 significance level. 
The hierarchy for testing the primary and secondary efficacy endpoints on the primary analysis 
population (mITT population) is below. 
1. (Pl) 5.2 mg dose vs. Placebo in the proportion of subjects free from headache pain at 2 
hours post dose 
2. (P2) 5.2 mg dose vs. Placebo in the proportion of subjects free from MBS at 2 hours post 
dose 
3. (S1) 5.2 mg dose vs. Placebo in the proportion of subjects with relief from headache pain 
at 2 hours post dose 
4. (S2) 5.2 mg dose vs. Placebo in the proportion of subjects who achieve normal function 
at 2 hours after dosing 
5. (S3) 5.2 mg dose vs. Placebo in the proportion of subjects who use rescue medication 
within 24 hours post dose 
6. (S4) 5.2 mg dose vs. Placebo in the proportion of subjects free from photophobia at 2 
hours post dose 
7. (S5) 5.2 mg dose vs. Placebo in the proportion of subjects free from headache pain at 3 
hours post dose 
8. (S6) 5.2 mg dose vs. Placebo in the proportion of subjects free from headache pain at 4 
hours post dose 
9. (S7) 5.2 mg dose vs. Placebo in the proportion of subjects free from headache pain at 6 
hours post dose 
10. (S8) 5.2 mg dose vs. Placebo in the proportion of subjects free from headache pain at 12 
hours post dose 
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11. (S9) 5.2 mg dose vs. Placebo in the proportion of subjects free from headache pain at 24 
hours post dose 
12. (S10) 5.2 mg dose vs. Placebo in the proportion of subjects free from phonophobia at 2 
hours post dose 
13. (S11) 5.2 mg dose vs. Placebo in the proportion of subjects free from MBS at 2 hours 
after dosing and remaining MBS free at 24 hours after dosing with no use of rescue 
medication and no relapse of any MBS 
14. (S12) 5.2 mg dose vs. Placebo in the proportion of subjects free from headache pain at 2 
hours post dose and remaining headache free for 24 hours post dose with no use of rescue 
medication and no relapse of any headache pain 
15. (S13) 5.2 mg dose vs. Placebo in the proportion of subjects achieving pain relief at 1 
hour post dose 
16. (S14) 5.2 mg dose vs. Placebo in the proportion of subjects free from MBS at 2 hours 
after dosing and remaining MBS free at 48 hours after dosing with no use of rescue 
medication and no relapse of any MBS 
17. (S15) 5.2 mg dose vs. Placebo in the proportion of subjects free from headache pain at 2 
hours post dose and remaining headache free for 48 hours post dose with no use of rescue 
medication and no relapse of any headache pain 
18. (S16) 5.2 mg dose vs. Placebo in the proportion of subjects free from nausea at 2 hours 
post dose 
19. (S17) 5.2 mg dose vs. Placebo in the proportion of subjects who use rescue medication 
within 48 hours after dosing 
20. (S18) 5.2 mg dose vs Placebo in the proportion of subjects with Sustained Normal 
Functioning (on FIS) from 2 to 24 hours 
21. (S19) 5.2 mg dose vs. Placebo in the proportion of subjects free from headache pain at 2 
hours post dose in attacks with allodynia at baseline 
22. (S20) 5.2 mg dose vs. Placebo in the proportion of subjects free from MBS at 2 hours 
post dose in attacks with allodynia at baseline 
23. (S21) 5.2 mg dose vs. Placebo in the proportion of subjects free from headache pain at 2 
hours post dose in attacks with severe headache at baseline 
24. (S22) 5.2 mg dose vs. Placebo in the proportion of subjects free from MBS at 2 hours 
post dose in attacks with severe headache at baseline 
25. (S23) 5.2 mg dose vs. Placebo in the proportion of subjects with headache relapse within 
48 hours after dosing 
Statistical testing may be performed for other secondary and exploratory endpoints without 
adjustment of multiplicity. The consistency of the testing results will aid in the evaluation of the 
overall treatment benefit of STS101. 
4.5.2 Primary Endpoint Analysis Methods 
For the primary analysis of the co-primary endpoints, missing data will be imputed based on a 
single-imputation method. Subjects who do not have evaluable assessments at the 2-hour time 
point, or who received rescue medications prior to the 2-hour time point will be considered as 
non-responders. Although this is a single-imputation method, the approach is conservative and 
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does not impute a favorable outcome (i.e., pain-free or MBS-free status) for subjects with 
missing data. 
The hypothesis test for the primary analysis is: 
where Pt is the proportion ofresponse for STSlOl, and Pp is the proportion ofresponse for 
placebo. 
A Chi-square test will be used to compare 5.2 mg STSlOl to placebo using the multiplicity 
strategy described in Section 4.5.1. The number needed to treat (defined as the inverse of the 
treatment difference) will also be included in the table. 
4.5.3 Key Secondary Endpoint Analysis Methods 
The key secondary parameters are listed in Section 4.4. Missing data on the composite estimands 
will be imputed based on a single-imputation method in the same manner described for the 
primary endpoints. 
The hypothesis test for the key secondary analyses is the same as the primary analyses. 
A Chi-square test will be used to compare 5.2 mg STSlOl to placebo using the multiplicity 
strategy described in Section 4.5.1. 
4.5.4 Additional Secondary Endpoint Analysis Methods 
The secondary efficacy endpoints (see Section 4.4) will be analyzed in the same manner as the 
estimands described for the primary/key secondary endpoints. No adjustment for multiplicity 
will be made on these analyses. 
Missing data will not be imputed, unless noted otherwise in the definitions of the parameters. 
Endpoints that use observed data are the patient global response, frequency of rescue 
medications, patient global impression, ease of use, and comparison of study medication with 
previously used migraine medication ratings. 
Time to event analyses will be performed for the following: 
• 
Time to freedom from headache pain 
• 
Time to freedom from MBS 
• 
Time to achieving relief from headache pain 
• 
Time to rescue medication use 
Time to freedom from headache pain, MBS, and relief from headache pain will be censored at 48 
hours if a subject uses rescue medication. If a subject does not have an event and does not use 
rescue medication, the subject will be censored at the last non-missing timepoint in the diary. 
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Time to rescue medication use will be censored at the last timepoint with a non-missing 
response. A log rank test (Kaplan-Meier method) will be used to compare treatment differences. 
A separate analysis will also be conducted on time to achieving relief from headache pain 
between O to 2 hours. If a subject uses rescue medication during the 2 hours, the subject will be 
censored at 2 hours. If a subject has not had relief from headache pain at 2 hours, the subject will 
be censored at the last non-missing timepoint with a maximum of2 hours. A Kaplan-Meier curve 
will be produced for this analysis. 
The Patient Impression Rating endpoints (patient global impression, ease of use, comparison of 
study medication with previously used migraine medication) will be analyzed using the Mantel-
Haenszel test. A Chi-square test will be used to analyze all other endpoints. 
Rescue medications taken during the study will be summarized by treatment using frequencies 
and percentages. A rescue medication will be counted once at most per subject in the summary. 
To fully describe the treatment benefit of STSlOl, the proportion of subjects who achieve 
freedom from headache pain, freedom from MBS, and relief from headache pain at various 
timepoints after dosing will be displayed graphically to show the time course of effect. 
To address the onset of efficacy, the Freedom from Headache Pain by Timepoint estimand will 
be used. The proportion of subjects achieving freedom from headache pain will be examined 
from the 2-hour time point towards the baseline in a sequential manner (i.e. 2 hours, 1.5 hours, 1 
hour, 45 minutes, 30 minutes, 15 minutes). A significance level of 0.05 will be used for this 
analysis. If the treatment comparison between STSlOl and placebo is significant at 0.05 level at 
2 hours, the significance at 1.5 hours will be examined next. If the comparison is significant at 
1.5 hours, then 1-hour timepoint will be examined next. The process will continue until the 
timepoint for which the significance level exceeds 0.05. The last timepoint for which the 
significant level is less than 0.05 is considered the timepoint of onset of efficacy. 
Additionally, all secondary endpoints, including the primary and key secondary endpoints, will 
be analyzed using the mITT, PP, and ITT populations. 
4.5.5 Exploratory Endpoint Analysis Methods 
Exploratory endpoints are listed in Section 4.4. Endpoints that are derived in the primary or 
secondary key endpoints will follow the estimands for handling of intercurrent events. Missing 
data for these endpoints will be imputed based on a single-imputation method in the same 
manner described for the analysis on the primary endpoints, unless noted otherwise in the 
definitions of the parameters. Endpoints that use observed data are the 24-hour Migraine Quality 
of Life scores. 
An analysis of variance (ANOVA) model with treatment as a factor will be used to test compare 
treatment differences for the 24-hour Migraine Quality of Life endpoints. The LS mean 
difference and 95% confidence interval will be presented in the table. A Chi-square test will be 
used to analyze the freedom from headache pain and MBS endpoints, and a Cochran-Mantel-
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Haenszel test will be used to compare treatment differences for all other endpoints stratified by a 
baseline variable. No adjustment for multiplicity will be made on these analyses. 
All exploratory endpoints will be analyzed using them.ITT, PP, and ITT populations. 
4.5.6 Sensitivity Analyses 
Sensitivity analyses using additional single-imputation (SI), multiple-imputation (Ml) with the 
tipping-point (TP) method, a worst-case scenario, and observed case analysis are planned. 
Another sensitivity analysis that will be conducted on the primary endpoints is the removal of 
subjects with a malfunction in their e-Diary. A description of the issue is below: 
Due to a core software defect the 2-hour ATD was unable to be completed by some subjects. 
Data interruptions occurred for these subjects when a transmission and an alarm/notification fire 
occurred at the exact same time, causing the device to timeout and not save the form at 
completion. 
The transmission/alarm amalgam issue was not caught in core testing as protocol STSl0l-007 
utilizes custom alarm functions which alter the state and break of transmissions. 
These subjects will be identified prior to database lock. All sensitivity analyses will be on the 
m.ITT population. 
Depending on the extent of missing data, additional sensitivity analysis with other pattern-
mixture model analyses may be considered. The inclusion of additional sensitivity analyses will 
be determined after the examination of the nature and the extent of missing data and before the 
unblinding of the study. Any additional analyses will be included in an addendum to the SAP. 
4.5.6.1 Additional Single-Imputation Method 
The additional SI method will be performed on the following endpoints: 
• 
Freedom from headache pain at 2 hours 
• 
Freedom from MBS at 2 hours 
• 
Relief from headache pain at 2 hours 
• 
Achieving normal function at 2 hours 
• 
Freedom from photophobia at 2 hours 
• 
Freedom from phonophobia at 2 hours 
• 
Freedom from nausea at 2 hours 
The estimands defined for each endpoint will be the same except for the Intercurrent event 
attribute. Intercurrent events will be handled as such: 
• 
Intercurrent event: If a subject took rescue medication at any time within the first 2 hours 
of dosing, non-response will be assumed at 2 hours or the timepoint of interest. If a 
subject is missing the 2-hour timepoint for any reason, the last observed variable (from 
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the estimand) value prior to the 2-hour timepoint will be carried forward to the 2-hour 
timepoint (LOCF). 
4.5.6.2 Multiple Imputation Method 
Multiple imputation will be performed on the co-primary endpoints: 
• 
Freedom from headache pain at 2 hours 
• 
Freedom from MBS at 2 hours 
Rubin's (1987) MI procedure will also be conducted to assess the impact of missing values in the 
co-primary endpoints. Instead of filling in a single value for each missing value, Rubin's 
procedure replaces each missing value with a set of plausible values that represent the 
uncertainty about the right value to impute. 
Two MI methods are planned: 
Markov chain Monte Carlo (MCMC) method (Schafer 1997): 
For non-monotone missing data patterns, MCMC assumes multivariate normality and generates 
multiple imputations using simulations from a Bayesian prediction distribution for normal data. 
Regression method: 
For monotone missing data patterns, a logistic regression model is fitted for each variable with 
missing values. Based on the resulting model, a new logistic regression model is used to impute 
subsequent missing values for the variable. Since the data set has a monotone missing data 
pattern, the process is repeated sequentially for variables with missing values. 
Based on these two MI methods, the missing data will be imputed using the following 
approaches. 
Step 1: non-monotone missing data will be imputed using the MCMC method by treatment 
group (or if necessary, use treatment group as a factor). 
Step 2: monotone missing data will be imputed using the regression method on the basis of the 
predicted future pattern. 
One hundred (100) imputed datasets will be generated for each MI analysis. If the MCMC 
method is needed to achieve monotone missing data for Step 2, then this imputation will generate 
100 imputed datasets and the regression method will be performed on each imputed dataset. The 
imputed values will range between O and 1. Imputed values greater than or equal to 0.5 will be 
categorized as a responder (1), and imputed values less than 0.5 will be categorized as a non-
responder (0). Each imputed dataset will be analyzed separately using PROC GENMOD with a 
binomial distribution and logit link, treatment as a factor and response at the 2 hour-timepoint as 
the dependent variable. The final estimate of the treatment difference will be the average of the 
estimates based on the 100 individual imputed datasets. The pooling of the individual estimates 
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and inferences based on the combined estimate will be handled by SAS procedure 
MIANALYZE. 
Page 31 
In addition to the above multiple imputation procedure, a tipping-point analysis will also be 
conducted where statistical significance occurs in the main analyses. A shift parameter, 
representing an adjustment of the effect size in the active treatment group, will be applied in the 
imputation of missing data. This shift parameter will be gradually increased towards the direction 
of reduced effect size, which imputes unfavorable outcomes for the missing data in the active 
treatment group. The shift parameter which results in a reversal of study conclusion (i.e. tipping 
point) will be identified and presented on the table. The plausibility of the shift parameter will 
inform the robustness of the study conclusion and the impact of the missing values. 
The estimands defined for each co-primary endpoint will be the same except for the Intercurrent 
event attribute. Intercurrent events will be handled as such: 
• 
Intercurrent event: If a subject took rescue medication at any time within the first 2 hours 
of dosing, non-response will be assumed at 2 hours or the timepoint of interest. If a 
subject is missing the 2-hour timepoint for any reason, the variable (from the estimand) 
values from the 15, 30, and 45 minutes, and 1, 1.5, 2 hour timepoints will be used in 
estimated missing data via the multiple imputation methods described above. 
4.5.6.3 Worst Case Scenario 
The worst case scenario will be performed on the following endpoints: 
• 
Freedom from headache pain at 2 hours 
• 
Freedom from MBS at 2 hours 
• 
Relief from headache pain at 2 hours 
• 
Achieving normal function at 2 hours 
• 
Freedom from photophobia at 2 hours 
• 
Freedom from phonophobia at 2 hours 
• 
Freedom from nausea at 2 hours 
The estimands defined for each endpoint will be the same except for the Intercurrent event 
attribute. Intercurrent events will be handled as such: 
Intercurrent event: If a subject took rescue medication at any time within the first 2 hours of 
dosing, non-response will be assumed at 2 hours or the timepoint of interest. If a subject is 
missing the 2-hour timepoint for any reason and the randomized treatment is STS101, the 2-hour 
timepoint will be imputed as non-response. If a subject has missing data at 2 hours and the 
randomized treatment is Placebo, the 2-hour timepoint will be imputed as a responder. 
4.5.6.4 Observed Case Analysis 
The observed case analysis will be performed on the following endpoints: 
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• 
Freedom from headache pain at 2 hours 
• 
Freedom from MBS at 2 hours 
• 
Relief from headache pain at 2 hours 
• 
Achieving normal function at 2 hours 
• 
Freedom from photophobia at 2 hours 
• 
Freedom from phonophobia at 2 hours 
• 
Freedom from nausea at 2 hours 
The estimands defined for each endpoint will be the same except for the Population and 
Intercurrent event attribute. Intercurrent events will be handled as such: 
Page 32 
Population: Subjects in the mITT population who have a non-missing response at 2 hours. 
Intercurrent event: If a subject took rescue medication at any time within the first 2 hours of 
dosing, non-response will be assumed at 2 hours. If a subject is missing the 2-hour timepoint for 
any reason, no imputation will be made. The observed data at the 2-hour timepoint will be used. 
Therefore, if a subject is missing data at the 2-hour timepoint, the subject will be excluded from 
the analysis. 
4.5.6.5 Primary Analysis with Subject Exclusion Due to e-Diary Software Defect 
The primary analysis with subject exclusion due to a software defect in thee-Diary will be 
performed on the co-primary endpoints: 
• 
Freedom from headache pain at 2 hours 
• 
Freedom from MBS at 2 hours 
The estimands defined for each endpoint will be the same except for the population: 
Population: Subjects in the mITT population who have a non-missing response at 2 hours and 
did not have a software defect in thee-Diary. 
4.5. 7 Subgroup Analyses 
Subgroup analyses of the freedom from headache pain at 2 hours, freedom from MBS at 2 hours, 
and relief from headache pain at 2 hours will be conducted to gain insight of the nature and 
consistency of the treatment effect. Subgroups prospectively identified include: 
1. age group (18-35 years, >35-50 years, >50-65 years) 
2. gender (male, female) 
3. race (white, other) 
4. baseline severity of attack (time 0) (moderate, severe) 
5. allodynia status (yes, no) 
6. menstrual related migraine attacks (yes, no) 
7. in subjects who wake up with migraine headache (yes, no) 
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8. baseline (Visit 2) HIT-6 score (severe impact, substantial impact, some impact, little/no 
impact) 
9. ethnicity (Hispanic, Not Hispanic) 
10. baseline weight ( <=median, >median) 
Among these subgroup analyses, several are also included in the secondary or exploratory 
endpoints; therefore, only those subgroups not already summarized will be tabulated. 
Because of the smaller sample sizes for each subgroup, the objective of the analysis is to 
evaluate the consistency of efficacy results across these factors. Statistical tests will be 
performed. However, the interpretation of the p-values will take into account sample size and 
multiplicity issues. Forest plots with estimates and 95% confidence intervals of the treatment 
effect across different subgroups will be presented. 
5. SAFETY 
The safety objective is to assess the safety and tolerability of a single dose of 5.2 mg STSlOl in 
the treatment of acute migraine attacks. This objective is assessed through adverse events, 
physical examinations, vital signs, objective nasal symptom assessments, electrocardiogram, and 
laboratory assessments. 
Safety analyses will be conducted for the safety population, which will include all subjects who 
received at least one dose of study medication. Clinical safety and tolerability data will be 
summarized by treatment group in tables and listed by treatment group and by subject. Adverse 
events will be coded using MedDRA version 24.0 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. 
5.1 Extent of Exposure 
Because this is a single-dose study with PRN use, each subject is expected to receive one dose 
only. The number of subjects exposed to each treatment group is the number of subjects in the 
Safety Population; therefore, a table summarizing exposure is not displayed. Study drug dosing 
and reported compliance will be listed by treatment group and subject. 
5.2 Adverse Events 
A treatment emergent adverse event (TEAE) is defined as an adverse event (AE) that begins 
after the dosing of study drug. 
An overview of adverse events will be presented by treatment group, which will include the 
number and percent of subjects who had at least one AE, TEAE, Serious TEAE, TEAE leading 
to discontinuation, TEAE related to study drug, and maximum severity of TEAE. 
Multiple occurrences of an AE are counted only once per subject per system organ class and 
preferred term for summary tables. 
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The following TEAEs will be summarized by SOC, PT and treatment group: 
• 
Incidence of all TEAEs 
• 
Local TEAEs (will be updated based on actual events prior to unblinding) 
• 
Cardiovascular TEAEs 
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• 
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 discontinuation of study drug 
The incidence of all TEAEs, Local TEAEs, Cardiovascular TEAEs and TEAEs by severity will 
also be summarized in subjects with preventative migraine medication use at screening. 
All data collected in the AE CRF will be listed in by subject listings. 
5.3 Assessment of Nasal Irritation 
The Objective Assessment of Nasal Irritation is a 5-item assessment completed by the site to 
assess the effects of the study drug on the nose at Screening, Day 1, and Follow-up visits. Nasal 
symptoms assessed are Nasal Erythema, Nasal Edema, Rhinorrhea, Nasal Bleeding, and Nasal 
Ulceration. The responses are categorical and range from O (none) to 3 (severe). The shift in 
responses from baseline to follow-up will be summarized by treatment group. Exploratory 
hypothesis testing may be performed to compare treatment group by question. No multiplicity 
adjustment will be applied to these tests. 
5.4 Physical Examination 
Physical examination findings will be presented in data listings by treatment group and subject. 
5.5 Vital Signs 
Vital signs, including weight, are recorded on subjects at Screening, Day 1, and Follow-up visits. 
Observed data at baseline and follow-up visits and the change from baseline for vital signs will 
be summarized by treatment group. 
Normal ranges for the following vital sign parameters 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 at each visit by treatment group 
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) 
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• 
Pulse: 50-100 beats/min.(inclusive) 
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• 
Temperature: 97.7-99.0 degrees F (36.5 - 37.5 degrees C, inclusive) 
5.6 Electrocardiogram 
Electrocardiogram (ECG) data is recorded in triplicate at Screening, Day 1, and Follow-up visits 
and will be averaged for summary purposes. Observed data at baseline and follow-up visits and 
the change from baseline in ECG parameters, heart rate (HR), RR, PR, QRS, and QT corrected 
with the Fridericia's formula (QTcF), will be summarized by treatment group. 
The ECG findings, as reported on the CRF, is also recorded in triplicate. For summary purposes, 
the worst finding will be selected. The number and percentage of subjects with clinically 
significant ECG findings as previously described will be summarized as a shift from baseline to 
follow-up visit by treatment group. 
5. 7 Laboratory Evaluations 
Laboratory evaluations will be conducted at Screening and Follow-up visits and pregnancy tests 
in females will be performed on Screening, Day 1, and Follow-up visits. The observed data and 
change from baseline (Visit 1 or ifre-draw: qualifying value) to the final study visit (Visit 3) in 
hematology, serum chemistry and quantitative urinalysis test results will be summarized by 
treatment group. 
For hematology and serum chemistry 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). 
For urinalysis, test results will be categorized as normal and abnormal. Frequency counts and 
percentages will be presented over time by treatment groups for these categorical data. 
In addition, shifts from baseline (shift to maximum value, shift to minimum value) to the follow-
up visit in quantitative laboratory tests with normal ranges will be summarized by treatment 
group. 
If a continuous laboratory value is reported as either below or above the limits of quantification, 
the qualifiers should be dropped and the numeric value used in the analysis ( e.g., "< 1" should be 
"1" and "> 100" should be "100"). 
5.8 Sheehan Suicidality Tracking Scale 
The Sheehan Suicidality Tracking Scale (S-STS) will be performed at Screening, Day 1, and 
Follow-up Visit. The total score, as derived on the CRF, will be summarized using descriptive 
statistics by treatment group. 
6. Interim Analysis 
No interim analysis is planned for this study. 
CONFIDENTIAL 
Final: October 17, 2022 


Satsuma Pharmaceuticals, Inc. - STSlOl-007 
Statistical Analysis Plan 
7. TABLES, LISTINGS, AND FIGURES 
Page 36 
Data listings will be sorted by subject number, treatment group, 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 the active 
treatment group and placebo. Descriptive statistics such as mean, median, minimum, and 
maximum will 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 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: October 17, 2022 


Satsuma Pharmaceuticals, Inc. - STSlOl-007 
Statistical Analysis Plan 
8. REFERENCES 
Page 37 
Ashkenazi A, Sholtzow M, Shaw JW, Burstein R, Young WB. Identifying cutaneous allodynia in 
chronic migraine using a practical clinical method. Cephalalgia. 2007;27(2):111-7. doi: 
10.l 111/j.1468-2982.2006.01255.x. 
Rubin D.B.: Multiple Imputation for Nonresponse in Surveys. New York: John Wiley and Sons, 
1987 
Schafer: Analysis of Incomplete Multivariate Data. Chapman & Hall, New York, 1997 
Ware JE: SF-36 Health Survey update. Spine, 25(24):3130--3139, 2000 
Tepper SJ, Kori SH, Goadsby PJ, Winner PK, Wang MH, Silberstein SD, Cutrer FM. MAP0004, 
orally inhaled dihydroergotamine for acute treatment of migraine: efficacy of early and late 
treatments. Mayo Clin Proc. 2011;86(10):948-55. doi: 10.4065/mcp.2011.0093. 
CONFIDENTIAL 
Final: October 17, 2022 


Satsuma STS101-007 Ph3 SAP Final 
Final Audit Report 
2022-10-18 
Created: 
2022-10-18 
By: 
Shelia Ligozio (shelia.ligozio@instat.com) 
Status: 
Signed 
Transaction ID: 
CBJCHBCAABAAJqkjWRwLJ3cywjBN2RNKk-pq1 0L-XNDi 
"Satsuma STS101-007 Ph3 SAP Final" History 
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