A Randomized, Double-blind, Single-dose, Placebo-controlled Study to Assess the Efficacy and Safety of AXS-07 (Meloxicam and Rizatriptan) for the Acute Treatment of Migraine in Adults
Phase: PHASE3
Conditions: Migraine
Sponsor: Axsome Therapeutics, Inc.

Document Type: Protocol
Protocol Title: INTERCEPT (Initiating Early Control of Migraine Pain and Associated 
Symptoms): A Randomized, Double-blind, Single-dose, Placebo-controlled Study to Assess the 
Efficacy and Safety of AXS-07 (meloxicam and rizatriptan) for the Acute Treatment of Migraine 
in Adults. 
ClinicalTrials.gov Identifier:  NCT04163185
Document Date: December 13, 2019
Certain information within this protocol has been redacted to protect either personally identifiable 
information (PII) or company confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
•
Named persons or organizations associated with the study.
•
Proprietary information, such as scales or coding systems, which are considered confidential
information.
•
Other information as needed to protect the confidentiality of Axsome Therapeutics, personal
information, or to otherwise protect the integrity of the clinical study.

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PROTOCOL 
 
COMPOUND 
NAME/NUMBER: 
 
AXS-07 
PROTOCOL NUMBER: 
 
AXS-07-303 
 
 
 
DEVELOPMENT PHASE: 
 
Phase 3 
PROTOCOL TITLE: 
INTERCEPT (Initiating Early Control of Migraine Pain and 
Associated Symptoms): 
A Randomized, Double-blind, Single-dose, Placebo-controlled 
Study to Assess the Efficacy and Safety of AXS-07 (meloxicam and 
rizatriptan) for the Acute Treatment of Migraine in Adults. 
 
PROTOCOL VERSION: 
 
Amendment 1 
PROTOCOL DATE: 
 
Original: June 24, 2019 
Amendment 1: December 13, 2019 
 
 
 
 
 
 
This study will be performed in compliance with Good Clinical Practices and applicable 
regulatory requirements, including the archiving of essential documents. Information contained 
in this protocol is confidential in nature, and may not be used, divulged, published, or otherwise 
disclosed to others except to the extent necessary to obtain approval of the institutional review 
board or independent ethics committee, or as required by law. Persons to whom this information 
is disclosed should be informed that this information is confidential and may not be further 
disclosed without the express permission of Axsome Therapeutics, Inc. 
 
 

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APPROVAL SIGNATURES 
 
PROTOCOL NUMBER: 
AXS-07-303 
PROTOCOL TITLE:  
INTERCEPT (Initiating Early Control of Migraine Pain and Associated 
Symptoms): 
A Randomized, Double-blind, Single-dose, Placebo-controlled Study 
to Assess the Efficacy and Safety of AXS-07 (meloxicam and 
rizatriptan) for the Acute Treatment of Migraine in Adults. 
 
Protocol Version:  
Amendment 1: December 13, 2019 
 
I, the undersigned, have read this protocol and confirm that to the best of my knowledge it 
accurately describes the planned conduct of the study. 

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1. SYNOPSIS 
 
PRODUCT 
NAME/NUMBER 
AXS-07  
PROTOCOL NUMBER 
AXS-07-303 
DEVELOPMENT 
PHASE 
Phase 3 
PROTOCOL TITLE 
INTERCEPT (Initiating Early Control of Migraine Pain and Associated Symptoms: 
A Randomized, Double-blind, Single-dose, Placebo-controlled Study to Assess the Efficacy and 
Safety of AXS-07 (meloxicam and rizatriptan) for the Acute Treatment of Migraine in Adults. 
INDICATION 
Acute treatment of migraine with or without aura in adults. 
OBJECTIVES 
Primary Objective: 
To evaluate the effect of AXS-07 as compared to placebo in the acute treatment of migraine 
headache in adults as evaluated by the following two co-primary efficacy variables:  1) pain freedom 
at Hour 2 and 2) absence of the most bothersome symptom (MBS; nausea, photophobia, or 
phonophobia) at Hour 2. 
Key Secondary Objectives: 
 
To assess the effect of AXS-07 on time to headache pain freedom and functional disability. 
Secondary Objectives: 
Secondary objectives include assessment of the effect of AXS-07 on: 
• 
Percentage of subjects with headache pain relief at Hour 2. 
• 
Change from baseline in headache pain relief over time. 
• 
Percentage of subjects with headache pain freedom over time. 
• 
Time to headache pain relief. 
• 
Time to sustained headache freedom through Hour 24. 
• 
Percentage of subjects able to perform normal activity over time. 
• 
Patient Global Impression of Change (PGI-C) scores at Hour 2. 
• 
Percentage of subjects with absence of MBS over time. 
• 
Percentage of subjects MBS free over time. 
• 
Percentage of subjects with headache pain freedom between Hours 2 and 24 (24-hour 
sustained pain-free). 
• 
Percentage of subjects with headache pain freedom between Hours 2 and 48 (48-hour 
sustained pain-free).     
• 
Percentage of subjects with pain relapse, where relapse is defined as the return of 
headache within 48 hours after dosing, for subjects who were pain free at Hour 2. 
• 
Percentage of subjects using rescue medication. 
• 
Time to rescue medication. 
• 
Treatment response based on presence of allodynia, BMI, pain intensity, presence of 
depression, and use of preventive medication. 
STUDY DESIGN 
The study is a Phase 3, multicenter, randomized, double-blind, single-dose, placebo-controlled trial 
to evaluate the efficacy and safety of AXS-07 in subjects with migraine attacks. The co-primary 
efficacy endpoints are the 1) percentage of subjects with headache pain freedom at Hour 2, with 
headache pain freedom defined as a reduction in headache severity to no pain, and 2) absence of the 
MBS (nausea, photophobia, or phonophobia) at Hour 2, with the MBS defined at the onset of 
migraine, prior to drug administration. The key secondary endpoints are the time to headache pain 
freedom and functional disability at Hour 2. 

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To qualify for the study, subjects must be 18 to 65 years of age, have an established diagnosis of 
migraine (history indicating the presence of migraine for at least 1 year) with or without aura as 
defined by the International Classification of Headache Disorder, 3rd Edition (ICHD-3) and 
experience an average of 2 to 8 migraine attacks per month (no more than 10 migraine days per 
month) over the past 3 months.  
Screening Period and Randomization 
Subjects who successfully complete the Screening visit (Visit 1) will enter into a 28-day Screening 
Period during which they will record the details (baseline characteristics, headache pain intensity, 
associated migraine symptoms, and treatments used) of all migraines during this time. The subject 
must report at least 1 and no more than 8 migraines during the 28-day period in order to continue to 
be eligible. Subjects who continue to meet all eligibility criteria, will be randomly assigned at Visit 
2 (randomization) to receive AXS-07 or placebo, dispensed for at-home treatment of a single 
migraine attack. Subjects will have 6 weeks to treat a qualifying migraine.  
Treatment and Follow-up Periods 
After randomization, as soon as possible after the onset of the next migraine, subjects will record 
baseline headache characteristics in the Headache Diary, and take the study medication, one tablet 
orally, when prompted by the diary. In the diary, subject will record the headache pain intensity (0-
none, 1-mild, 2-moderate, and 3-severe), functional disability, presence or absence of associated 
symptoms (photophobia, phonophobia, nausea), and Patient Global Impression of Change (PGI-C). 
Subjects will complete the diary for 48 hours after the onset of the migraine and study drug dosing. 
Subjects will be instructed to follow restrictions regarding use of other medications, including rescue 
medications, and must not sleep or nap for at least 2 hours after taking study drug. 
A follow-up visit (Visit 3) will occur after treating one attack.  The visit is to be scheduled as soon 
as possible but within 1 week after dosing, or within 6 weeks after randomization (Visit 2) if the 
study medication is not used. 
Headache Diary Assessments 
Diaries will be provided and subjects will be instructed to complete the diary for 48 hours after 
taking study medication for a migraine. 
Headache pain intensity (measured by a 4-point rating scale; 0-none, 1-mild, 2-moderate, or 3-
severe), will be recorded by subjects in the diary as soon as possible after the onset of each migraine 
(prior to dosing in the Treatment Period), and at the following time points: 20, 30 and 45 minutes, 
and 1, 1.5, 2, 4, 12, 16, 24, and 48 hours.   
At the onset of each migraine, and prior to dosing in the Treatment Period, the subject will define 
their most bothersome symptom (nausea, photophobia, phonophobia) and will assess the presence 
or absence of it at the following time points 30 minutes and 1, 2, and 4 hours after dosing.  In 
addition, functional disability with regard to daily activities (on a 4-point scale) will be recorded at 
the following time points: Baseline (prior to dosing during the Treatment Period), 30 minutes, and 
1, 2, 4, 12, and 24 hours after dosing. During the Treatment Period, subjects will report PGI-C 2 
hours after dosing. 

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Safety and Other Assessments 
A physical examination will be performed at Screening. Samples for clinical laboratory testing 
(hematology and chemistry) will be collected at Screening. A urine pregnancy test will be performed 
at Screening, randomization (Visit 2), and Follow-up (Visit 3). ECGs will be performed at Screening 
and Follow-up (Visit 3). At each visit, vital signs will be assessed and concomitant medications will 
be reviewed.  
Presence of allodynia will be collected via the Allodynia Symptom Checklist-12 Item (ASC-12). 
Baseline assessment of migraine disability will be collected via the Migraine Disability Assessment 
(MIDAS). 
Adverse events will be assessed following dosing with study drug. 
Concomitant and Rescue Medications 
During the Screening Period, subjects can treat each migraine according to their standard-of-care.   
In the Treatment Period, barbiturates, ergotamine-containing medications, analgesics, and other 
migraine medications (except prophylactic agents as described below) may not be used 24 hours 
before, concurrently or within 24 hours after treatment with study drug. The use of MAO-A 
inhibitors, methylergonovine, or cimetidine are not permitted in the 2 weeks before randomization 
and for the duration of the study.  
Migraine prophylactic agents and selective serotonin reuptake inhibitors (SSRIs) / serotonin 
norepinephrine reuptake inhibitors (SNRIs) are permitted if the subject has been on stable doses for 
8 weeks (2 months) prior to randomization; however, subjects taking ergot alkaloids for prophylaxis 
will be excluded. The use of calcitonin gene-related peptide (CGRP) monoclonal antibodies and 
onabotulinumtoxinA (Botox®) for migraine prophylaxis is allowed if the subject has been on stable 
doses for at least 6 months prior to randomization.  Propranolol use is not allowed during the study 
or for 2 weeks prior to randomization. 
No rescue medication use is allowed prior to 2 hours after the start of the migraine attack. If the 
subject has inadequate relief from the study medication, they may take an allowed rescue medication 
after the Hour 2 timepoint. Barbiturates and ergotamine-containing medications are not allowed as 
rescue medications. Allowed medications include triptans, NSAIDs, antiemetics, non-NSAID 
analgesics (e.g., acetaminophen), and sedatives. 
PLANNED NUMBER 
OF SUBJECTS 
A total of approximately 300 subjects (approximately 150 per group, AXS-07 and placebo) are 
planned for the trial.   
STUDY ENTRY 
CRITERIA 
Inclusion criteria: 
A subject will be eligible for study participation if the subject meets all of the following criteria: 
1. Is male or female 18 to 65 years of age inclusive. 
2. Is willing and able to provide written informed consent to participate in the study, and 
willing and able to understand and comply with the procedures and study requirements. 
3. Has an established diagnosis of migraine (history indicating the presence of migraine for 
at least 1 year) with or without aura as defined by the ICHD-3 criteria. 
4. Has a diagnosis of migraine attacks with or without aura, presenting before age 50. 
5. Has a history, on average, of 2 to 8 migraine attacks per month over the past 3 months. 
NOTE:  The subject must report at least 1, and no more than 8 migraines during the 
Screening Period. 
6. Has a history of usual migraine duration of > 3 hours untreated (by history) for the 3 months 
prior to screening. 
7. Has the ability to differentiate between migraine and non-migraine headaches. 
8. Has a body weight ≥ 45 kg and a body mass index (BMI) ≤ 40 kg/m2. 
9. If receiving a selective serotonin reuptake inhibitor (SSRI) or serotonin norepinephrine 
reuptake inhibitor (SNRI), the dose has been stable for at least 8 weeks prior to 
randomization. 

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10. If female, is either not of childbearing potential (defined as postmenopausal for at least 1 
year or surgically sterile [bilateral tubal ligation, bilateral oophorectomy, or 
hysterectomy]); or is nonlactating and nonpregnant (has negative pregnancy test results at 
Screening and Baseline), does not plan to get pregnant during the study or for at least one 
month after, and is using a reliable method of contraception, before study drug 
administration and for the duration of the trial. Reliable methods of contraception include 
hormonal, double-barrier methods (e.g., condom and diaphragm, condom and foam, 
condom and sponge, each with spermicidal jellies or cream), intrauterine devices, 
vasectomized partners (>6 months prior to Visit 2), and abstinence. 
11. Is willing and able to complete the Headache Diary. 
Exclusion criteria: 
A subject will be excluded from the study if the subject meets any of the following criteria: 
1. Has a known history of allergic reaction, hypersensitivity, or clinically significant 
intolerance to rizatriptan or another triptan, acetaminophen, aspirin, or any NSAIDs, 
including meloxicam; history of NSAID-induced bronchospasm (subjects with the triad of 
asthma, nasal polyps, and chronic rhinitis are at greater risk for bronchospasm and should 
be considered carefully); or hypersensitivity, allergy, or significant reaction to any 
ingredients of the study drug. 
2. Has experienced > 8 migraine attacks monthly during either of the 2 months before 
screening. 
3. Is suffering from cluster headaches (every day or every other day), tension headaches, or 
other types of migraine. 
4. Has experienced chronic daily headache (≥ 15 days per month of non-migraine headaches 
during each of the 3 months before screening). 
5. Has a history of brain stem aura, ophthalmoplegic or hemiplegic migraine headache, or any 
potentially serious neurological condition that is associated with headache. 
6. Has confirmed or suspected cardiovascular or cerebrovascular disease. 
7. Has history, symptoms, or significant risk factors for ischemic heart (e.g., silent ischemia, 
angina, myocardial infarction); coronary artery vasospasm; arrhythmia (e.g., atrial 
fibrillation or flutter, frequent premature ventricular contractions, atrioventricular block); 
clinically significant findings on ECG; cardiac accessory conduction pathway disorder 
(e.g., Wolff-Parkinson-White syndrome); or other cardiovascular disease. 
8. Has history of stroke, transient ischemic attack or other cerebrovascular syndrome; 
peripheral vascular disease; or ischemic bowel disease. 
9. Has uncontrolled hypertension (diastolic blood pressure > 95 mm Hg or systolic blood 
pressure > 160 mm Hg). 
10. Is a female subject and is taking estrogenic contraceptives who, in addition, smokes and 
has experienced migraine attack with aura. 
11. Has a concurrent medical condition(s) that requires the chronic (daily or near daily) use of 
analgesics, narcotic analgesics, steroidal or non-steroidal anti-inflammatory (NSAIDs) 
agents, tranquilizers, sedatives-hypnotics, antipsychotics, or nitrates or their use for 
prevention of migraine attacks. 
12. Clinically significant abnormalities indicated from the medical history, physical exam, 
clinical chemistry, hematology, urine drug screen. 
13. Had a diagnosis or suspicion of drug induced or chronic daily headaches within 1 year. 
14. Has used MAO inhibitor, lithium, methylergonovine, or cimetidine in the 2 weeks before 
randomization 
15. Has a history or current diagnosis of any clinically significant cardiac, pulmonary, 
neurological, immunological, hematological, gastrointestinal, hepatic, renal, or endocrine 
disease or any other condition which, in the opinion of the investigator, could compromise 

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the subject’s welfare, ability to communicate with the study staff, or otherwise 
contraindicate study participation. 
16. Has a history or current diagnosis of schizophrenia or another significant psychiatric 
disorder which, in the opinion of the investigator, would affect the subject’s ability to 
comply with the study requirements.  Stable bipolar disease and stable major depressive 
disorder is allowed. 
17. Is receiving systemic chemotherapy, has an active malignancy of any type, or has been 
diagnosed with cancer within 5 years before Screening (excluding squamous or basal cell 
carcinoma of the skin). 
18. Has a known or suspected history of alcoholism or drug abuse or misuse within 1 year 
before Screening or evidence of tolerance or physical dependence before study drug 
administration. 
19. Has, or has had within 1 year, any clinically significant gastrointestinal (GI) disorder, 
including peptic or gastric ulcers or GI bleeding. 
20. Has a medical or surgical condition of the GI system (including motility dysfunction) or 
renal system that might significantly alter the absorption, distribution, or excretion of any 
drug substance. 
21. Is considered by the investigator, for any reason (including, but not limited to, the risks 
described as precautions, warnings, and contraindications in the current version of the 
investigator’s brochure for AXS-07 tablets), to be an unsuitable candidate to receive the 
study drug. 
22. Is using or expects to use concurrent analgesic, including NSAIDs (except aspirin at a dose 
of ≤ 325 mg daily for cardiovascular prophylaxis) during the trial. NOTE: NSAIDs and 
other analgesics maybe used during the Screening Period.  
23. Is currently receiving or expects to use anticoagulants (e.g., heparin, warfarin, nutritional 
supplements having anticoagulant properties); or has bleeding problems, coagulation 
abnormalities, active blood dyscrasia, hemorrhagic disease, anemia, porphyria, 
phenylketonuria, bone marrow suppression, or immunosuppression. 
24. Is currently receiving propranolol or has received propranolol within 2 weeks prior to 
randomization.  
25. Has been treated with agents that could affect the analgesic response (such as central alpha 
agents adrenergic [clonidine and tizanidine]) within 2 weeks before randomization or 
expects to use such agents during the treatment period. 
26. Has tested positive for drugs of abuse on the urine drug screen at randomization (Visit 2). 
Subjects who test positive at Screening and can produce a prescription for the medication 
from their physician may be considered for study enrollment at the discretion of the 
investigator. NOTE: The use of marijuana, medical or otherwise, is not permitted during 
the study and a positive test for THC will be exclusionary.  
27. Has clinically significant abnormalities indicated from the medical history, physical exam, 
and laboratory findings at Screening that in the investigator’s opinion contraindicates study 
participation. 
28. Is HIV positive. 
29. Has previously participated in another clinical study of AXS-07 or received any 
investigational drug or device or investigational therapy within 30 days before Screening. 
30. Has significant difficulty swallowing tablets or is unable to tolerate oral medication. 
INVESTIGATIONAL 
PRODUCT 
AXS-07 (20 mg meloxicam/10 mg rizatriptan) tablet for oral administration.  
REFERENCE 
PRODUCT 
Matching placebo tablets for oral administration. 

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• 
Sustained ability to function at a normal level (functional disability = none) from Hours 2 
to 48. 
Most Bothersome Symptoms 
• 
Percentage of subjects with absence of MBS over time. 
• 
Sustained freedom from MBS from Hour 2 to Hour 24. 
• 
Sustained freedom from MBS from Hour 2 to Hour 48. 
• 
Absence of photophobia at Hour 2 in the subset of subjects that reported the presence of 
photophobia at headache baseline. 
• 
Absence of phonophobia at Hour 2 in the subset of subjects that reported the presence of 
phonophobia at headache baseline. 
• 
Absence of nausea at Hour 2 in the subset of subjects that reported the presence of nausea 
at headache baseline. 
• 
Absence of photophobia at over time in the subset of subjects that reported the presence of 
photophobia at headache baseline. 
• 
Absence of phonophobia over time in the subset of subjects that reported the presence of 
phonophobia at headache baseline. 
• 
Absence of nausea over time the subset of subjects that reported the presence of nausea at 
headache baseline. 
Rescue Medication Use 
• 
Percentage of subjects using rescue medication within 24 hours after administration of 
study medication. 
• 
Time to rescue medication use. 
Other Secondary Endpoints 
• 
Patient Global Impression of Change (PGI-C) scores at Hour 2. 
• 
PGI-C scores over time. 
• 
Treatment response based on presence of allodynia, BMI, pain intensity, presence of 
depression, and use of preventive medication. 
Safety Endpoints: 
• 
Treatment-emergent adverse events (TEAEs) 
• 
Vital signs 
• 
Physical exam findings 
• 
Clinical laboratory parameters 
• 
ECG 
STATISTICAL 
METHODS 
Analysis Populations:  
The following analysis populations are planned for this study:  
• 
Intent-to-Treat (ITT) Population: the ITT population is the primary analysis population and 
will include data from all subjects who are randomized and have a qualifying migraine 
episode.  
• 
Safety Population: The Safety Population will include all subjects who receive study 
medication. 
Membership in the analysis populations will be determined before unblinding. 
There are two co-primary efficacy variables, percentage of subjects with pain freedom at Hour 2 and 
percentage of subjects with absence of MBS at Hour 2.  To establish the efficacy, AXS-07 must be 
significantly better than placebo at a two-sided significant level of 0.05 for each of the two co-
primary efficacy variables.   
The variables related to the percentages will be analyzed via chi-square tests.  The percentages, 
differences in the percentages as well as the two-sided 95% confidence intervals of the differences 
will be presented.  The confidence intervals will be constructed using normal approximations. 
SAMPLE SIZE 
DETERMINATION 
In this study, approximately 300 subjects will be randomized 1:1 to either AXS-07 or placebo group. 

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For the primary endpoint, approximately 150 subjects per group will provide 90% power to detect 
a treatment difference at a two-sided significance level of 0.05, assuming that the responder rate for 
pain freedom at Hour 2 is ≤15% for placebo and ≥29% for AXS-07.  
STUDY AND 
TREATMENT 
DURATION 
The duration of participation will be up to 10 weeks as follows: 
Screening Period: 28 days. 
Treatment Period: up to 6 weeks. 

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Schedule of Assessments 
 
Visit 1 
Visit 2 
Visit 3 
 
Screening 
Randomization 
Follow-upd / 
EOS 
 
Day –28 
Day 1 
Within 7 days 
of dosing 
Informed Consent 
X 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
Demographics 
X 
 
 
Medical History 
X 
 
 
Migraine Headache History 
X 
X 
 
Medications, Prior and Concomitant, or Non-drug Therapy  
X 
X 
X 
Physical Examination, including height and weight 
X 
 
X 
Vital Signs (seated blood pressure, pulse, oral body temp.) 
X 
X 
X 
ECG 
X 
 
X 
Clinical Laboratory Tests 
X 
 
X 
Urine Pregnancy Testa 
X 
X 
X 
Urine Drug Screen 
X 
X 
 
ASC-12 
 
X 
 
MIDAS 
 
X 
 
Randomization 
 
X 
 
Dispense Headache Diary and Instruct on Use 
X 
X 
 
Review Compliance with Headache Diary 
 
X 
X 
Dispense Study Drug & Provide Dosing Instructions 
 
X 
 
Subject Completes Diary Datab 
 
X 
 
Phone call contactc 
 
X 
 
Return Headache Diary 
 
 
X 
Collect/Inventory Study Medication 
 
 
X 
Adverse Eventse 
 
X 
X 
Abbreviations:  ASC-12 = 12-item Allodynia Symptom Checklist; ECG = electrocardiogram; MIDAS = Migraine Disability 
Assessment; PGI-C = patient global impression of change. 
a. For women of child-bearing potential only. Test results must be negative at Screening and Randomization for the subject to 
continue in the study. 
b. Headache Diary data will be collected at the following times: Baseline (pre-dose during Treatment Period) and 20, 30 and 45 
minutes, and 1, 1.5, 2, 4, 12, 16, 24, and 48 hours after dosing 
c. The subject should be contacted within 24 hours after administering study medication.  During the post-dose call, the site should 
re-confirm study drug dosing instructions and check for changes in concomitant medications. Following the onset of a 
qualifying migraine, assess compliance with migraine pain diary, rescue medication use, and to schedule the follow up 
appointment. 
d. Final visit after treating one attack (to be scheduled as soon as possible but within 7 days of dosing), or within 6 weeks after 
Visit 2 if the study medication not used. 
e. Adverse events are not required to be collected if subjects do not receive a dose of study medication. 

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2. TABLE OF CONTENTS 
1. 
SYNOPSIS ...................................................................................................................4 
2. 
TABLE OF CONTENTS ...........................................................................................13 
3. 
LIST OF ABBREVIATIONS .....................................................................................18 
4. 
INTRODUCTION ......................................................................................................19 
 
Background and Rationale ................................................................................19 
 
Clinical Experience with Rizatriptan ................................................................19 
5. 
OBJECTIVES .............................................................................................................20 
 
Primary Objective .............................................................................................20 
 
Key Secondary Objectives ................................................................................20 
 
Secondary Objectives ........................................................................................20 
6. 
STUDY DESIGN .......................................................................................................21 
 
Overall Study Design and Plan .........................................................................21 
 
Discussion of Study Design ..............................................................................23 
 
Study Sites .........................................................................................................23 
 
Point of Contact ................................................................................................23 
7. 
SUBJECT POPULATION .........................................................................................24 
 
Selection of Study Population and Diagnosis ...................................................24 
 
Study Entry Criteria ..........................................................................................24 
 Inclusion Criteria ...................................................................................24 
 Exclusion Criteria ..................................................................................24 
 
Premature Subject Withdrawal .........................................................................27 
 
Subject Replacement Criteria ............................................................................27 
8. 
TREATMENTS ..........................................................................................................27 
 
Identification of Investigational Product ...........................................................27 
 
Labeling and Packaging ....................................................................................27 
 Labeling .................................................................................................27 
 Packaging ..............................................................................................28 
 
Study Medication Administration .....................................................................28 
 
Dispensing and Storage .....................................................................................28 
 
Method of Assigning Subjects to Treatment Groups ........................................28 
 
Blinding and Unblinding Treatment Assignment .............................................28 
 
Selection of Doses in the Study ........................................................................29 
 
Selection of Timing of Dose for Each Subject..................................................29 
 
Dose Adjustment Criteria ..................................................................................29 
 Drug Accountability ..........................................................................................29 

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 Treatment Compliance ......................................................................................30 
 Permitted and Prohibited Therapies ..................................................................30 
 Rescue Medication ................................................................................30 
 Permitted Therapies ...............................................................................30 
 Prohibited Therapies ..............................................................................30 
 Treatment After the End of Study .....................................................................31 
9. 
STUDY PROCEDURES ............................................................................................31 
 
Study Periods, Visits, and Procedures ..............................................................31 
 Visit 1: Screening (Day -28) .................................................................31 
 Screening Period (Day -28 to Day -1) ...................................................32 
 Visit 2: Randomization (Day 1) ............................................................32 
 End of Study: Visit 3 (within 7 days of study drug administration) .....33 
 Early Termination Visit .........................................................................33 
 
Study Duration ..................................................................................................33 
 
Assessments ......................................................................................................33 
 Efficacy .................................................................................................33 
9.3.1.1 
Headache Diary .........................................................................33 
9.3.1.2 
Allodynia Symptom Checklist (ASC-12) .................................34 
9.3.1.3 
Migraine Disability Assessment (MIDAS) ...............................34 
 Clinical Pharmacology ..........................................................................35 
9.3.3 Safety .....................................................................................................35 
9.3.3.1 
Adverse Events .........................................................................35 
9.3.3.2 
Clinical Laboratory Safety Assessments ...................................35 
9.3.3.3 
Clinical Examinations ...............................................................36 
10. ADVERSE EVENTS ..................................................................................................36 
 Definitions .........................................................................................................36 
 Adverse Events ......................................................................................36 
 Adverse Drug Reaction .........................................................................37 
 Unexpected Adverse Event/Adverse Drug Reaction ............................37 
 Serious Adverse Events/Drug Reaction ................................................37 
 Significant Adverse Events ...................................................................38 
 Treatment-Emergent Adverse Events ...................................................38 
 Management of Adverse Events .......................................................................38 
 Collection of Adverse Events ................................................................38 
 Evaluation of Adverse Events ...............................................................38 
10.2.2.1 Severity of Adverse Events .......................................................38 
10.2.2.2 Seriousness ................................................................................39 

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10.2.2.3 Action(s) Taken .........................................................................39 
10.2.2.4 Outcome at the Time of Last Observation ................................39 
10.2.2.5 Adverse Event Relationship to the Study Drug ........................39 
 Documentation ......................................................................................41 
 Treatment of Adverse Events ................................................................41 
 Follow-up of Adverse Events ................................................................41 
 Notification ............................................................................................41 
10.2.6.1 Serious Adverse Events.............................................................41 
10.2.6.2 Adverse Drug Reactions ...........................................................42 
10.2.6.3 Nonserious Adverse Events ......................................................42 
 Special Considerations ......................................................................................43 
 Adverse Events of Special Interest ........................................................43 
 Pregnancy ..............................................................................................43 
 Overdose ................................................................................................43 
11. DATA SAFETY MONITORING BOARD ...............................................................43 
12. STATISTICS ..............................................................................................................43 
 Study Endpoints ................................................................................................44 
 Primary Endpoints .................................................................................44 
 Key Secondary Endpoints .....................................................................44 
 Secondary Endpoints .............................................................................44 
 Safety Endpoints ....................................................................................46 
 Sample Size Determination ...............................................................................46 
 Analysis Populations .........................................................................................46 
 Statistical Analyses ...........................................................................................46 
 Study Subjects and Demographics ........................................................46 
12.4.1.1 Disposition and Withdrawals ....................................................46 
12.4.1.2 Protocol Deviations ...................................................................46 
12.4.1.3 Demographics and Other Baseline Characteristics ...................47 
 Exposure and Compliance .....................................................................47 
 Efficacy Analyses ..................................................................................47 
12.4.3.1 Primary Efficacy Analysis ........................................................47 
12.4.3.2 Secondary Efficacy Analyses ....................................................47 
 Adverse Events ......................................................................................47 
 Vital Signs .............................................................................................47 
 Physical Examination Findings .............................................................47 
 Interim Analysis ....................................................................................47 
13. STUDY CONDUCT ...................................................................................................48 

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 Sponsor and Investigator Responsibilities ........................................................48 
 Sponsor Responsibilities .......................................................................48 
 Investigator Responsibilities .................................................................48 
 Site Initiation .....................................................................................................48 
 Study Documents ..............................................................................................49 
 Investigator’s Regulatory Documents ...................................................49 
 Case Report Forms ................................................................................49 
 Source Documents .................................................................................49 
 Data Quality Control .........................................................................................50 
 Monitoring Procedures ..........................................................................50 
 Data Management ..................................................................................50 
 Quality Assurance/Audit .......................................................................51 
 Study Termination .............................................................................................51 
 Regular Study Termination ...................................................................51 
 Premature Study Termination ...............................................................51 
 Study Site Closure .................................................................................52 
 Record Retention ...................................................................................52 
 Changes to the Protocol ....................................................................................52 
 Use of Information and Publication ..................................................................52 
14. FINAL CLINICAL STUDY REPORT ......................................................................53 
15. ETHICAL AND LEGAL CONSIDERATIONS ........................................................53 
 Declaration of Helsinki and Good Clinical Practice .........................................53 
 Subject Information and Informed Consent ......................................................53 
 Approval by Institutional Review Board and Independent Ethics Committee .54 
 Finance and Insurance .......................................................................................54 
16. REFERENCES ...........................................................................................................55 
17. ATTACHMENTS .......................................................................................................56 
 Schedule of Assessments ..................................................................................56 
 Investigator’s Agreement ..................................................................................57 
APPENDICES ...................................................................................................................58 
A. 
Address List ......................................................................................................59 
 
 
 
 
 
 
E. 
Regulations and Good Clinical Practice Guidelines .........................................63 
1. 
Regulations ............................................................................................63 

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2. 
Good Clinical Practice Guidelines ........................................................63 
 
 

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3. LIST OF ABBREVIATIONS 
ADR 
adverse drug reaction 
AE 
adverse event 
ATC 
Anatomical Therapeutic Chemical 
BMI 
body mass index 
CFR 
Code of Federal Regulations 
CRA 
clinical research associate 
CGRP 
calcitonin gene-related peptide 
eCRF 
electronic case report form 
CSR 
clinical study report 
DSMB 
Data Safety Monitoring Board 
EDC 
electronic data capture 
EOS 
End of Study 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
IB 
investigator’s brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
ICHD-3 
International Classification of Headache Disorder, 3rd Edition 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IWRS 
interactive web response system 
MBS 
most bothersome symptom 
MedDRA 
Medical Dictionary for Regulatory Activities 
NSAID 
nonsteroidal anti-inflammatory drug 
PGI-C 
Patient Global Impression of Change 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SOC 
system organ class 
SNRI 
serotonin norepinephrine reuptake inhibitor 
SSRI 
selective serotonin reuptake inhibitor 
TEAE 
treatment-emergent adverse event 
UADR 
unexpected adverse drug reaction 
UAE 
unexpected adverse event 
US 
United States 
WHO 
World Health Organization 
 

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4. INTRODUCTION 
 
Background and Rationale 
AXS-07 is a novel, oral, rapidly absorbed, investigational medicine consisting of MoSEIC™ 
meloxicam and rizatriptan being developed for the acute treatment of migraine with or without 
aura in adults. Rizatriptan is a 5-HT1B/D agonist (triptan) currently approved for the acute treatment 
of migraine, and meloxicam is a nonsteroidal anti-inflammatory drug (NSAID) currently approved 
for the relief of the signs and symptoms of osteoarthritis and rheumatoid arthritis [1,2]. The 
MoSEIC™ meloxicam formulation in AXS-07 tablets provides faster dissolution and absorption 
of meloxicam as compared to standard preparations, enabling its use for the treatment of migraine. 
Migraine is a disorder characterized by recurrent attacks of pulsating, unilateral or bilateral head 
pain, often associated with nausea, photophobia, and phonophobia [3]. Migraine attacks may occur 
with or without an aura, which is a focal neurological symptom (e.g. vision changes) that typically 
precedes other symptoms. Migraine attacks generally last from 4 to 72 hours and are often severe 
and disabling, requiring bed rest [3]. 
The rationale for the development of AXS-07 in the treatment of migraine is based on the rapid 
absorption and long half-live of MoSEIC™ meloxicam in AXS-07 and the potential additive 
efficacy of MoSEIC™ meloxicam and rizatriptan. The MoSEIC™ meloxicam in AXS-07 
contributes a distinct mechanism of action, and reaches Cmax in approximately one hour after oral 
administration, thereby providing the potential for greater efficacy and a more rapid onset of action 
as compared to rizatriptan alone. In addition, the MoSEIC™ meloxicam in AXS-07 maintains an 
approximately 20-hour half-life, which may provide more sustained efficacy with less recurrence 
of symptoms as compared to rizatriptan alone. 
Triptans have been shown to be efficacious for moderate to severe migraine [1,4] and are 
considered by many the drugs of choice for the abortive treatment of attacks. However, triptans, 
including rizatriptan, suffer from several limitations. Firstly, they do not successfully treat all 
patients or all attacks. Secondly, they do not work as quickly as patients require. Thirdly, migraine 
recurrence within 24 hours after treatment with triptans is common. Meloxicam is a potent and 
well characterized NSAID whose utility has been limited by slow absorption resulting in a delayed 
Tmax [2]. Results of completed Phase 1 trials of AXS-07 revealed a faster Tmax after oral 
administration, making this formulation more suitable for the treatment of migraine [2]. By 
combining rizatriptan with MoSEIC™ meloxicam, AXS-07 may overcome these limitations.  
 
Clinical Experience with Rizatriptan 
The efficacy of rizatriptan in the acute treatment of migraine in adults was established in four 
multicenter, randomized, placebo-controlled trials. In all studies, the percentage of patients 
achieving headache response 2 hours after treatment was significantly greater in patients who 
received either 5 or 10 mg rizatriptan as compared to those who received placebo. Headache 
response, defined as a reduction of moderate or severe headache pain to no or mild headache pain, 
was experienced 2 hours after treatment by 67-77% of subjects who received 10 mg rizatriptan 
versus 35-40% of subjects who received placebo. Rizatriptan treatment was also superior for 
complete pain relief and demonstrated lower symptom recurrence as compared to placebo. [1] 

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• Absence of phonophobia at Hour 2 in the subset of subjects that reported the presence of 
phonophobia at headache baseline. 
• Absence of nausea at Hour 2 in the subset of subjects that reported the presence of nausea 
at headache baseline. 
• Absence of photophobia at over time in the subset of subjects that reported the presence 
of photophobia at headache baseline. 
• Absence of phonophobia over time in the subset of subjects that reported the presence of 
phonophobia at headache baseline. 
• Absence of nausea over time the subset of subjects that reported the presence of nausea at 
headache baseline. 
Rescue Medication Use 
• Percentage of subjects using rescue medication within 24 hours after administration of 
study medication. 
• Time to rescue medication use. 
Other Objectives 
• Patient Global Impression of Change (PGI-C) scores at Hour 2. 
• Treatment response based on presence of allodynia, BMI, pain intensity, presence of 
depression, and use of preventive medication. 
6. STUDY DESIGN 
 
Overall Study Design and Plan 
The study is a Phase 3, multicenter, randomized, double-blind, single-dose, placebo-controlled 
trial to evaluate the efficacy and safety of AXS-07 in subjects with migraine attacks. The co-
primary efficacy endpoints are the 1) percentage of subjects with headache pain freedom at Hour 
2, with headache pain freedom defined as a reduction in headache severity to no pain, and 2) 
absence of the MBS (nausea, photophobia, or phonophobia) at Hour 2, with the MBS defined at 
the onset of migraine, prior to drug administration. The key secondary endpoints are the time to 
headache pain freedom and functional disability at Hour 2. 

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Figure 6.1 
Study Design 
 
To qualify for the study, subjects must be 18 to 65 years of age, have an established diagnosis of 
migraine (history indicating the presence of migraine for at least 1 year) with or without aura as 
defined by the International Classification of Headache Disorder, 3rd Edition (ICHD-3) and 
experience an average of 2 to 8 migraine attacks per month (no more than 10 migraine days per 
month) over the past 3 months.  
Screening Period and Randomization 
Subjects who successfully complete the Screening visit (Visit 1) will enter into a 28-day Screening 
Period during which they will record the details (baseline characteristics, headache pain intensity, 
associated migraine symptoms, and treatments used) of all migraines during this time. The subject 
must report at least 1 and no more than 8 migraines during the 28-day period in order to continue 
to be eligible. Subjects who continue to meet all eligibility criteria, will be randomly assigned at 
Visit 2 (randomization) to receive AXS-07 or placebo, dispensed for at-home treatment of a single 
migraine attack. Subjects will have 6 weeks to treat a qualifying migraine.  
Treatment and Follow-up Periods 
After randomization, as soon as possible after the onset of the next migraine, subjects will record 
baseline headache characteristics in the Headache Diary, and take the study medication, one tablet 
orally, when prompted by the diary. In the diary, subject will record the headache pain intensity 
(0-none, 1-mild, 2-moderate, and 3-severe), functional disability, presence or absence of 
associated symptoms (photophobia, phonophobia, nausea), and Patient Global Impression of 
Change (PGI-C). Subjects will complete the diary for 48 hours after the onset of the migraine and 
study drug dosing. Subjects will be instructed to follow restrictions regarding use of other 
medications, including rescue medications, and must not sleep or nap for at least 2 hours after 
taking study drug. 
A follow-up visit (Visit 3) will occur after treating one attack.  The visit is to be scheduled as soon 
as possible but within 1 week after dosing, or within 6 weeks after randomization (Visit 2) if the 
study medication is not used. 
Headache Diary Assessments 
Diaries will be provided and subjects will be instructed to complete the diary for 48 hours after 
taking study medication for a migraine. 

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Headache pain intensity (measured by a 4-point rating scale; 0-none, 1-mild, 2-moderate, or 3-
severe), will be recorded by subjects in the diary as soon as possible after the onset of each 
migraine (prior to dosing in the Treatment Period), and at the following time points: 20, 30 and 45 
minutes, and 1, 1.5, 2, 4, 12, 16, 24, and 48 hours.   
At the onset of each migraine, and prior to dosing in the Treatment Period, the subject will define 
their most bothersome symptom (nausea, photophobia, phonophobia) and will assess the presence 
or absence of it at the following time points 30 minutes and 1, 2, and 4 hours after dosing.  In 
addition, functional disability with regard to daily activities (on a 4-point scale) will be recorded 
at the following time points: Baseline (prior to dosing during the Treatment Period), 30 minutes, 
and 1, 2, 4, 12, and 24 hours after dosing. During the Treatment Period, subjects will report PGI-
C 2 hours after dosing. 
Safety and Other Assessments 
A physical examination will be performed at Screening. Samples for clinical laboratory testing 
(hematology and chemistry) will be collected at Screening. A urine pregnancy test will be 
performed at Screening, randomization (Visit 2), and Follow-up (Visit 3). ECGs will be performed 
at Screening and Follow-up (Visit 3). At each visit, vital signs will be assessed and concomitant 
medications will be reviewed. 
Presence of allodynia will be collected via the Allodynia Symptom Checklist-12 Item (ASC-12). 
Baseline assessment of migraine disability will be collected via the Migraine Disability 
Assessment (MIDAS). 
Adverse events will be assessed following dosing with study drug.  
 
Discussion of Study Design 
A double-blind design is appropriate for assessing the efficacy and safety of AXS-07. 
Randomization was included to avoid bias. Placebo was chosen as the primary comparator to show 
treatment effect of AXS-07.  
The use of a single dose to treat an acute migraine is consistent with the FDA guidance on 
developing drugs for the acute treatment of migraine. The safety and efficacy assessments used in 
this study are recognized and validated standards of measurement. 
 
Study Sites 
The study will take place at up to 50 study sites in the United States. Each site is anticipated to 
screen a sufficient number of subjects to be able to randomize approximately 10 subjects.  A study 
site with a high recruitment rate may be allowed to recruit more subjects if other sites have slow 
enrollment. 
 
Point of Contact 
A point of contact will be identified to provide information to subjects about where to obtain 
information on the study, the rights of the subject, and whom to contact in case of study-related 
injury. This information will be provided in the subject information and ICF. 

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7. SUBJECT POPULATION 
 
Selection of Study Population and Diagnosis 
Eligible subjects must have a confirmed diagnosis of migraine, meeting the ICHD-3 criteria, with 
an average of 2 to 8 migraines per month, over the past 3 months.  Approximately 300 subjects 
will be enrolled at up to 50 study centers in the US.   
Eligible subjects will be otherwise generally healthy, as required by the inclusion and exclusion 
criteria, documented by medical history, physical examination, and clinical laboratory 
examinations. 
 
Study Entry Criteria 
 Inclusion Criteria 
A subject will be eligible for study participation if the subject meets all of the following criteria: 
1. Is male or female 18 to 65 years of age inclusive. 
2. Is willing and able to provide written informed consent to participate in the study, and 
willing and able to understand and comply with the procedures and study requirements. 
3. Has an established diagnosis of migraine (history indicating the presence of migraine for 
at least 1 year) with or without aura as defined by the ICHD-3 criteria. 
4. Has a diagnosis of migraine attacks with or without aura, presenting before age 50. 
5. Has a history, on average, of 2 to 8 migraine attacks per month over the past 3 months. 
NOTE:  The subject must report at least 1, and no more than 8 migraines during the 
Screening Period. 
6. Has a history of usual migraine duration of > 3 hours untreated (by history) for the 3 months 
prior to screening. 
7. Has the ability to differentiate between migraine and non-migraine headaches. 
8. Has a body weight ≥ 45 kg and a body mass index (BMI) ≤ 40 kg/m2. 
9. If receiving a selective serotonin reuptake inhibitor (SSRI) or serotonin norepinephrine 
reuptake inhibitor (SNRI), the dose has been stable for at least 8 weeks prior to 
randomization. 
10. If female, is either not of childbearing potential (defined as postmenopausal for at least 1 
year or surgically sterile [bilateral tubal ligation, bilateral oophorectomy, or 
hysterectomy]); or is nonlactating and nonpregnant (has negative pregnancy test results at 
Screening and Baseline), does not plan to get pregnant during the study or for at least one 
month after, and is using a reliable method of contraception, before study drug 
administration and for the duration of the trial. Reliable methods of contraception include 
hormonal, double-barrier methods (e.g., condom and diaphragm, condom and foam, 
condom and sponge, each with spermicidal jellies or cream), intrauterine devices, 
vasectomized partners (>6 months prior to Visit 2), and abstinence. 
11. Is willing and able to complete the Headache Diary. 
 
 Exclusion Criteria 
A subject will be excluded from the study if the subject meets any of the following criteria: 

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1. Has a known history of allergic reaction, hypersensitivity, or clinically significant 
intolerance to rizatriptan or another triptan, acetaminophen, aspirin, or any NSAIDs, 
including meloxicam; history of NSAID-induced bronchospasm (subjects with the triad of 
asthma, nasal polyps, and chronic rhinitis are at greater risk for bronchospasm and should 
be considered carefully); or hypersensitivity, allergy, or significant reaction to any 
ingredients of the study drug. 
2. Has experienced > 8 migraine attacks monthly during either of the 2 months before 
screening. 
3. Is suffering from cluster headaches (every day or every other day), tension headaches, or 
other types of migraine. 
4. Has experienced chronic daily headache (≥ 15 days per month of non-migraine headaches 
during each of the 3 months before screening). 
5. Has a history of brain stem aura, ophthalmoplegic or hemiplegic migraine headache, or any 
potentially serious neurological condition that is associated with headache. 
6. Has confirmed or suspected cardiovascular or cerebrovascular disease. 
7. Has history, symptoms, or significant risk factors for ischemic heart (e.g., silent ischemia, 
angina, myocardial infarction); coronary artery vasospasm; arrhythmia (e.g., atrial 
fibrillation or flutter, frequent premature ventricular contractions, atrioventricular block); 
clinically significant findings on ECG; cardiac accessory conduction pathway disorder 
(e.g., Wolff-Parkinson-White syndrome); or other cardiovascular disease. 
8. Has history of stroke, transient ischemic attack or other cerebrovascular syndrome; 
peripheral vascular disease; or ischemic bowel disease. 
9. Has uncontrolled hypertension (diastolic blood pressure > 95 mm Hg or systolic blood 
pressure > 160 mm Hg). 
10. Is a female subject and is taking estrogenic contraceptives who, in addition, smokes and 
has experienced migraine attack with aura. 
11. Has a concurrent medical condition(s) that requires the chronic (daily or near daily) use of 
analgesics, narcotic analgesics, steroidal or non-steroidal anti-inflammatory (NSAIDs) 
agents, tranquilizers, sedatives-hypnotics, antipsychotics, or nitrates or their use for 
prevention of migraine attacks. 
12. Clinically significant abnormalities indicated from the medical history, physical exam, 
clinical chemistry, hematology, urine drug screen. 
13. Had a diagnosis or suspicion of drug induced or chronic daily headaches within 1 year. 
14. Has used MAO inhibitor, lithium, methylergonovine, or cimetidine in the 2 weeks before 
randomization 
15. Has a history or current diagnosis of any clinically significant cardiac, pulmonary, 
neurological, immunological, hematological, gastrointestinal, hepatic, renal, or endocrine 
disease or any other condition which, in the opinion of the investigator, could compromise 
the subject’s welfare, ability to communicate with the study staff, or otherwise 
contraindicate study participation. 
16. Has a history or current diagnosis of schizophrenia or another significant psychiatric 
disorder which, in the opinion of the investigator, would affect the subject’s ability to 

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comply with the study requirements.  Stable bipolar disease and stable major depressive 
disorder is allowed. 
17. Is receiving systemic chemotherapy, has an active malignancy of any type, or has been 
diagnosed with cancer within 5 years before Screening (excluding squamous or basal cell 
carcinoma of the skin). 
18. Has a known or suspected history of alcoholism or drug abuse or misuse within 1 year 
before Screening or evidence of tolerance or physical dependence before study drug 
administration. 
19. Has, or has had within 1 year, any clinically significant gastrointestinal (GI) disorder, 
including peptic or gastric ulcers or GI bleeding. 
20. Has a medical or surgical condition of the GI system (including motility dysfunction) or 
renal system that might significantly alter the absorption, distribution, or excretion of any 
drug substance. 
21. Is considered by the investigator, for any reason (including, but not limited to, the risks 
described as precautions, warnings, and contraindications in the current version of the 
investigator’s brochure for AXS-07 tablets), to be an unsuitable candidate to receive the 
study drug. 
22. Is using or expects to use concurrent analgesic, including NSAIDs (except aspirin at a dose 
of ≤ 325 mg daily for cardiovascular prophylaxis) during the trial. NOTE: NSAIDs and 
other analgesics maybe used during the Screening Period.  
23. Is currently receiving or expects to use anticoagulants (e.g., heparin, warfarin, nutritional 
supplements having anticoagulant properties); or has bleeding problems, coagulation 
abnormalities, active blood dyscrasia, hemorrhagic disease, anemia, porphyria, 
phenylketonuria, bone marrow suppression, or immunosuppression. 
24. Is currently receiving propranolol or has received propranolol within 2 weeks prior to 
randomization.  
25. Has been treated with agents that could affect the analgesic response (such as central alpha 
agents adrenergic [clonidine and tizanidine]) within 2 weeks before randomization or 
expects to use such agents during the treatment period. 
26. Has tested positive for drugs of abuse on the urine drug screen at randomization (Visit 2). 
Subjects who test positive at Screening and can produce a prescription for the medication 
from their physician may be considered for study enrollment at the discretion of the 
investigator. NOTE: The use of marijuana, medical or otherwise, is not permitted during 
the study and a positive test for THC will be exclusionary.  
27. Has clinically significant abnormalities indicated from the medical history, physical exam, 
and laboratory findings at Screening that in the investigator’s opinion contraindicates study 
participation. 
28. Is HIV positive. 
29. Has previously participated in another clinical study of AXS-07 or received any 
investigational drug or device or investigational therapy within 30 days before Screening. 
30. Has significant difficulty swallowing tablets or is unable to tolerate oral medication. 
 

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 Packaging 
The study drug will be packaged in bottles, which will include 1 tablet and will blinded to the 
investigator, the study clinic personnel, and subjects. 
 
Study Medication Administration 
Eligible subjects will be randomized and dispensed study drug at Visit 2.  At this visit, the site will 
instruct the subject how to use the Headache Diary and when to take the dose of study medication.  
Study medication will be taken upon the occurrence of a migraine.    
Once a migraine occurs, the subject will be prompted by the Headache Diary to self-administer 
the dose of study medication with water.  The subject must not sleep or nap for at least 2 hours 
after taking study drug.  If the subject reports vomiting within 2 hours of study drug dosing, the 
exact time of vomiting should be recorded in the eCRF. 
 
Dispensing and Storage 
The study drug is to be used exclusively in this clinical study according to the instructions of this 
protocol. The investigator or designee is responsible for dispensing the study drug according to 
the dosage scheme and for ensuring its proper storage. 
The investigator or designee must confirm the receipt of the study drug. A copy of this receipt 
must be kept by the investigator or designee and another copy will be stored at Axsome and/or its 
designee. The study drug will be dispensed to the subject at Visit 2 (randomization).  The study 
drug will be self-administered by the subject at the onset of a migraine attack.  The subject will 
have up to 6 weeks after being randomized to treat a migraine attack with study drug. 
Once study drug has been received on site it must be stored at 25°C (77°F) and in a dry place in a 
securely locked area that is not generally accessible. Excursions between 15° and 30°C (59° and 
86°F) are permitted.  The storage area will be accessible only to those persons authorized by the 
investigator. 
 
Method of Assigning Subjects to Treatment Groups 
In this parallel-group randomized study, subjects who meet study entry criteria will be randomly 
assigned in a 1:1 ratio to AXS-07 or placebo. The randomization schedule will be computer 
generated using a permuted block algorithm that will randomly allocate the study drug to 
randomization numbers. The randomization numbers will be assigned sequentially through a 
central interactive web response system (IWRS) as subjects are entered into the study. The 
randomization schedule will not be stratified. Study center will not be a blocking factor in the 
randomization schedule. 
The randomization schedule will be prepared before the start of the study. No one involved in the 
study performance will have access to the randomization schedule before official unblinding of 
treatment assignment. No subject will be randomized into this study more than once. 
 
Blinding and Unblinding Treatment Assignment 
All subjects, investigators, and study personnel involved in the conduct of the study, including 
data management, will be blinded to treatment assignment with the exception of a specified 
independent unblinded statistician and clinical supply manager who will have access to the 
randomization code. The unblinded study personnel will not otherwise participate in study 
procedures or data analysis before unblinding of the study data to all study related personnel. 

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Study personnel will strive to safeguard the integrity of the study blind to minimize bias in the 
conduct of the study. Treatment unblinding is discouraged if knowledge of the treatment 
assignment will not materially change the planned management of a medical emergency. 
Unblinding will be permitted in a medical emergency that requires immediate knowledge of the 
subject’s treatment assignment. Unblinding should be discussed in advance with the medical 
monitor if possible. For emergency unblinding, the investigator will use the IWRS. If the 
investigator is not able to discuss treatment unblinding in advance, then he or she must notify the 
medical monitor as soon as possible about the unblinding incident without revealing the subject’s 
treatment assignment. The investigator or designee must record the date and reason for study 
discontinuation on the appropriate eCRF for that subject. In all nonemergency cases, the 
investigator must discuss the event with the medical monitor before unblinding the subject’s 
treatment assignment. 
If treatment assignment is unblinded for an individual subject, study personnel will be notified of 
that subject’s treatment assignment without unblinding those of the remaining subjects in the 
study. Thus, the overall study blind will not be compromised. If a subject’s treatment assignment 
is unblinded, he or she may or may not be asked to withdraw from the study. The investigator will 
make this decision after consultation with the medical monitor. 
Official study unblinding will occur after the last subject has completed and the database has been 
locked. 
 
Selection of Doses in the Study 
The dose of AXS-07 in this study incorporates a rizatriptan dose (10 mg) which was selected 
because it is currently approved for the acute treatment of migraine, and because it has been shown 
to be efficacious in several large controlled clinical trials. The oral meloxicam dose (20 mg) in 
AXS-07 was selected based on an analysis of the dose-dependent effect of intravenously 
administered meloxicam in the treatment of acute pain, observed in a large controlled trial. 
 
Selection of Timing of Dose for Each Subject 
A single dose will be taken upon the first onset of migraine pain. The study medication is to be 
taken orally with water. 
 
Dose Adjustment Criteria 
Dose adjustment is not allowed during this study. 
 Drug Accountability 
The investigator, or designee, must maintain adequate records showing the receipt, dosing, or other 
disposition of the study drug provided, including the date, quantity, batch or code number, and 
identification of subjects (subject number and initials) who received it. The investigator will not 
supply the study drug to any person except those named as sub-investigators on the Form 
FDA 1572, designated study personnel, and subjects in this study. The investigator will not 
dispense the study drug from any study sites other than those listed on the Form FDA 1572. The 
study drug may not be relabeled or reassigned for use by other subjects. If any of the study drug is 
not dispensed; is lost, stolen, spilled, unusable; or is received in a damaged container, this 
information must be documented and reported to Axsome Therapeutics and appropriate regulatory 
agencies, as required. 

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Upon completion of the study, the study drug (unused and empty packaging, e.g., study drug 
bottles) must be left in the original packaging and returned to Axsome or its designee for 
destruction. 
 Treatment Compliance 
Study drug will be self-administered by the subject. Dosing details will be recorded in the subject’s 
Headache Diary. 
 Permitted and Prohibited Therapies 
All concomitant medications and treatments used (including over-the-counter medications and 
herbal supplements) will be recorded in the source document and on the appropriate eCRF. All 
effort should be made to record medications taken for migraine over the past 3 months. This 
includes both current and prior medications. 
During the Screening Period, subjects may treat their migraines according to their standard of care.  
All medications used to treat migraines will be recorded in the Headache Diary. 
 Rescue Medication 
No rescue medication use is allowed within 2 hours after the start of the migraine attack. After the 
2-hour diary time point has been recorded, if the subject has inadequate relief from the study 
medication, they may take an allowed rescue medication. Barbiturates and ergotamine-containing 
medications are not allowed as rescue medications.  
Examples of allowed medications include triptans, NSAIDs, antiemetics, non-NSAID analgesics 
(e.g., acetaminophen, gabapentin), and sedatives.  
 Permitted Therapies  
Migraine prophylactic agents and selective serotonin reuptake inhibitors (SSRIs) / SNRIs are 
permitted if the subject has been on a stable dose for 8 weeks (2 months) prior to randomization.  
The 
use 
of 
calcitonin 
gene-related 
peptide 
(CGRP) 
monoclonal 
antibodies 
and 
onabotulinumtoxinA (Botox®) for migraine prophylaxis is allowed if the subject has been on stable 
doses for at least 6 months prior to randomization.  No changes in dose will be permitted during 
the study. 
The following medications for acute migraine treatment will be permitted during screening and 
prior to receiving study drug.  These medications may not be used 24 hours before, concurrently 
or within 24 hours after treatment with study drug. 
• Ergotamine-containing medications 
• Barbiturates 
 Prohibited Therapies 
The following medications are not permitted in the 2 weeks before randomization and for the 
duration of the study. 
• MAO-A inhibitors 
• Methylergonovine  
• Cimetidine  

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• Propranolol 
• Opioids 
Subjects taking ergot alkaloids for prophylaxis for acute migraine will be excluded from the study.   
 Treatment After the End of Study 
After the end of the study, each subject will be treated according to standard clinical practice. 
9. STUDY PROCEDURES 
Subjects will provide written informed consent before any study-related procedures are initiated, 
including the cessation of prohibited concomitant therapy. 
For the timing of assessments and procedures throughout the study, refer to the schedule of events 
(Section 17.1). Throughout the study, every reasonable effort should be made by study personnel 
to follow the timing of assessments and procedures in the schedule of events for each subject. If a 
subject misses a study visit for any reason, the visit should be rescheduled within the visit window 
specified below. 
 
  Study Periods, Visits, and Procedures 
 Visit 1: Screening (Day -28) 
Subjects will sign an ICF before any screening-related procedures are performed. The following 
procedures will be performed at the Screening: 
• Obtain written informed consent. 
• Assign an enrollment number. 
• Review inclusion/exclusion criteria.   
• Confirm diagnosis of migraine with or without aura as defined by the ICHD-3 criteria.  
• Record demographics and detailed medical history, including history of depression, a 
review of medications taken within 30 days before Screening, and migraine medications 
taken for the last 3 months. 
• Record concomitant medications, including planned medications to treat acute migraines 
during the Screening Period. 
• Perform a complete physical examination (excluding breast and genitourinary 
examination) with review of body systems. 
• Record vital signs (blood pressure, heart rate, respiratory rate, and oral body temperature) 
after the subject has been in a seated position for at least 5 minutes. 
• Measure height and weight. 
• Collect ECG. 
• Collect blood and urine samples for clinical laboratory tests (hematology, biochemistry, 
and urinalysis); see Section 9.3.3.2.1 for a complete list of required laboratory tests. 
• Conduct onsite urine analysis for the following: 
• Pregnancy test for females of childbearing potential. 
• Drug screen. 

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• Review the use of a Headache Diary and confirm subject will be willing and able to 
complete diary assessments.  
• Dispense Headache Diary and train on diary completion.  
 
 Screening Period (Day -28 to Day -1) 
The Screening Period is a fixed 28 days prior to randomization, if needed to accommodate 
scheduling the Screening period can be ± 3 days.   
During the Screening Period, the subjects will record and complete the Headache Diary in a similar 
manner that they will during the Treatment Period.  Subjects must have at least 1 migraine and no 
more than 8 migraines during this period in order to be eligible for the study.  Additionally, subjects 
must report at an average of at least 80% compliance of timepoints on the Headache Diary to be 
eligible.   
Subjects will treat all migraines according to their standard of care during the Screening Period 
and all medications will be recorded. 
 Visit 2: Randomization (Day 1) 
Day 1 (Visit 2) is the randomization visit. The following procedures will be performed at Visit 2: 
• Confirm subject continues to meets all inclusion/exclusion criteria.  
• Record vital signs (blood pressure, heart rate, respiratory rate, and oral body temperature) 
after the subject has been in a seated position for at least 5 minutes. 
• Record weight. 
• Conduct onsite urine analysis for the following: 
• Pregnancy test for females of childbearing potential. 
• Drug screen. 
• Review instructions with the subject on how to use the electronic diary. 
• Complete ASC-12 and MIDAS. 
• Randomize and dispense study medication. 
• Train subject on when to take study medication. 
• Record new or changes to concomitant medications. 
Following the Baseline visit and prior to treating a migraine, the subject should be contacted 
regularly to review the following: 
• Record new or changes to concomitant medications. 
• Review instructions completion of the Headache Diary. 
• Review when to take study medication. 
Once the subject has a qualifying migraine, the subject should be contacted as soon as possible, 
within 24 hours, following study drug administration.  During the call, the following should be 
reviewed: 
• Record AEs and rescue medication use. 

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• If study drug was taken on an empty stomach. If not, the type of food and timing relative 
to study drug should be recorded.  
• If applicable, timing of migraine related to menstrual cycle. 
• Ensure subject is completing migraine pain diary and questionnaires & assess compliance. 
• Schedule Visit 3, within 7 days of dose. 
 End of Study: Visit 3 (within 7 days of study drug administration) 
The following procedures should be conducted at the End of Study visit: 
• Record AEs and concomitant medications. 
• Record vital signs (blood pressure, heart rate, respiratory rate, and oral body temperature) 
after the subject has been in a seated position for at least 5 minutes. 
• Record weight. 
• Perform a physical examination. 
• Collect ECG. 
• Collect blood and urine samples for clinical laboratory tests (hematology, biochemistry, 
and urinalysis); see Section 9.3.3.2.1 for a complete list of required laboratory tests. 
• For females of childbearing potential, conduct a urine pregnancy test. 
• Collect Headache Diary from subject. 
• Collect study drug. 
 Early Termination Visit 
An early termination visit will occur if the subject is randomized, but does not receive study drug.  
During the visit, the following will occur.   
• Record reason for early termination. 
• Collect Headache Diary from subject. 
• Collect study drug. 
 
Study Duration 
The study will last up to approximately 10 weeks for an individual subject. 
 
Assessments 
 Efficacy 
9.3.1.1 Headache Diary  
A Headache Diary will be provided to subjects who will be trained by study personnel on how to 
use the diary at Screening. 
The Headache Diary will be completed for 28 days during the Screening Period to record each 
migraine. After randomization, the subject will log the migraine in the diary, which will prompt 
the subject when to take the dose.  

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The diary will be used to record baseline headache characteristics (eg, severity, location, and 
quality of pain), and the ongoing severity of the headache pain (0-none, 1-mild, 2-moderate, 3-
severe), presence or absence of associated symptoms (photophobia, phonophobia, nausea), 
functional disability (none, mild, moderate, or severe), and Patient Global Impression of Change 
(PGI-C). Subjects will be instructed to complete the diary at the specified time points for 48 hours 
after a migraine. 
9.3.1.1.1 Headache Pain Intensity  
Headache pain intensity (measured by a 4-point rating scale; 0-none, 1-mild, 2-moderate, or 3-
severe), will be recorded by the subject in the Headache Diary.  
Pain intensity will be collected at the following time points: baseline, 20, 30 and 45 minutes, and 
1, 2, 4, 12, 16, 24, and 48 hours after dosing. 
9.3.1.1.2 Most Bothersome Symptom Reporting 
The presence or absence of the following migraine symptoms will be recorded by the subject in 
the Headache Diary: nausea, photophobia, phonophobia.  At the beginning of each migraine, (and 
prior to dosing in the Treatment Period) the subject will define the most bothersome symptom and 
will assess the presence or absence of each symptom at the following time points: 30 minutes, and 
1, 2, and 4 hours after dosing.   
9.3.1.1.3 Functional Disability  
Patient-reported level of functional disability (degree of interference with normal activities) will 
be measured using a 4-point rating scale. Functional disability will be recorded by the subject in 
the Headache Diary at the beginning of each migraine (prior to dosing during the Treatment 
Period), and at 30 minutes, and 1, 2, 4, 12, and 24 hours after dosing. 
9.3.1.1.4 Patient Global Impression of Change 
The PGI-C is 7-point scale completed by a patient.  It measures a general assessment of the 
improvement or worsening of the underlying disease (migraine headache).  Subjects will complete 
the PGI-C at 2 hours following reporting a migraine.  
9.3.1.2 Allodynia Symptom Checklist (ASC-12) 
The ASC-12 is a validated checklist to assess the degree of allodynia in migraine sufferers [8, 9].  
Sum scores on the ASC-12 range from 0 to 24 and are divided into no allodynia (0-2), mild 
allodynia (3–5), moderate allodynia (6–8), and severe allodynia (≥9). 
Allodynia will be assessed at Baseline using the ASC-12.   
9.3.1.3 Migraine Disability Assessment (MIDAS) 
The MIDAS questionnaire is a validated 5-item questionnaire developed to assess headache-
related disability [10, 11,12]. The MIDAS score is based on five disability questions in three 
dimensions: school/job, housework, and social. Each of the 5 questions is answered based on the 
number of days, in the past 3 months, of activity limitations due to migraine. The score is the sum 
of responses which are categorized in to the following categories: little or no disability (0 – 5), 
mild disability (6 - 10), moderate disability (11 – 20), and severe disability (21+). Two 

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supplemental non-scored questions provide additional clinical information about headache 
frequency and the average pain intensity of headaches over the previous three months.   
The MIDAS questionnaire will be administered at Baseline. 
 Clinical Pharmacology 
Not applicable for this study. 
9.3.3 
Safety 
Safety assessments will include the evaluation of treatment emergent adverse events (TEAEs); 
clinical laboratory test results; vital sign measurements; and physical examination findings. 
9.3.3.1 Adverse Events 
The definitions and management of and special considerations for AEs are provided in Section 10. 
9.3.3.2 Clinical Laboratory Safety Assessments 
9.3.3.2.1 Clinical Laboratory Tests to be Performed 
Samples for the following laboratory tests will be collected at the time points specified in the 
schedule of events (Section 17.1). 
Hematology 
Hemoglobin, hematocrit, red blood cell count, red blood cell indices, 
mean corpuscular hemoglobin, mean corpuscular hemoglobin 
concentration, platelet count (or estimate), and white blood cell count, 
including differential 
Serum Chemistry 
Albumin, total bilirubin, direct bilirubin, total protein, calcium, alkaline 
phosphatase, alanine aminotransferase, aspartate aminotransferase, 
blood urea nitrogen, creatinine, glucose, sodium, potassium, and 
chloride.  
Urinalysis 
Sp. gravity, pH, glucose, total protein, ketones, color, sample aspect 
(appearance) 
Pregnancy Test 
For women of childbearing potential only. A urine test will be 
performed at screening, randomization, and end of study. 
Urine Drug Screen 
Amphetamines, barbiturates, benzodiazepines, cocaine, opiates, 
phencyclidine, and tetrahydrocannabinol (THC). 
Blood samples for hematology, serum chemistry, and urine samples for urinalysis will be sent to 
a central laboratory for analyses. Urine drug screens and urine pregnancy tests will be conducted 
at the study sites. 
9.3.3.2.2 Specimen Handling Requirements 
The transmission of infectious agents may occur through contact with contaminated needles and 
blood or blood products. Consequently, appropriate blood and body fluid precautions should be 
employed by all study personnel involved in the collection of blood and handling of specimens in 
both the clinic and laboratory settings. Refer to current recommendations of the appropriate 
authorities. 
In addition to appropriate handling of subject samples, specific regulations exist about the 
shipment of biologic/etiologic samples. Procedures and regulations for the packaging and shipping 

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of infectious samples are outlined in the study laboratory manual. The investigator or designee is 
responsible for ensuring that all study samples that are to be transported to another location are 
appropriately packed and shipped according to the applicable regulations.  
9.3.3.2.3 Evaluation of Clinical Laboratory Values 
The normal ranges of values for clinical laboratory assessments in this study will be provided by 
the responsible laboratory and submitted to Axsome or its designee before the start of the study. 
These will be regarded as the reference ranges on which decisions will be made. 
If a clinical laboratory value is out of the reference range, it is not necessarily clinically relevant. 
The investigator is responsible for determining whether these occurrences are considered as AEs. 
All clinical laboratory values that in the investigator’s opinion show clinically relevant or 
pathological changes during or after termination of the treatment must be reported as AEs and 
followed as described in Section 10.2.5. 
All measurements described in this section are recognized standard methods. 
9.3.3.3 Clinical Examinations 
9.3.3.3.1 Vital Signs 
Vital signs will include blood pressure, heart rate, respiratory rate, and oral body temperature. 
Blood pressure will be measured after the subject has been in a sitting position for 5 minutes. 
Height will be measured at Visit 1, and weight will be measured at all visits.  
9.3.3.3.2 Physical Examination 
A complete physical examination (excluding breast and genitourinary examination) will be 
performed at screening and end of study. 
9.3.3.3.3 Electrocardiogram (ECG) 
A 12-lead ECG will be conducted after the subject has been resting for at least 2 minutes. At a 
minimum, the following parameters should be collected; heart rate, PR interval, QRS duration, QT 
interval, and QTcF. 
If the subject reports cardiac related adverse events, they should return for an unscheduled visit 
and an ECG should be conducted. 
10. ADVERSE EVENTS 
 Definitions 
 Adverse Events 
An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product that does not necessarily have a causal relationship with 
the product. An AE can therefore be any unfavorable and unintended sign (including a new, 
clinically important abnormal laboratory finding), symptom, or disease, temporally associated 
with the product, whether or not related to the product. 
Pre-existing diseases or conditions will not be considered AEs unless there is an increase in the 
frequency or severity, or a change in the quality, of the disease or condition. (Worsening of a 
pre-existing condition is considered an AE.) 

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Events that occur in subjects treated with placebo or active comparator or during treatment-free 
periods of the study are also considered AEs. 
 Adverse Drug Reaction 
All noxious and unintended responses to a study drug related to any dose should be considered 
adverse drug reactions (ADRs). 
The phrase “responses to a study drug” means that a causal relationship between a study drug and 
an AE is at least a reasonable possibility, i.e., the relationship cannot be ruled out. All AEs judged 
by either the reporting investigator or the sponsor as having a reasonable causal relationship to a 
study drug qualify as ADRs. 
All AEs for which the judgment of relationship to the study drug is “possible” or higher will be 
considered ADRs. If a relationship to the study drug is not given, then the AE must be treated as 
if the relationship to the study drug were “possible.”  
 Unexpected Adverse Event/Adverse Drug Reaction 
An expected AE or ADR is an event for which the nature or severity is consistent with the known 
AE profile of the product. For a study drug, the known information is contained in the IB. For a 
marketed product, the known information is contained in the current package insert for the product. 
An unexpected adverse event (UAE) or unexpected adverse drug reaction (UADR) is an event for 
which the specificity or severity is not consistent with the current IB. For example, hepatic necrosis 
would be unexpected (greater severity) if the IB only listed elevated hepatic enzymes or hepatitis. 
Likewise, cerebral thromboembolism and cerebral vasculitis would be unexpected (greater 
specificity) if the IB only listed cerebral vascular accidents. 
Furthermore, reports that add significant information on specificity or severity of a known, already 
documented adverse reaction constitute unexpected events. Examples would be a) acute renal 
failure as an expected adverse reaction with a subsequent new occurrence of interstitial nephritis 
(interstitial nephritis would be unexpected) and b) hepatitis with a first occurrence of fulminant 
hepatitis (fulminant hepatitis would be unexpected). 
 Serious Adverse Events/Drug Reaction 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose: 
• Results in death. 
• Is life-threatening. 
NOTE: The term “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. 
• Requires inpatient hospitalization or prolongation of existing hospitalization. 
NOTE: Inpatient hospitalization is defined as 24 hours in a hospital or an overnight stay. 
An elective hospital admission to treat a condition present before exposure to the study 
drug, or a hospital admission for a diagnostic evaluation of an AE, does not qualify the 
condition or event as an SAE. Further, an overnight stay in the hospital that is only due to 
transportation, organization, or accommodation problems and without medical 
background does not need to be considered an SAE. 
• Results in persistent or significant disability/incapacity. 

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• Is a congenital anomaly. 
NOTE: A congenital anomaly in an infant born to a mother who was exposed to the study 
drug during pregnancy is an SAE. However, a newly diagnosed pregnancy in a subject who 
has received a study drug is not considered an SAE unless it is suspected that the study 
drug(s) interacted with a contraceptive method and led to the pregnancy.  
• Is an important medical event. 
NOTE: Medical and scientific judgment should be exercised in deciding whether it is 
appropriate to consider other situations serious, such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require intervention to prevent 1 of the other outcomes listed in the 
definition above. Examples of such events are intensive treatment in an emergency room or 
at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalization, or development of drug dependency or drug abuse. The occurrence of 
malignant tumors is also to be considered serious 
 Significant Adverse Events 
Other significant AEs are defined as marked hematological and other laboratory abnormalities 
(other than those meeting the definition of serious) and any events that led to an intervention, 
including significant additional concomitant therapy. 
 Treatment-Emergent Adverse Events 
An AE is defined as treatment emergent if the first onset or worsening is after the first 
administration of the study drug and not more than 5 days after the last study visit. 
 Management of Adverse Events 
Adverse events will be collected after administration of study drug through Visit 3. 
 Collection of Adverse Events 
The investigator is responsible for the detection and documentation of events meeting the criteria 
and definition of an AE or SAE described previously. At each visit, the subject will be allowed 
time to spontaneously report any issues since the last visit or evaluation. The investigator will then 
monitor and/or ask about or evaluate AEs using nonleading questions, such as: 
• “How are you feeling?” 
• “Have you experienced any issues since your last visit?” 
• “Have you taken any new medications since your last visit?” 
Any clinically relevant observations made during the visit will also be considered AEs. 
 Evaluation of Adverse Events 
10.2.2.1 Severity of Adverse Events 
The clinical severity of an AE will be classified as: 

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Mild 
Usually transient and may require only minimal treatment or therapeutic 
intervention. The event does not generally interfere with usual activities of 
daily living. 
Moderate 
Usually alleviated with additional specific therapeutic intervention. The event 
interferes with usual activities of daily living, causing discomfort but poses no 
significant or permanent risk of harm to the subject. 
Severe 
Interrupts usual activities of daily living, or significantly affects clinical status, 
or may require intensive therapeutic intervention. 
It is important to distinguish between severe AEs and SAEs. Severity is a classification of intensity 
whereas an SAE is an AE that meets serious criteria, as described in Section 10.1.4. 
10.2.2.2 Seriousness 
The investigator is to evaluate whether the AE meets serious criteria, as described in 
Section 10.1.4. 
10.2.2.3 Action(s) Taken 
Action(s) taken may consist of: 
Dose not changed 
An indication that a medication schedule was maintained. 
Not applicable 
Determination of a value is not relevant in the current context. 
Unknown 
Not known, not observed, not recorded, or refused. 
10.2.2.4 Outcome at the Time of Last Observation 
The outcome, including Fatal, at the time of last observation will be classified per eCRF 
completion instructions.  Only select fatal as an outcome when the AE results in death. If more 
than 1 AE is possibly related to the subject’s death, the outcome of death should be indicated for 
each such AE. Although “fatal” is usually an event outcome, events such as sudden death or 
unexplained death should be reported as SAEs. 
10.2.2.5 Adverse Event Relationship to the Study Drug 
The investigator will also assess the relationship (if any) between the AE and the study treatment 
(not related, unlikely, possibly, probably or definitely). 
The investigator will use the following definitions to classify the relationship of an AE to study 
medication: 
Not related: 
AEs which, after careful consideration, are clearly and undeniably because of 
extraneous causes (e.g. disease, environment); 
Unlikely: 
This category can generally be considered applicable to those AEs which, after 
careful medical consideration at the time they are evaluated, are judged to be 
unrelated to the test drug. An AE may be considered unlikely to be related if or 
when at least two of the following criteria are fulfilled: 

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1) The event does not follow a reasonable temporal sequence from administration 
of the test drug; 
2) The event could readily have been produced by the patient’s clinical state, 
environmental or toxic factors, or other modes of therapy administered to the 
patient; 
3) The event does not follow a known pattern of response to the test drug; 
4) The event does not reappear or worsen when the drug is re-administered. 
Possibly:  
This category applies to those AEs for which, after careful medical consideration at 
the time they are evaluated, a connection with the test drug administration appears 
unlikely, but cannot be ruled out with certainty. An AE may be considered possibly 
related if or when at least two of the following criteria are fulfilled: 
1) The event follows a reasonable temporal sequence from administration of the 
drug; 
2) The event could not readily have been produced by the patient’s clinical state, 
environmental or toxic factors, or other modes of therapy administered to the 
patient; 
3) The event follows a known pattern of response to the test drug. 
Probably: 
This category applies to those AEs which, after careful medical consideration at the 
time they are evaluated, are felt with a high degree of certainty to be related to the 
test drug. An AE may be considered probably related if or when least three of the 
following criteria are fulfilled: 
1) The event follows a reasonable temporal sequence from administration of the 
drug; 
2) The event could not be reasonably explained by the known characteristics of the 
patient’s clinical state, environmental or toxic factors, or other modes of therapy 
administered to the patient; 
3) The event disappears or decreases on stopping or reducing the dose. There are 
important exceptions when an AE does not disappear upon discontinuation of 
the drug, but drug-relatedness clearly exists, e.g. bone marrow depression, fixed 
drug eruptions, tardive dyskinesia; 
4) The event follows a known pattern of response to the test drug. 
Definitely: 
This category applies to those AEs, which the investigator feels are undeniably 
related to the test drug. An AE may be assigned an attribution of definitely related 
if or when all the following criteria are fulfilled: 
1) The event follows a reasonable temporal sequence from administration of the 
drug; 
2) The event could not be reasonably explained by the known characteristics of the 
patient’s clinical state, environmental or toxic factors, or other modes of therapy 
administered to the patient; 
3) The event disappears or decreases on stopping or reducing the dose and reappears 
with re-exposure to study medication (Note: this does not mean that the patient 
is to be re-exposed to study medication, however, a category of definitely related 
can only be used when recurrence is observed); 

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4) The event follows a known pattern of response to the test drug. 
 Documentation 
All AEs occurring within the period of observation for the study must be documented in the eCRF 
with the following information, where appropriate. (The period of observation for the study is 
described in Section 10.2.) 
• AE name or term. 
• When the AE first occurred (start date and time). 
• When the AE stopped (stop date and time or an indication of “ongoing”). 
• Severity of the AE. 
• Seriousness (e.g., hospitalization or death). 
• Actions taken. 
• Outcome. 
• Investigator opinion regarding the AE relationship to the study drug(s). 
 Treatment of Adverse Events 
Adverse events that occur during the study will be treated if necessary by established standards of 
care. If such treatment constitutes a deviation from the protocol, the subject may continue in the 
study at the discretion of Axsome after consultation with the investigator and/or medical monitor. 
If AEs occur in a subject that are not tolerable, or for which continued administration of the study 
drug is not reasonable in view of the potential benefit to the subject, the investigator must decide 
whether to stop the study and/or treat the subject. Special procedures may be recommended for the 
specific study drug, such as the collection of a serum sample for blood concentrations of the study 
drug, specific tapering procedures, or treatment regimens, as appropriate. 
For double-blinded studies, it is not necessary to unblind a subject’s treatment assignment in most 
circumstances, even if an SAE has occurred. If unblinding is necessary, see Section 8.6 for a 
description of the unblinding procedures. 
 Follow-up of Adverse Events 
Any AE will be followed (up to a maximum of 30 days after the subject’s last visit in the study) 
to a satisfactory resolution, until it becomes stable, or until it can be explained by another known 
cause(s) (i.e., concurrent condition or medication) and clinical judgment indicates that further 
evaluation is not warranted. All findings relevant to the final outcome of an AE must be reported 
in the subject’s medical record and recorded on the appropriate eCRF. 
 Notification 
10.2.6.1 Serious Adverse Events 
The investigator or designee must report all SAEs within 24 hours of first becoming aware of the 
event by completing the Serious Adverse Event Report Form.  
 
 At the time of first notification, the 
investigator or designee should provide the following information, if available: 
• Protocol number. 

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• Reporter (study site and investigator). 
• Subject’s study number and initials. 
• Subject’s date of birth. 
• Subject’s gender. 
• Date of dose of study drug. 
• Adverse event term. 
• Time and date of occurrence of the event. 
• A brief description of the event, outcome to date, and any actions taken. 
• The seriousness criteria(on) that were met. 
• Concomitant medication at onset of the event. 
• Relevant past history information. 
• Relevant laboratory test findings. 
• Investigator’s opinion of the relationship to the study drug(s). (“Is there a reasonable possibility 
that the study drug caused the SAE? Yes or No?”). 
• Whether and when the investigator was unblinded as to the subject’s treatment assignment. 
The investigator must also promptly provide any available supporting information which is 
requested after review of the initial SAE Report Form. 
Any missing or additional relevant information concerning the SAE should be provided in a 
follow-up SAE Report Form. Ensure that any additional information requested about the event 
(e.g., hospital reports, autopsy reports) is provided as soon as it is available. 
The investigator is required to comply with applicable regulations (including local laws and 
guidance’s) regarding the notification of his or her health authorities, Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC), principal and coordinating investigators, study 
investigators, and institutions. The detailed reporting duties and division of responsibilities 
between Axsome and designated vendors will be provided in a separate document (see the Safety 
Management Plan). Each investigator is obligated to learn about the reporting requirements for 
investigators in his or her country. The study monitor may be able to assist with this. 
10.2.6.2 Adverse Drug Reactions 
Axsome will report all ADRs related to the study drug to the proper health authorities; serious 
ADRs will be reported immediately and nonserious ADRs will be reported after completion of the 
study. Suspected serious adverse drug reactions must be reported to Axsome immediately, 
regardless of the time that has elapsed since the end of the period of observation. 
10.2.6.3 Nonserious Adverse Events 
Axsome will review nonserious AEs that are recorded in the eCRF on a regular basis. 

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 Special Considerations 
 Adverse Events of Special Interest 
No AEs of special interests have been defined for this study. 
 Pregnancy 
All women of childbearing potential who participate in the study should be counseled on the need 
to practice adequate birth control (from the time of Screening through 30 days beyond the End of 
Study) and on the importance of avoiding pregnancy during study participation. Women should 
be instructed to contact the investigator or study staff immediately if pregnancy occurs or is 
suspected. 
Pregnancy testing will be conducted before administration of the study drug on every woman of 
childbearing potential. A woman who is found to be pregnant at the Screening Visit will be 
excluded from the study and considered a screen failure. 
A woman who becomes pregnant during study drug treatment or within 30 days of discontinuing 
the study drug will be immediately discontinued from study participation. The investigator must 
report the pregnancy as if it were an SAE within 24 hours of learning of the pregnancy. The 
investigator should record information related to the pregnancy on the Pregnancy and Lactation 
Exposure Form provided by Axsome or its designee. 
Early termination visit assessments are required as soon as possible after learning of the pregnancy. 
The investigator is also responsible for following the pregnancy until delivery or termination. 
Findings must be reported on the Pregnancy and Lactation Exposure Form and reported to Axsome 
or its designee. The event meets the SAE criterion only if it results in a spontaneous abortion or a 
congenital anomaly. 
 Overdose 
Subjects should receive no more than one dose of study drug in this study.   
Overdose that occurs during the study will be treated and documented as an AE/UAE/SAE if it 
fulfills the criteria. If the overdose does not result in an AE, it should be reported in written form 
to the designated individual(s) who receive SAE notification. The information contained therein 
should include study site identification, reporter identification, subject identification, study drug, 
dose, action taken (e.g., administration of antidote [if available] or supportive measures or 
therapy), and any comments. 
11. DATA SAFETY MONITORING BOARD 
Not applicable. 
12. STATISTICS 
This section describes the statistical methods to be used to analyze efficacy and safety. These 
methods may be revised and updated due to reasons such as regulatory requirements or need for 
further clarifications. The final analysis plan will be documented in a formal statistical analysis 
plan (SAP) that must be finalized before database lock. The SAP will include details on how 
variables will be derived, how missing data will be handled, and how data will be presented as 

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• Percentage of subjects able to perform normal activity (functional disability = none) at 
Hour 2. 
• Time to being able to perform normal activity (functional disability = none). 
• Percentage of subjects able to perform normal activity (functional disability = none) at 
Hour 1.5. 
• Percentage of subjects able to perform normal activity (functional disability = none) at 
Hour 1. 
• Percentage of subjects able to perform normal activity (functional disability = none) over 
time. 
• 
Sustained ability to function at a normal level (functional disability = none) from Hours 2 
to 24. 
• Sustained ability to function at a normal level (functional disability = none) from Hours 2 
to 48. 
 
Most Bothersome Symptoms 
• Percentage of subjects with absence of MBS over time. 
• Sustained freedom from MBS from Hour 2 to Hour 24. 
• Sustained freedom from MBS from Hour 2 to Hour 48. 
• Absence of photophobia at Hour 2 in the subset of subjects that reported the presence of 
photophobia at headache baseline. 
• Absence of phonophobia at Hour 2 in the subset of subjects that reported the presence of 
phonophobia at headache baseline. 
• Absence of nausea at Hour 2 in the subset of subjects that reported the presence of nausea 
at headache baseline. 
• Absence of photophobia at over time in the subset of subjects that reported the presence 
of photophobia at headache baseline. 
• Absence of phonophobia over time in the subset of subjects that reported the presence of 
phonophobia at headache baseline. 
• Absence of nausea over time the subset of subjects that reported the presence of nausea at 
headache baseline. 
 
Rescue Medication Use 
• Percentage of subjects using rescue medication within 24 hours after administration of 
study medication. 
• Time to rescue medication use. 
 
Other Secondary Endpoints 
• Patient Global Impression of Change (PGI-C) scores at Hour 2. 
• PGI-C scores over time. 
• Treatment response based on presence of allodynia, BMI, pain intensity, presence of 
depression, and use of preventive medication. 
 

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 Safety Endpoints 
Safety endpoints will include the following: 
• Treatment-emergent adverse events (TEAEs) 
• Vital sign measurements 
• Physical exam findings 
• Clinical laboratory parameters 
• ECG 
 Sample Size Determination 
In this study, approximately 150 subjects will be randomized to the AXS-07 and placebo groups. 
Approximately 150 subjects per arm will provide 90% power to detect a treatment difference at a 
two-sided significance level of 0.05, assuming that the responder rate for pain freedom at Hour 2 
is ≤15% for the placebo control and ≥ 29%.   
 Analysis Populations 
The following analysis populations are planned for this study:  
• Intent-to-Treat (ITT) Population: the ITT Population is the primary analysis population and 
will include data from all subjects who are randomized and treat a migraine episode with 
study drug.  
• Safety Population: The Safety Population will include all subjects who receive at study 
medication. 
 Statistical Analyses 
Unless otherwise indicated, all testing of statistical significance will be 2-sided, and a difference 
resulting in a P value of less than or equal to 0.05 will be considered statistically significant. 
Furthermore, the baseline will be the last assessment before the first dosing of the study 
medication. 
Summary statistics will be provided for the variables described in the following sections. For 
continuous variables, these statistics will typically include the number of subjects, mean, standard 
deviation (SD), median, minimum, and maximum. For categorical variables, these statistics will 
typically include the number and percentage of subjects in each category. 
 Study Subjects and Demographics 
12.4.1.1 Disposition and Withdrawals 
The numbers of subjects completing, withdrawing, and discontinuing treatment, along with 
reasons for discontinuation or withdrawal, will be tabulated overall, and by treatment group. The 
number of subjects in each analysis population will be reported. 
12.4.1.2 Protocol Deviations 
Major protocol deviations will be classified and documented by Axsome before database lock and 
will be discussed in the clinical study report (CSR).  All protocol deviations, both minors and 
majors, will be presented in a data listing. 

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12.4.1.3 Demographics and Other Baseline Characteristics 
Demographic and baseline characteristics (including age, sex, race, weight, and height) will be 
summarized for each treatment group and for the overall population by descriptive statistics. 
Medical history and clinical laboratory tests will be listed. 
Prior and concomitant medications will be summarized by treatment group, by the number and 
percentage of subjects taking each medication, classified using World Health Organization (WHO) 
Drug Dictionary, Anatomical Therapeutic Chemical (ATC) classes, and preferred terms. 
 Exposure and Compliance 
Study drug administration will be summarized in terms of dose taken (yes / no) by treatment group. 
 Efficacy Analyses 
Efficacy variables will be summarized and analyzed using the ITT population unless otherwise 
specified. 
12.4.3.1 Primary Efficacy Analysis 
The co-primary efficacy endpoints are the 1) percentage of subjects with headache pain freedom 
at 2 hours after dosing, with headache pain freedom defined as a reduction in headache severity to 
no pain, and 2) absence of the most bothersome symptom (MBS; nausea, photophobia, or 
phonophobia) 2 hours after dosing, with the MBS defined at the onset of migraine, prior to drug 
administration.  Full details of the analysis will be outlined in the SAP. 
12.4.3.2 Secondary Efficacy Analyses 
The secondary efficacy endpoints will be analyzed using methods similar to those outlined for the 
primary efficacy analysis.  Full details of the analysis will be outlined in the SAP. 
 Adverse Events 
Adverse events will be coded by system organ class (SOC) and preferred term using the Medical 
Dictionary for Regulatory Activities (MedDRA) reporting system. Treatment-emergent AEs are 
defined as AEs with onset on the date of first dose of treatment with the study drug through Visit 
3/End of Study (EOS). 
The number and percentage of subjects with TEAEs will be displayed for each treatment group by 
SOC and preferred term. Additionally, TEAEs will be tabulated for each treatment group by 
severity and by relationship to the study drug. A listing of SAEs will be provided if applicable. 
 Vital Signs 
Descriptive summaries (mean, SD, median, minimum, and maximum) of actual values and 
changes from Baseline will be calculated for systolic blood pressure, diastolic blood pressure, heart 
rate, respiratory rate, and oral body temperature. 
 Physical Examination Findings 
Physical examination data will be presented in the listings. 
 Interim Analysis 
None. 

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13. STUDY CONDUCT 
Steps to ensure the accuracy and reliability of data include the selection of qualified investigators 
and appropriate study sites, review of protocol procedures with the investigator and associated 
personnel before the study, periodic monitoring visits, and meticulous data management. 
 Sponsor and Investigator Responsibilities 
 Sponsor Responsibilities 
Axsome is obligated to conduct the study in accordance with strict ethical principles (Section 15). 
Axsome reserves the right to withdraw a subject from the study (Section 7.3), to terminate 
participation of a study site at any time (Section 13.5.3), and/or to discontinue the study 
(Section 13.5.2). 
Axsome agrees to provide the investigator with sufficient material and support to permit the 
investigator to conduct the study according to the study protocol. 
 Investigator Responsibilities 
By signing the Investigator’s Agreement (Section 17.2), the investigator indicates that he or she 
has carefully read the protocol, fully understands the requirements, and agrees to conduct the study 
in accordance with the procedures and requirements described in this protocol. 
The investigator also agrees to conduct this study in accordance with all laws, regulations, and 
guidelines of the pertinent regulatory authorities (Section 15.1 and Appendix E). While delegation 
of certain aspects of the study to sub investigators and study coordinators is appropriate, the 
investigator will remain personally accountable for closely overseeing the study and for ensuring 
compliance with the protocol and all applicable regulations and guidelines. The investigator is 
responsible for maintaining a list of all persons that have been delegated study-related 
responsibilities (e.g. sub investigators and study coordinators) and their specific study-related 
duties. 
Investigators should ensure that all persons who have been delegated study-related responsibilities 
are adequately qualified and informed about the protocol, study drugs, and their specific duties 
within the context of the study. Investigators are responsible for providing Axsome with 
documentation of the qualifications, GCP training, and research experience for themselves and 
their staff as required by Axsome and the relevant governing authorities. 
To ensure compliance with the guidelines, the study will be audited by an independent person. The 
investigator agrees, by written consent to this protocol, to cooperate fully with compliance checks 
by allowing access to all study documentation by authorized individuals. 
 Site Initiation 
Study personnel may not screen or enroll subjects into the study until after receiving notification 
from Axsome that the study can be initiated at the study site. The study site will not be authorized 
for study initiation until: 
• The study site has received the appropriate IRB/IEC approval for the protocol and the 
appropriate ICF. 
• All regulatory/GCP documents have been submitted to and approved by Axsome. 
• The study site has a Clinical Trial Agreement in place. 

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• Study site personnel, including the investigator, have participated in a study initiation 
meeting/visit. 
 Study Documents 
All documentation and material provided by Axsome for this study are to be retained in a secure 
location and treated as confidential material. 
 Investigator’s Regulatory Documents 
The regulatory documents are listed as follows: 
• Signed original protocol (i.e., Investigator’s Agreement). 
• Curricula vitae of the principal investigator and sub investigators. 
• Name and address of the laboratories. 
• List of laboratory reference ranges, and if available, a quality certificate. 
• Form Signature Log/Delegation of Study-related Duties. 
• Any other relevant GCP documents. 
The regulatory documents must be received from the investigator and reviewed and approved by 
Axsome before the study site can initiate the study and before Axsome will authorize shipment of 
study drug to the study site. Copies of the investigator’s regulatory documents must be retained at 
the study site in a secure location. Additional documents, including a copy of the protocol and 
applicable amendment(s), the AXS-07 IB, eCRF completion guidelines, copies of regulatory 
references, copies of IRB/IEC correspondence, and study drug accountability records should also 
be retained as part of the investigator’s regulatory documents. It is the investigator’s responsibility 
to ensure that copies of all required regulatory documents are organized, current, and available for 
inspection. 
 Case Report Forms 
By signing the Investigator’s Agreement (Section 17.2), the investigator agrees to maintain 
accurate eCRFs and source documentation as part of the case histories for all subjects who sign an 
ICF. 
Case report forms are considered confidential documents and should be handled and stored 
accordingly. Axsome or its designee will provide the necessary training on the use of the specific 
eCRF system used during the study to ensure that the study information is captured accurately and 
appropriately. 
To ensure data accuracy, eCRF data for individual subject visits should be completed as soon as 
possible after the visit. All requested information must be entered in the electronic data capture 
(EDC) system according to the completion guidelines provided by Axsome or its designee. 
The eCRFs may be signed by the investigator or a sub investigator. These signatures serve to attest 
that the information contained in the eCRF is accurate and true. 
 Source Documents 
All information recorded in the EDC system must be supported by corresponding source 
documentation. Examples of acceptable source documentation include, but are not limited to, 
hospital records, clinic and office charts, laboratory notes, and recorded data from automated 

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instruments, memoranda, and pharmacy dispensing records. Investigators should make attempts 
to collect outside medical records. 
During the study, select eCRF data may be used as original data collection tools as long as a 
description of this documentation process is maintained in the investigator’s study files. Before 
the study starts, a list identifying any data to be recorded directly on the eCRFs (i.e., no prior 
written or electronic record of data) and considered to be source data will be provided. 
Clinical laboratory data required by the protocol will be electronically transferred from the central 
laboratory to Axsome as well as the investigator. A copy of the laboratory results should be 
retained with each subject’s source data. 
 Data Quality Control 
Axsome and its designees will perform quality control checks on this clinical study. 
 Monitoring Procedures 
Axsome will conduct site visits to monitor the study and ensure compliance with the protocol, 
GCP, and applicable regulations and guidelines. The assigned clinical research associate(s) 
(CRA[s]) will visit the investigator and study site at periodic intervals and maintain periodic 
communication. The investigator agrees to allow the CRA(s) and other authorized Axsome 
personnel access. The CRA(s) will maintain current personal knowledge of the study through 
observation, review of study records and source documentation, and discussion of the conduct of 
the study with the investigator and staff. While on site, the CRA(s) will review the following: 
• Regulatory documents, directly comparing entries in the EDC system with the source 
documents. 
• Consenting procedures. 
• AE procedures. 
• Storage and accountability of the study drug and study materials. 
The CRA will ask for clarification and/or correction of any noted inconsistencies. Procedures for 
correcting the eCRF are described in the CRF completion guidelines. As representatives of 
Axsome, CRAs are responsible for notifying project management of any noted protocol deviations. 
By signing the Investigator’s Agreement (Section 17.2), the investigator agrees to meet with the 
CRA(s) during study site visits; to ensure that study staff is available to the CRA(s) as needed; to 
provide the CRA(s) access to all study documentation, to the clinical supplies dispensing and 
storage area; and to assist the monitors in their activities, if requested. Further, the investigator 
agrees to allow Axsome or designee auditors or inspectors from regulatory agencies to review 
records and to assist the inspectors in their duties, if requested. 
 Data Management 
Axsome or its designee will be responsible for activities associated with the data management of 
this study. The standard procedures for handling and processing records will be followed per GCP 
and Axsome or its vendors’ standard operating procedures. A comprehensive data management 
plan will be developed including a data management overview, database contents, annotated CRF, 
pre-entry review list, self-evident correction conventions, query contacts, and consistency checks. 
Study site personnel will be responsible for providing resolutions to all data queries. The 
investigator will be required to document electronic data review to ensure the accuracy of the 

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corrected and/or clarified data. Procedures for soliciting and documenting resolution to data 
queries are described in the CRF completion guidelines. 
 Quality Assurance/Audit 
This study will be subject to audit by Axsome or its designee. The audits will be undertaken to 
check compliance with GCP guidelines and will include a minimum of: 
• In-house study file audit. 
• Audit of computer database quality control. 
• Audit of clinical report quality control. 
Axsome or its designee may conduct additional audits on a selection of study sites, requiring access 
to subject notes, study documentation, and facilities or laboratories used for the study. 
The study site, facilities, all data (including source data), and documentation will be made available 
for audit by quality assurance auditors and for IRB/IEC or regulatory authorities according to GCP 
guidelines. The investigator agrees to cooperate with the auditor during the visit and will be 
available to supply the auditor with CRFs or other files necessary to conduct that audit. Any 
findings will be strictly confidential. 
If a regulatory authority informs the investigator that it intends to conduct an inspection, the 
investigator shall notify Axsome immediately. 
 Study Termination 
The study may be terminated at Axsome’s discretion at any time and for any reason. 
 Regular Study Termination 
The end of this study is defined as the date of the last visit of the last subject (last subject out or 
last subject last visit) participating in the study. Within 90 days of the end of the clinical study, 
Axsome will notify the IRBs/IECs and regulatory authorities on the regular termination of the 
study as required according to national laws and regulations. 
 Premature Study Termination 
The study may be terminated prematurely for any reason and at any time by Axsome, IRBs/IECs, 
regulatory authorities, respective steering committees, or the coordinating investigator. A decision 
to prematurely terminate the study is binding to all investigators of all study sites. 
Within 15 days of premature termination of a clinical study, Axsome or its designee will notify 
the IRB/IEC and regulatory authorities as appropriate on the premature termination as required 
according to national laws and regulations. Axsome or its designee must clearly explain the reasons 
for premature termination. 
If the study is terminated prematurely, all investigators have to inform their subjects and take care 
of appropriate follow-up and further treatment of the subjects to ensure protection of the subjects’ 
interests. Study sites may be asked to have all subjects currently participating in the study complete 
all of the assessments for the Early Termination Visit. 

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 Study Site Closure 
A study site’s participation in the study may be terminated at any time by Axsome.  At the end of 
the study, all study sites will be closed.  This will include the Investigators final approval and lock 
of all patient data, return of unused study material and investigational product unless otherwise 
provided for in writing by Axsome, and final visits by study monitors. 
 Record Retention 
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should be 
separated into two categories: investigator’s study file and patient clinical source documents. 
The investigator’s study file will contain the protocol and protocol amendments (if applicable), 
eCRF guidelines, IRB / IEC approval with correspondence, informed consent, drug records, staff 
curriculum vitae and authorization forms and other appropriate documents and correspondence. 
Patient clinical source documents (which are usually defined by the project in advance to record 
key efficacy and/or safety parameters independent of the eCRF) may include patient and/or 
hospital clinical records, physician’s and nurse’s notes, appointment book, original laboratory 
reports, X-ray, pathology and special assessment reports, consultant’s letters, screening and 
enrollment log, etc. 
The patient’s involvement in the study should be clearly documented in the study site’s clinical 
records. Details should include the study protocol number, the patient’s screening and 
randomization number, the patient’s consent to take part in the study (including the date of 
consent), the dates of all study visits, details of any treatments withdrawn because of study 
participation, the dates of dispensing study medication, details of any AEs (including any SAEs), 
and changes in concomitant medications. 
Study documents should not be destroyed without prior written agreement between Axsome and 
the investigator. If the investigator wishes to assign the study records to another party or move 
them to another location, Axsome must be notified in advance. 
If the investigator cannot guarantee this archiving requirement for any or all the documents at the 
investigational site, arrangements must be made between the investigator and Axsome to store 
these in a sealed container(s) outside the site. The sealed container(s) can therefore be returned to 
the investigator in case of a regulatory audit. Where source documents are required for the 
continued care of the patient, appropriate copies should be made for storing outside the site. 
 Changes to the Protocol 
This protocol cannot be altered or changed except through a formal protocol amendment, which 
requires the written approval of Axsome. The protocol amendment must be signed by the 
investigator and approved by the IRB/IEC before it may be implemented at a site. Protocol 
amendments will be filed with the appropriate regulatory agencies having jurisdiction over the 
conduct of the study. 
 Use of Information and Publication 
All information concerning AXS-07, Axsome’s operations, patent applications, formulas, 
manufacturing processes, basic scientific data, and formulation information supplied by Axsome 

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or its designee to the investigator and not previously published, is considered confidential and 
remains the sole property of Axsome. Case report forms also remain the property of Axsome. The 
investigator agrees to use this information for purposes of study execution through finalization and 
will not use it for other purposes without the written consent of Axsome. 
The information developed in this study will be used by Axsome in connection with the continued 
development of AXS-07 and thus may be disclosed as required to other clinical investigators or 
government regulatory agencies. 
The information generated by this study is the property of Axsome. Publication or other public 
presentation of AXS-07 data resulting from this study requires prior review and written approval 
of Axsome. Abstracts, manuscripts, and presentation materials should be provided to Axsome for 
review and approval at least 30 days before the relevant submission deadline. Data from individual 
study sites must not be published separately, unless otherwise agreed to in writing by the Axsome. 
It is agreed that the results of the study will not be submitted for presentation, abstract, poster 
exhibition or publication by the investigator until Axsome has reviewed and commented on such 
a presentation or manuscript for publication. 
14. FINAL CLINICAL STUDY REPORT 
Axsome will retain ownership of the data generated from the study. 
The final clinical study report will be written within 1 year of completion of the clinical part of the 
study. This report will include a summary of the study results based on a statistical evaluation and 
clinical assessment of the protocol-defined endpoints. 
15. ETHICAL AND LEGAL CONSIDERATIONS 
 Declaration of Helsinki and Good Clinical Practice 
This study will be conducted in compliance with the April 1996 ICH Guidance for Industry E6 
GCP (including archiving of essential study documents), the 1996 Version of the Declaration of 
Helsinki, and the applicable regulations of the countries in which the study is conducted. 
See Appendix E for regulations and guidelines. 
 Subject Information and Informed Consent 
A properly constituted, valid IRB/IEC must review and approve the protocol, the investigator’s 
informed consent document, and related subject information and recruitment materials before the 
start of the study. 
It is the responsibility of the investigator to ensure that written informed consent is obtained from 
the subject before any activity or procedure is undertaken that is not part of routine care. 
According to the Declaration of Helsinki and ICH GCP, subjects must provide their written 
informed consent before enrollment in a clinical study and before any protocol-specified 
procedures are performed. Subjects must declare their consent by personally signing and dating 
the ICF. The written ICF will embody the elements of informed consent as described in the 
Declaration of Helsinki and will also comply with local regulations.  
Each subject should be made aware by the investigator of the nature of the study (i.e., objectives, 
methods, and potential hazards and benefits) and the procedures involved, using the information 
on the ICF. Information should be given in both oral and written form whenever possible and 

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deemed appropriate by the IRB/IEC. Subjects, their relatives (or if necessary, legal representatives) 
must be given ample opportunity to inquire about details of the study. 
Subject information and the ICF must be in a language fully comprehensible to the prospective 
subject. The written information must be provided to the subject to give him or her sufficient time 
to understand the information and to prepare questions before being asked for his or her consent. 
The investigator must confirm that the text was understood by the subject. The subject will then 
sign and date the IRB/IEC-approved consent form indicating that he or she has given his or her 
consent to participate in the study. The signature confirms the consent is based on information that 
has been understood. The form will also be signed by the investigator obtaining the consent and 
annotated with the study subject number. Each subject’s signed ICF must be kept on file by the 
investigator for possible inspection by regulatory authorities, Axsome, and/or designated 
personnel. Collection of informed consent has to be documented on the eCRF. 
Furthermore, the subject will be informed that if he or she wishes to dropout or withdraw (see 
Section 7.3) at any time during the study, this will not have any negative consequences. Subjects 
may be withdrawn by the investigator if any change related to safety or ethics precludes further 
participation in the study. Subjects will be asked to agree to a final assessment in the event of an 
early termination of the study. 
Subjects will be informed that data from their case may be stored in a computer without inclusion 
of their name and such data will not be revealed to any unauthorized third party. Data will be 
reviewed by the monitor, an independent auditor, and possibly by representatives of regulatory 
authorities and/or IRBs/IECs. The terms of the local data protection legislation will be applied as 
appropriate. 
 Approval by Institutional Review Board and Independent Ethics Committee 
For investigational new drug studies, the minimum standards of conduct and requirements for 
informed consent are defined in the US FDA regulations. 
A valid IRB/IEC must review and approve this protocol before study initiation. Written 
notification of approval is to be submitted by the investigator to the Axsome monitor before 
shipment of investigational drug supplies and will include the date of the committee’s approval 
and the chairperson’s signature. This written approval must consist of a completed Axsome IRB 
Approval Form or written documentation from the IRB/IEC containing the same information. 
Until written approval by the IRB/IEC has been received by the investigator, no subject may 
undergo any procedure solely for determining eligibility for this study. 
Protocol amendments must also be reviewed and approved by the IRB/IEC. Axsome must receive 
their written approval before implementation. This written approval will consist of a completed 
IRB/IEC approval form or written documentation from the IRB/IEC containing the same 
information. 
 Finance and Insurance 
Details on finance and insurance will be provided in a separate agreement between the investigator 
and Axsome. 
 

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16. REFERENCES 
1. Merck & Co., Inc. Maxalt® (rizatriptan) FDA Package Insert. Revised 3/2015. 
2. Boehringer Ingelheim, Inc.  Mobic® (meloxicam) FDA Package Insert. Revised 6/2016. 
3. Demaagd G. The pharmacological management of migraine, part 1: overview and abortive 
therapy. P T. 2008 Jul;33(7):404-16. 
4. Pernix Therapeutics Limited. Treximet® (sumatriptan and naproxen sodium) FDA Package 
Insert. Revised 05/2016. 
5. Lipton RB, Fanning KM, Serrano D, Reed ML, Cady R, and Buse DC.  Ineffective acute 
treatment of episodic migraine is associated with new-onset chronic migraine. Neurology. 
2015 Feb 17; 84(7): 688–695. 
6. Lipton RB, Kolodner K, Bigal ME, Valade D, Láinez MJ, Pascual J, Gendolla A, Bussone G, 
Islam N, Albert K, Parsons B. Validity and reliability of the Migraine-Treatment Optimization 
Questionnaire. Cephalalgia. 2009 Jul;29(7):751-9. 
7. Lipton RB, Manack AN, Serrano D, and Buse DC.  Acute treatment optimization for migraine: 
results of the American migraine prevalence and prevention (AMPP) study. The Journal of 
Headache and Pain 2013. 14(Suppl 1):P201. 
8. Lipton RB, Bigal ME, Ashina S, et al. Cutaneous allodynia in the migraine population. Ann 
Neurol 2008;63: 148–158. 
9. Bigal ME, Ashina S, Burstein R, et al. Prevalence and characteristics of allodynia in headache 
sufferers: a population study. Neurology 2008;70:1525–1533. 
10. Stewart WF, Lipton RB, Kolodner KB, Sawyer J, Lee C, Liberman JN. Validity of the 
Migraine Disability Assessment (MIDAS) score in comparison to a diary-based measure in a 
population sample of migraine sufferers. Pain 2000;88:41-52 
11. Stewart WF, Lipton RB, Whyte J, Dowson A, Kolodner K, Liberman JN, Sawyer J. An 
international study to assess reliability of the Migraine Disability Assessment (MIDAS) score. 
Neurology 1999; 53:988-94 
12. Stewart WF, Lipton RB, Kolodner K, Liberman J, Sawyer J. Reliability of the migraine 
disability assessment score in a population-based sample of headache sufferers. Cephalalgia 
1999; 19:107-14 
 
 

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17. ATTACHMENTS
Schedule of Assessments
Visit 1 
Visit 2 
Visit 3 
Screening 
Randomization 
Follow-upd / EOS 
Day  -28 
Day 1 
Within 7 days of 
dosing 
Informed Consent 
X 
Inclusion/Exclusion Criteria 
X 
X 
Demographics 
X 
Medical History 
X 
Migraine Headache History 
X 
X 
Medications, Prior and Concomitant, or Non-drug Therapy  
X 
X 
X 
Physical Examination, including height and weight
X 
X 
Vital Signs (seated blood pressure, pulse, oral body temp.) 
X 
X 
X 
ECG 
X 
X 
Clinical Laboratory Tests 
X 
X 
Urine Pregnancy Testa 
X 
X 
X 
Urine Drug Screen 
X 
X 
MIDAS 
X 
ASC-12 
X 
Randomization 
X 
Dispense Headache Diary and Instruct on Use 
X 
X 
Review Compliance with Headache Diary 
X 
X 
Dispense Study Drug & Provide Dosing Instructions 
X 
Subject Completes Diary Datab 
X 
Phone call contactc 
X 
Return Headache Diary 
X 
Collect/Inventory Study Medication 
X 
Adverse Eventse 
X 
X 
Abbreviations:  ASC-12 = 12-item Allodynia Symptom Checklist; ECG = electrocardiogram; MIDAS = Migraine Disability 
Assessment; PGI-C = patient global impression of change. 
a.
For women of child-bearing potential only. Test results must be negative at Screening and Randomization for the subject to
continue in the study.
b.
Headache Diary data will be collected at the following times: Baseline (at first onset of migraine pain (pre-dose) and 20, 30
and 45 minutes, and 1, 1.5, 2, 4, 12, 16, 24, and 48 hours after dosing
c.
The subject should be contacted within 24 hours after administering study medication.  During the post-dose call, the site should 
re-confirm study drug dosing instructions and check for changes in concomitant medications. Following the onset of a
qualifying migraine, assess compliance with migraine pain diary, rescue medication use, and to schedule the follow up
appointment.
d.
Final visit after treating one attack (to be scheduled as soon as possible but within 7 days of dosing), or within 6 weeks after
Visit 2 if the study medication not used.
e.
Adverse events are not required to be collected if subjects do not receive a dose of study medication.

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Version Date: Amendment 1, December 13, 2019 
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 Investigator’s Agreement 
PROTOCOL NUMBER: 
AXS-07-303 
PROTOCOL TITLE: 
INTERCEPT (Initiating Early Control of Migraine Pain and Associated 
Symptoms): 
A Randomized, Double-blind, Single-dose, Placebo-controlled Study 
to Assess the Efficacy and Safety of AXS-07 (meloxicam and 
rizatriptan) for the Acute Treatment of Migraine in Adults. 
VERSION: 
Amendment 1 - December 13, 2019 
I have read this protocol and the investigator’s brochure and agree to conduct this clinical study as 
outlined herein. I will ensure that all sub-investigators and other study staff members have read 
and understand all aspects of this protocol. I agree to cooperate fully with Axsome and its 
designated vendors during the study. I carry out the study in accordance with the revised 
Declaration of Helsinki 1996. I will adhere to all FDA, ICH, and other applicable regulations and 
guidelines regarding clinical studies on a study drug during and after study completion. 
Having considered fully all the available information, I consider it is ethically justifiable to give 
the study drug to selected subjects in my care according to the study protocol. I: 
• Agree to use the study material, including the study drug, only as specified in the protocol and 
understands that changes cannot be made to the protocol without prior written approval from 
Axsome. 
• Understand that any violation of the protocol may lead to early termination of the study. 
• Agree to report to Axsome within time any clinical AE or abnormal laboratory value that is 
serious, whether or not considered related to administration of the study drug. 
• Agree to comply with Axsome and regulatory requirements for the monitoring and auditing of 
this study. 
I, the undersigned, have carefully read this protocol and agree that it contains all the necessary 
information required to conduct the study. 
Principal Investigator: 
 
 
Printed Name: 
 
 
 
 
 
 
 
 
Signature: 
 
 
 
 
 
 
 
Date: 
 
 
 
 

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Version Date: Amendment 1, December 13, 2019 
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APPENDICES 
A. Address List 
 
 
 
E. Regulations and Good Clinical Practice Guidelines 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Version Date: Amendment 1, December 13, 2019 
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E. Regulations and Good Clinical Practice Guidelines 
 
1. 
Regulations 
Refer to the following United States Code of Federal Regulations (CFR): 
• FDA Regulations 21 CFR, Parts 50.20 – 50.27 
Subpart B – Informed Consent of Human Subjects 
• FDA Regulations 21 CFR, Parts 56.107 – 56.115 
Part 56 – Institutional Review Boards 
Subpart B – Organization and Personnel 
Subpart C – IRB Functions and Operations 
Subpart D – Records and Reports 
• FDA Regulations 21 CFR, Parts 312.50 – 312.70 
Subpart D – Responsibilities of Sponsors and Investigators 
 
2. 
Good Clinical Practice Guidelines 
ICH GCP guidelines can be found at the following URL: 
http://www.ich.org/LOB/media/MEDIA482.pdf