Clinical trial NCT05679908
Conditions: Chronic Migraine Chronic Migraine, Headache Chronic Migraine Without Aura Aura Migraine
Keywords: Migraine Chronic Migraine Headache Chronic Migraine Without Aura Aura Migraine
Sponsor: Tonix Pharmaceuticals, Inc.
Start date: 2022-12-06; Completion date: 2023-10-23
Enrollment: 88 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a phase 2, double-blind, randomized, multicenter, placebo-controlled, three arm parallel study to evaluate the efficacy and safety of two different dosages (30 IU daily and 60 IU daily) of TNX-1900 in patients with chronic migraine.

Detailed description:

Arms: arm 1: 30 IU oxytocin taken intranasally twice daily. arm 2: 30 IU oxytocin taken intranasally once daily. Placebo taken intranasally once daily. arm 3: Placebo taken intranasally twice daily.
Interventions: intervention 1: TNX-1900 intervention 2: Placebo Nasal Spray
Intervention descriptions: intervention 1: Patients will spray TNX-1900 once into each nostril. intervention 2: Patients will spray placebo nasal spray once into each nostril.

Protocol documents:
Prot_000.pdf: 


TNX-1900 
 
Tonix Pharmaceuticals, Inc. 
Clinical Trial Protocol TNX-OX-CM201 
 
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Amendment 4, 11 January  2023  
 
 
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prohibited. 
INVESTIGATOR’S AGREEMENT 
I have read the TNX-OX-CM201 protocol entitled “A Phase 2, Double-blind, Randomized, 
Multicenter, Placebo-controlled, Three Arm Parallel Study to Evaluate the Efficacy and 
Safety of TNX-1900 (Intranasal Oxytocin) in Patients with Chronic Migraine, Amendment 
03” and agree to conduct the study as outlined. I also agree to maintain the confidentiality of 
all information received or developed in connection with this protocol.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date 
 


TNX-1900 
 
Tonix Pharmaceuticals, Inc. 
Clinical Trial Protocol TNX-OX-CM201 
 
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Amendment 4, 11 January  2023  
 
 
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prohibited. 
PROCEDURES IN CASE OF EMERGENCY 
 
Emergency Contact Information 




TNX-1900 
 
Tonix Pharmaceuticals, Inc. 
Clinical Trial Protocol TNX-OX-CM201 
 
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days in the Run-In period, but every effort should be made to minimize to the 
fewest days needed for the given washout period(s) in the protocol.   
 
During the Run-In, patients will be required to answer questions daily 
regarding headaches and rescue (abortive) medication use on an electronic 
diary (e-diary) regardless of whether patients experienced a headache on that 
day. It is a patient’s responsibility to be compliant with e-diary entries. Each 
patient’s headache frequency, as well as e-diary compliance, will be 
evaluated at the end of the Run-in Period to ensure a patient meets all 
required eligibility criteria for treatment randomization. For evaluating 
randomization eligibility, the last 28 days of Run-In diary entries will be 
used, which includes diary entries logged on the morning of the Baseline 
Visit. A patient must not be informed of the minimum number of headache 
days and migraine headache days required to be randomized to study 
treatment as this might bias e-diary entries during Run-in Period. 
 
During this Screening and Run-In Period, if any test results come back and 
indicate a patient’s ineligibility for the study, the patient should be considered 
a screen-failure (SF) and informed that they are not eligible for the study and 
can stop completing the e-diary.  However, if the investigator determines that 
the patient should be brought back into the clinic for re-testing, the patient 
should continue completing the e-diary until a final determination regarding 
eligibility is made. 
 
In addition, any patients not meeting the randomization criteria will be 
considered a failure. 
 
Double-blind Treatment Period (V2: Baseline/Randomization Visit; and V3, 
4, 5: Treatment Visits) 
The Treatment Period will last for about 84 days. At Visit 2, eligible patients 
will be randomized 1:1:1 to one of 3 treatment arms (A, B or C) as 
summarized above. Randomization will be stratified by study site and 
concomitant migraine preventative medication (use of a single preventative 
vs no preventative). Patients will be required to answer daily questions 
regarding headaches, rescue (abortive) medication use, and study drug 
compliance using an e-diary, regardless of whether a headache occurred that 
day. 
All patients who withdraw early from the study will be encouraged to 
complete the Early Termination Visit for safety evaluations (Visit 5 [V5]) 
within 7 days from withdrawal, followed by the Safety Follow-up Visit 
(Visit 6) approximately 14 days from the last study drug administration. 
Safety Follow-up Period (Visit 6: in-person Safety Follow-up Visit) 
Approximately 14 days (+4 days window) after Visit 5 or End of Treatment 
(ET) Visit, all randomized patients will attend a Safety Follow-up Visit. 
  


TNX-1900 
 
Tonix Pharmaceuticals, Inc. 
Clinical Trial Protocol TNX-OX-CM201 
 
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prohibited. 
 
Dose and 
Route of 
Administration: 
Investigational Product (TNX-1900) 
TNX-1900 is provided as a preservative-free, aqueous, oxytocin containing 
solution for intranasal delivery. TNX-1900 will be supplied as a 150 IU/mL 
concentration of oxytocin. One dose of study drug requires 2 administration 
sprays into the nostrils (1 spray per nostril). The volume of each spray is 
0.10 mL. Given the 150 IU/mL concentration, each spray delivers 15 IU of 
study drug. Consequently, one dose (2 sprays: one spray per nostril) equates 
to a 30 IU oxytocin total dose. 
 
Dose  
Treatment 
Administration 
30 IU QAM / 
Placebo QPM 
A 
1 dose from ‘MORNING’ nasal spray bottle = 1 spray 
each nostril of TNX-1900 (2 sprays total) 
1 dose from ‘EVENING’ nasal spray bottle = 1 spray 
each nostril of placebo (2 sprays total) 
30 IU QAM / 
30 IU QPM 
B 
1 dose from ‘MORNING’ nasal spray bottle = 1 spray 
each nostril of TNX-1900 (2 sprays total) 
1 dose from ‘EVENING’ nasal spray bottle = 1 spray 
each nostril of TNX-1900 (2 sprays total) 
Placebo QAM / 
Placebo QPM 
C 
1 dose from ‘MORNING’ nasal spray bottle = 1 spray 
each nostril of placebo (2 sprays total) 
1 dose from ‘EVENING’ nasal spray bottle = 1 spray 
each nostril of placebo (2 sprays total) 
 
The nasal spray bottle of MORNING study drug will be clearly labeled 
‘MORNING’. The EVENING study drug will be clearly labeled 
‘EVENING’. 
 
During the double-blind Treatment Period, patients will be instructed to self-
administer ONE dose (2 sprays total, 1 spray per nostril) of ‘MORNING’ 
study drug daily at a fixed time in the morning and ONE dose (2 sprays total, 
1 spray per nostril) of ‘EVENING’ study drug at a fixed time in the evening. 






TNX-1900 
 
Tonix Pharmaceuticals, Inc. 
Clinical Trial Protocol TNX-OX-CM201 
 
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Amendment 4, 11 January  2023  
 
 
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prohibited. 
7. The patient is willing and able to comply with all protocol-specified 
requirements. 
8. Capable of reading and understanding English and able to provide 
written informed consent to participate.  
Exclusion 
Criteria: 
 
1. History of cluster headache. 
2. Presence of headaches more than 26 days a month on average for the 6 
months prior to Screening. 
3. Failed to benefit from an adequate dose and duration, in the 
investigator’s judgment (e.g., one month of β-blocker), of 3 or more 
migraine preventive medications. 
4. History of seizure disorder other than childhood febrile seizures. 
5. The patient is at increased risk of suicide based on the investigator’s 
judgment, or the results of the Columbia Suicide Severity Rating Scale 
(C-SSRS) conducted at Screening and Baseline (e.g., C-SSRS Type 3, 4 
or 5 ideation during the preceding 6 months and/or any suicidal behavior 
within the past 12 months). 
6. In general, chronic use of systemic steroidal or non-steroidal anti-
inflammatory drugs (NSAIDs) and combination products containing 
NSAIDs for any indication will be prohibited during the Screening 
Period and during the study. The following instructions should be 
followed: 
a. Excepting topical usage, chronic use of systemic steroidal anti-
inflammatory drugs is not allowed for any indication. 
b. Chronic use of NSAIDs on a daily basis is not allowed; therefore, 
those on daily NSAIDs necessary for treatment of other medical 
conditions, e.g., arthritis, should not be enrolled; NSAIDs may be 
used as needed (PRN) for headache pain only if they are part of 
patient’s typical migraine/headache abortive treatment regimen; 
other use of NSAIDs is allowed as needed for other acute pain 
syndromes, but daily use is not allowed. 
7. Use of opiates or barbiturates more than 4 days per month for more than 
3 consecutive months prior to Visit 1 and during the study. 
8. Use of the following non-pharmacological treatments for headache or 
any other indication, is prohibited within 90 days prior to Screening and 
throughout the entire study: any electrical or magnetic stimulating 
devices (e.g., non-invasive vagal nerve stimulation [GammaCore], 
transcranial magnetic stimulation [TMS Mini], or Remote Electrical 
Neuromodulation [REN or Nerivio]). Any types of psychotherapy stress 
management, acupuncture, chiropractic manipulation, and physical 
therapy is prohibited within 90 days of Screening and throughout the 
entire study only if the treatment is specifically targeted for the relief of 
headaches, migraines, or any type of head and neck pain. Otherwise, 
such treatments must have been ongoing for at least 90 days prior to 
Visit 1 with a plan to continue throughout the study to be eligible. Also, 
occipital nerve blocks or botulinum toxin treatments for any indication 
are prohibited within 90 days of Screening and throughout the entire 
study. 


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Tonix Pharmaceuticals, Inc. 
Clinical Trial Protocol TNX-OX-CM201 
 
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prohibited. 
9. Use of over-the-counter (OTC) nasal products (i.e., saline spray, Neti-
Pot, Naväge® etc.) during the study. 
10. History of unstable psychiatric illness requiring hospitalization in the 
12 months prior to Visit 1. Coexisting conditions, such as depression and 
anxiety, may be included if they are stable on current treatment regimens 
(with no change in treatment regimen for the last 90 days) and no 
planned changes during the study. 
11. History of or evidence supporting a diagnosis of borderline personality 
disorder (BPD) based on a score of ≥ 7 on the McLean Screening 
Instrument for BPD (MSI-BPD) at Visit 1 (Screening) and/or the 
investigator’s opinion. 
12. Body mass index (BMI) > 40 kg/m2. 
13. Any clinically significant medical condition that, in the opinion of the 
investigator, would make the patient unsuitable for study participation 
and completion. 
14. Any use of intranasal corticosteroid medications or conditions in which 
use of intranasal corticosteroids may be indicated during the study, e.g., 
unstable allergic rhinitis that has previously required intranasal 
corticosteroids. Intranasal corticosteroid use is not allowed within 
28 days of Baseline/Randomization/Visit 2 and during the treatment 
phase or follow-up period of the study. 
15. Clinically significant laboratory or ECG abnormality (in the 
investigator’s opinion) based on Screening laboratory tests, or any of the 
following: 
a. Aspartate aminotransferase (AST) and/or alanine aminotransferase 
(ALT) > 2 times the upper level of normal (ULN) 
b. Serum creatinine > 1.2 times the ULN 
c. Thyroid stimulating hormone (TSH) > 1.5 times the ULN 
d. HbA1c > 7.5% 
e. Resting heart rate ≤ 45 bpm or ≥ 100 bpm 
f. Clinically significant arrhythmia or heart block 
g. Corrected QT interval by the Fridericia formula (QTcF) > 470 ms 
for females; and > 450 ms for males. 
16. History of chronic nasal obstruction or local pathology in nostril 
pathway which, in the opinion of the investigator, would prevent 
appropriate nasal administration of the study drug. 
17. Known allergy or hypersensitivity to oxytocin containing products. 
18. Positive results for illegal or abused substances other than 
cannabis/tetrahydrocannabinol at Screening or Baseline.  
19. Women who are pregnant, planning to become pregnant, or nursing 
during the study. 
20. Currently enrolled in or have participated within the last 30 days in a 
clinical trial involving an investigational product prior to Visit 1 (does 
not apply to anti-CGRP agent studies covered in Exclusion 21). 
21. Patients who recently discontinued treatment with an anti-calcitonin-
gene-related peptide (CGRP) antibody or participated in an anti-CGRP 
antibody clinical study must be at least 4 months from the last drug 


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Clinical Trial Protocol TNX-OX-CM201 
 
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prohibited. 
administration prior to Visit 1. Patients in an extended observational 
period  from such an anti-CGRP antibody study and are at least 4 months 
from the last drug administration prior to Visit 1 are eligible. Small 
molecule anti-CGRP treatments, e.g., gepants, are treated similarly but 
only must be at least 1 month from last drug administration prior to Visit 
1. 
22. History of clinically significant and currently relevant cardiovascular 
disease or vascular ischemia (including myocardial, cerebral, peripheral 
extremity or other ischemic event) or thromboembolic events (arterial or 
venous thrombotic or embolic events) such as cerebrovascular accident, 
deep vein thrombosis, or pulmonary embolism. Recent myocardial 
infarction (within the last 2 years). Diagnosed with heart failure. 
23. History of alcohol or drug abuse within the prior year, or alcohol or drug 
dependence within the prior 5 years, as defined by the Diagnostic and 
Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). 
Eligibility 
Criteria for 
Randomization: 
Up to approximately 30% of the patients randomized into the study can be on 
1 migraine preventative medication. Once this category is filled, only patients 
who are not on any preventative medications can be randomized into the 
study. From study start, sites should enroll patients into both categories in 
parallel until informed otherwise. 
 
For a patient to be eligible for randomization, the following should be 
observed during the last 28 days of the Run-in Period: 
1. Demonstrate an ability to properly use e-diary. 
2. Complete ≥ 82% of the e-diary daily entries (at least 23 days out of the 
28-day period). 
3. At least 14 headache (migraine-like or tension-type-like) days  
4. At least 8 days where the patient experiences any of the following: 
• 
An attack lasting 4 hours or more and meeting the ICHD-3 criteria 
(diagnostic criteria C and D) for migraine without aura (Appendix A) 
• 
Migraine with aura 
• 
Probable migraine (a migraine subtype fulfilling all but one criterion 
(B-D) for migraine without aura) 
• 
An attack of any duration that was believed by the patient to be a 
migraine and was relieved by a triptan, ergot derivative, or other 
migraine-specific abortive medication. 
 
It is important to note that the last 28 days of Run-In diary entries includes 
diary entries logged on morning of the Baseline Visit. Patients should be 
reminded to complete the required e-diary entries on the morning of the 
Baseline Visit. 
 
Patients may be withdrawn from the Run-in Period prior to the end of 
28 days if patients are determined mathematically to be unable to meet the 
headache criteria required by the protocol. 
 




TNX-1900 
 
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Clinical Trial Protocol TNX-OX-CM201 
 
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Amendment 4, 11 January  2023  
 
 
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prohibited. 
Efficacy 
Secondary 
Endpoints: 
 
• Mean change from Baseline in the Migraine Disability Assessment 
(MIDAS) Test total score at Week 12. 
• Mean change from Baseline in the Hospital Anxiety and Depression 
Scale (HADS) total score at Week 12. 
• Mean change from Baseline in patient-rated Changes in Sexual 
Functioning Questionnaire Short-Form (CSFQ-14) total score in males 
and in females, analyzed separately, at Week 12. 
Exploratory 
Endpoints: 
• Proportion of patients experiencing a ≥ 75% reduction in the number of 
migraine headache days from the last 28 days of Baseline to the last 28 
days of treatment in each treatment group.  
• Proportion of patients with fewer than 14 headache days or fewer than 8 
migraine headache days per 4 weeks over the 12-week period. 
• Mean change from Baseline in number of headache free days from the 
last 28 days of Baseline to the last 28 days of treatment. 
• PGIC rating (1-7) at Week 12 
 
Safety 
Endpoints: 
 
• Change in suicidality using the C-SSRS scale 
• Incidence of adverse events (AEs) 
• Changes from Baseline in clinical laboratory tests 
• Changes from Baseline in vital signs 
• Change from Baseline in ECG parameters 
• Clinically significant change(s) in physical examination findings 
• Clinically significant change(s) in nasal examination findings 
• Changes from Baseline in the Hospital Anxiety and Depression Scale 
(HADS) total score at Week 12 
• Changes from Baseline in patient-rated Changes in Sexual Functioning 
Questionnaire Short-Form (CSFQ-14) in males and in females, 
described separately 
Statistical 
Methods: 
 
The modified intention-to-treat population (mITT), defined as all randomized 
patients who receive at least 1 dose of study drug and have at least one post-
Baseline, evaluable month (that is, at least one of the three 28-day periods has 
at least 14 non-missing e-diary entries), will be used as the primary 
population for all efficacy analyses. The sample size and power calculations 
for this study are based on the analysis of the primary efficacy outcome 
variable: mean change in the number of migraine headache days from the last 
28 days of Baseline to the last 28 days of treatment in each treatment group. 
Efficacy Analysis 
The primary efficacy endpoint of change from Baseline will be analyzed 
using a mixed-effects model of repeated measures (MMRM) with fixed 
effects of treatment, month, baseline value, treatment by month interaction, 


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Clinical Trial Protocol TNX-OX-CM201 
 
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prohibited. 
baseline by month interaction, site, and stratification factor (preventive 
medication use); an unstructured covariance matrix will be used.   
Several secondary efficacy outcomes will be measured and compared 
between treatment groups. Appropriate methodology for multiplicity will be 
applied across doses and to the key secondary efficacy endpoints to maintain 
overall alpha of 0.05; this will be specified in the Statistical Analysis Plan 
(SAP). 
Formal safety data monitoring is not planned for this study. 
An interim analysis will be performed once 50% of the planned patients have 
enrolled and those patients have either completed or discontinued the study. 
The purpose of the interim will be to potentially increase the sample size to 
maintain statistical power conditioned on the results of the first 50% of 
patients; or continue as planned if conditional probability of success at end of 
the Treatment Period is above a pre-specified threshold; or to stop the study 
early for futility if the conditional power is sufficiently low. Full details of 
the interim analysis will be included in the SAP and finalized prior to 
execution of the interim analysis. 
Safety Analysis 
AEs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) and will be summarized overall and by preferred term and system 
organ class. AEs will also be summarized by severity and relationship to 
study drug. Serious AEs, AEs involving the nasal passages, and AEs leading 
to discontinuation of study drug will also be summarized. Actual values and 
changes from Baseline for clinical laboratory test results, ECG parameters, 
vital signs, HADS scores, and CSFQ-14 scores will be summarized using 
descriptive statistics (n, mean, SD, median, minimum, and maximum). The 
number of patients with baseline and treatment-emergent suicidal ideation 
and/or suicidal behavior, based on the C-SSRS, will be summarized by 
treatment group.  


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Clinical Trial Protocol TNX-OX-CM201 
 
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Amendment 4, 11 January  2023  
 
 
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SCHEDULE OF ASSESSMENTS 
 
Study Phase 
Screening/Washout 
(Up to 21 days) 
 
Run-In 
(At least 28 days*) 
 
Treatment 
84 days 
Follow-upb 
14 days 
Study Visit 
V1 
Screening  
V2 
Baseline/ 
Randomization 
V3 
V4 
V5 
Or Early 
Terminationa 
Visit 6 
End-of-
Study In-
Person  
Study Week 
 
 
 
Week 4 
Week 8 
Week 12 
Week 14 
Study Days 
Day -49 to Day -1 
Day 1 
Day 29 + 4d 
Day 57 + 4d 
Day 85 + 4d 
Day 99 + 4d 
Informed Consent 
X 
 
 
 
 
 
Inclusion/ Exclusion Criteria 
X 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Medical and Medication History 
X 
Xc 
 
 
 
 
Adverse Events Assessment 
 
X 
X 
X 
X 
X 
Concomitant Medication 
X 
X 
X 
X 
X 
 
Physical Exam 
X 
X 
 
 
X 
 
Nasal Exam 
X 
X 
X 
X 
X 
Xd 
Vital Signs 
X 
X 
X 
X 
X 
X 
12-Lead ECG 
X 
X 
X 
X 
X 
 
Blood Hematology-Central 
X 
 
 
 
X 
Xf 
Blood Chemistry-Central 
X e 
X e 
X e 
X e 
Xe 
Xe,f 
Urinalysis-Central 
X 
X 
X 
X 
X 
Xf 
Pregnancy Testg 
X 
X 
X 
X 
X 
X 
Urine Drug Testh (UDT)-Central 
X 
 
 
 
 
 
Thyroid Stimulating Hormone (TSH)-
Central 
X 
 
 
 
 
 
HbA1c 
X 
 
 
 
 
 


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Clinical Trial Protocol TNX-OX-CM201 
 
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Study Phase 
Screening/Washout 
(Up to 21 days) 
 
Run-In 
(At least 28 days*) 
 
Treatment 
84 days 
Follow-upb 
14 days 
Study Visit 
V1 
Screening  
V2 
Baseline/ 
Randomization 
V3 
V4 
V5 
Or Early 
Terminationa 
Visit 6 
End-of-
Study In-
Person  
Study Week 
 
 
 
Week 4 
Week 8 
Week 12 
Week 14 
Study Days 
Day -49 to Day -1 
Day 1 
Day 29 + 4d 
Day 57 + 4d 
Day 85 + 4d 
Day 99 + 4d 
Optional Pharmacogenomics 
 
X 
*s 
* s 
* s 
* s 
C-SSRSi 
X 
X 
X 
X 
X 
X 
MSI-BPDj 
X 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
Placebo Response Training 
Xt 
X 
X 
X 
X 
 
E-diary Trainingk 
X 
X 
X 
X 
 
 
E-diary Assessmentl 
X 
X 
X 
X 
 
 
Dispense Study Drug 
 
Xm 
X 
X 
 
 
Return study drug and Perform 
Accountability  
 
 
X 
X 
X 
 
Review e-diary 
 
X 
X 
X 
X 
 
PGICn 
 
 
X 
X 
X  
 
HADSo 
 
X 
X 
X 
X 
 
MIDASp 
 
X 
 
 
X 
 
MSQq 
 
X 
X 
X 
X 
 
CSFQ-14r 
 
X 
 
 
X 
 
*     Any extension beyond 28 days is only allowed for scheduling purposes or e-diary compliance due to technical issues and up to a maximum of 7 days. 
a 
An Early Termination Visit will be conducted approximately 7 days (+3 days) of withdrawing from study 


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Clinical Trial Protocol TNX-OX-CM201 
 
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b 
Follow-up visit will be conducted approximately 14 days (± 4 days) after Visit 5 
c 
Record any changes to the medication history obtained at Screening 
d 
Nasal exam will only be performed at Visit 6 if any abnormality on exam at Visit 5 or any report of a nasal cavity AE 
e 
Chemistry panel only: triggered serum osmolality will be measured from same specimen if sodium is below the lower limit of normal  
f 
Urinalyses, hematology and chemistry labs will only be repeated at Visit 6 if clinically significant findings were observed at Visit 5 
g 
Women of childbearing potential only: screening serum pregnancy test will be analyzed at Central laboratory; consecutive urine pregnancy tests will be 
conducted on-site at every subsequent study visit 
h 
Urine drug test: cocaine, phencyclidine (PCP), barbiturates, amphetamines, cannabis, and opiates 
i 
C-SSRS: Columbia Suicide Severity Rating Scale 
j 
MSI-BPD: McLean Screening Instrument for Borderline Personality Disorder 
k 
E-diary training will be conducted at Visit 1 (Screening Visit) and Visit 2 (Treatment) and will be repeated at Visits 3 and 4. E-diary is collected at Visit 5 
l 
Patients will start completing their e-diary the day after their Screening Visit. 
m 
Study drug administration training performed at Visit 2 in addition to dispensation of study drug 
n 
PGIC: Patient Global Impression of Change 
o 
HADS: Hospital Anxiety and Depression Scale 
p 
MIDAS: Migraine Disability Assessment questionnaire 
q 
MSQ: Migraine-Specific Quality of Life Questionnaire v2.1  
r 
CSFQ-14: Changes in Sexual Functioning Questionnaire Short-Form 
s 
Pharmacogenomics should be drawn at Baseline but if it is not drawn, drawing at a subsequent visit is allowed. 
t 
Placebo Response training will be conducted in the form of a video that patients watch at Visit 1. At subsequent visits (V2-V5), training will be conducted 
via a paper script that the site staff reviews with the patient.


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Clinical Trial Protocol TNX-OX-CM201 
 
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TABLE OF CONTENTS 
SCHEDULE OF ASSESSMENTS ..........................................................................................15 
TABLE OF CONTENTS .........................................................................................................18 
1 
INTRODUCTION .................................................................................................24 
2 
STUDY OBJECTIVES ..........................................................................................26 
3 
INVESTIGATIONAL PLAN ................................................................................27 
3.1 
Overall Study Design and Plan ........................................................................27 
3.2 
Rationale for Study Design and Placebo Group ..............................................29 
3.3 
Study Duration and Dates ................................................................................29 
4 
STUDY POPULATION SELECTION .................................................................30 
4.1 
Inclusion Criteria for Enrollment .....................................................................30 
4.2 
Exclusion Criteria for Enrollment ....................................................................31 
4.3 
Eligibility Criteria for Randomization .............................................................33 
4.4 
Withdrawal of Patients .....................................................................................34 
5 
STUDY TREATMENT(S) ....................................................................................36 
5.1 
Description of Treatment(s) .............................................................................36 
5.1.1 
Study Drugs .........................................................................................36 
5.2 
Treatments Administered .................................................................................36 
5.3 
Method of Assigning Patients to Treatment Groups ........................................37 
5.4 
Blinding and Unblinding..................................................................................37 
5.5 
Concomitant Therapy.......................................................................................38 
5.5.1 
Permitted Therapy ................................................................................38 
5.5.2 
Prohibited Therapy ...............................................................................39 
5.6 
Restrictions ......................................................................................................39 
5.6.1 
Prior Therapy .......................................................................................39 
5.6.2 
Fluid and Food Intake ..........................................................................39 
5.6.3 
Reproductive Restrictions ....................................................................39 
5.7 
Treatment Compliance .....................................................................................40 
5.8 
Packaging and Labeling ...................................................................................40 
5.9 
Dispensing, Storage and Accountability ..........................................................41 
6 
STUDY PROCEDURES .......................................................................................42 
6.1 
Informed Consent.............................................................................................42 
6.2 
Medical, Psychiatric and Medication History ..................................................42 
6.3 
Physical Examination.......................................................................................42 
6.4 
Nasal Examination ...........................................................................................42 
6.5 
Vital Signs ........................................................................................................43 


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Clinical Trial Protocol TNX-OX-CM201 
 
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6.6 
Electrocardiogram (ECG) ................................................................................43 
6.7 
Clinical Laboratory Tests .................................................................................43 
6.7.1 
Laboratory Parameters .........................................................................43 
6.7.2 
Sample Collection, Storage, and Shipping ..........................................44 
6.7.3 
Abnormalities .......................................................................................45 
6.8 
Efficacy Assessments .......................................................................................45 
6.8.1 
Patient Global Impression of Change ..................................................45 
6.8.2 
Hospital Anxiety and Depression Scale ...............................................45 
6.8.3 
Migraine Disability Assessment Questionnaire ...................................46 
6.8.4 
Migraine-Specific Quality of Life Questionnaire v2.1 ........................47 
6.8.5 
E-Diary Assessments ...........................................................................47 
6.9 
Safety Assessments ..........................................................................................48 
6.9.1 
Adverse Events Assessments ...............................................................48 
6.9.2 
Columbia- Suicide Severity Rating Scale ............................................48 
6.9.3 
Assessments of Changes in Sexual Function: Changes in Sexual 
Functioning Questionnaire Short-Form (CSFQ-14) ............................49 
6.10 
Optional Pharmacogenomics ...........................................................................49 
7 
ADVERSE EVENTS .............................................................................................51 
7.1 
Adverse Events ................................................................................................51 
7.1.1 
Unexpected Adverse Events ................................................................51 
7.1.2 
Treatment-Emergent Adverse Events ..................................................51 
7.1.3 
Severity ................................................................................................52 
7.1.4 
Serious Adverse Events .......................................................................52 
7.2 
Adverse Event Assessment ..............................................................................53 
7.2.1 
Performing Adverse Events Assessments ............................................53 
7.2.2 
Reporting Serious Adverse Events ......................................................54 
7.2.3 
Documentation of Adverse Events ......................................................55 
7.2.4 
Treatment of Adverse Events ...............................................................56 
7.2.5 
Adverse Event Relationship .................................................................56 
7.2.6 
Expectedness ........................................................................................57 
7.2.7 
Clinical Significance ............................................................................57 
7.2.8 
Special Considerations .........................................................................57 
8 
STUDY ACTIVITIES ...........................................................................................60 
8.1 
Screening Visit 1 ..............................................................................................60 
8.2 
Baseline/Randomization Visit 2 (Day 1) .........................................................61 
8.3 
Visits 3 (Week 4) and 4 (Week 8) ...................................................................63 
8.4 
Visit 5 (Week 12) or Early Termination Visit .................................................64 
8.5 
Visit 6 (Week 14)/Safety Follow-up  ...............................................................65 


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8.6 
Early Termination (After Randomization) .......................................................65 
9 
QUALITY CONTROL AND ASSURANCE .......................................................67 
10 
PLANNED STATISTICAL METHODS ..............................................................68 
10.1 
General Considerations ....................................................................................68 
10.1.1 
Estimand ..............................................................................................68 
10.1.2 
Multiple Comparisons ..........................................................................68 
10.1.3 
Missing Data ........................................................................................68 
10.2 
Determination of Sample Size .........................................................................69 
10.3 
Analysis Populations ........................................................................................69 
10.3.1 
All Patients Population ........................................................................70 
10.3.2 
Modified Intent-to-Treat Population ....................................................70 
10.3.3 
Safety Population .................................................................................70 
10.4 
Demographics and Baseline Characteristics ....................................................70 
10.5 
Primary Endpoint(s) .........................................................................................70 
10.5.1 
Primary Safety Endpoint(s)..................................................................70 
10.5.2 
Primary Efficacy Endpoint(s) ..............................................................70 
10.6 
Secondary Endpoint(s) .....................................................................................71 
10.6.1 
Key Secondary Efficacy Endpoint(s) ...................................................71 
10.6.2 
Secondary Efficacy Endpoint(s) ..........................................................71 
10.6.3 
Exploratory Endpoint(s) .......................................................................72 
10.7 
Analysis Methods.............................................................................................72 
10.7.1 
Disposition and Demographics ............................................................72 
10.7.2 
Efficacy Analysis .................................................................................72 
10.7.3 
Safety Analysis ....................................................................................74 
10.8 
Interim Analysis ...............................................................................................75 
11 
ADMINISTRATIVE CONSIDERATIONS ..........................................................76 
11.1 
Institutional Review Board or Ethics Committee Approval ............................76 
11.2 
Ethical Conduct of the Study ...........................................................................76 
11.3 
Patient Information and Consent .....................................................................76 
11.4 
Patient Confidentiality .....................................................................................77 
11.5 
Study Monitoring .............................................................................................77 
11.6 
Case Report Forms and Study Records ...........................................................78 
11.7 
Protocol Violations/Deviations ........................................................................78 
11.8 
Access to Source Documentation ....................................................................78 
11.9 
Data Management ............................................................................................79 
11.9.1 
Quality Assurance/Audit ......................................................................79 
11.10 
Retention of Data .............................................................................................79 
11.11 
Financial Disclosure .........................................................................................80 


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11.12 
Publication and Disclosure Policy ...................................................................80 
12 
REFERENCE LIST ...............................................................................................81 
 
LIST OF IN-TEXT TABLES 
Table 1. 
List of Laboratory Tests .............................................................................43 
 
 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
adverse event 
ALT 
alanine aminotransferase (SGPT) 
ANOVA 
analysis of variance 
AP 
alkaline phosphatase 
AST 
aspartate aminotransferase (SGOT) 
BID 
twice daily 
BMI 
body mass index 
BUN 
blood urea nitrogen 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CM 
Chronic migraine 
CMH 
Cochran-Mantel-Haenszel 
CRF 
CSFQ-14 
case report form 
Changes in Sexual Functioning Questionnaire Short-Form 
CV 
coefficient of variation 
DMP 
data management plan 
DOB 
date of birth 
EM 
Episodic migraine 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
Hct 
hematocrit 
Hgb 
hemoglobin 
HIPAA 
Health Information Portability and Accountability Act 
ICH 
International Council on Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug  
IRB 
Institutional Review Board 
mITT 
modified intent-to-treat 
LDH 
lactate dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
ms 
Mixed-Effects Model of Repeated Measures 
millisecond(s) 
MSI-BPD 
McLean Screening Instrument for Borderline Personality Disorder 
NDA 
New Drug Application 
NSAIDs 
Non-steroidal anti-inflammatory drugs 
OTC 
over-the-counter 
PRN 
pro re nata (as needed) 
PRO 
patient-reported outcome 
QD 
once daily 
RBC 
red blood cell (count) 
SAE 
serious adverse event 


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SD 
standard deviation 
SE 
standard error 
SF 
screen failure 
SGOT 
serum glutamic oxaloacetic transaminase (AST) 
SGPT 
serum glutamic pyruvic transaminase (ALT) 
TEAE 
Treatment-Emergent Adverse Event 
TSH 
thyroid stimulating hormone 
ULN 
upper limit of normal 
US 
United States 
WBC 
white blood cell (count) 
WoCBP 
women of childbearing potential 


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1 
INTRODUCTION 
Migraine affects an estimated 14.7% of the world’s population (Steiner, et al., 2013) and is 
ranked sixth by the World Health Organization as the cause of years lost due to disability 
(WHO, 2016). Chronic migraine (CM) is defined by the International Classification of 
Headache Disorders 3rd edition (ICHD-3) as headache occurring on ≥ 15 days/month for 
> 3 months with features of migraine on ≥ 8 days/month. CM affects approximately 2% of 
the world’s population with prevalence 2.5 to 6.5 times higher in women (1.7 to 4.0%) than 
in men (0.6 to 0.7%) (Natoli, et al., 2010). While migraine therapy has improved 
significantly since the introduction of serotonin 5-HT1-receptor agonists (i.e., triptans) and 
more recently, monoclonal antibodies to calcitonin gene-related protein (CGRP) or small 
molecule inhibitors to its receptor, a substantial number of patients continue to be treated 
inadequately. 
The pathophysiology of CM is not fully understood, but there is evidence that functional 
changes occur in the brain including increased cortical hyperexcitability, central trigemino-
thalamic sensitization, and defective descending pain modulatory activity (Mathew, 2011; Su 
and Yu, 2018). It is postulated that recurring episodic migraine (EM) (Goadsby, et al., 2017) 
and comorbid conditions, such as medication overuse or anxiety/depression, may lead to 
dysfunction of pain modulation pathways, with reduced nociceptive thresholds and atypical 
release of nociceptive molecules. This may cause increased central sensitization of the 
trigeminal and thalamic neurons, with little recovery between attacks, leading to progression 
from EM to CM. CGRP is involved in pain modulation, perception and sensitization, and has 
a major role in the pathogenesis of migraine (Ho, et al., 2010; Edvinsson, 2015). Activation 
of transient receptor potential channels, which coexist with CGRP in the same nociceptive 
neurons, promotes excitation of the trigemino-vascular pathway, release of CGRP, and pain 
(Benemei, et al., 2013; Benemei, et al., 2014; Dussor, et al., 2014). 
Oxytocin is a nonapeptide produced in the supraoptic and paraventricular nucleus of the 
hypothalamus which is released into the systemic circulation through the posterior pituitary 
gland (Moller, 2021). There are also collateral oxytocin producing neurons from the 
hypothalamus that project to diverse brain regions such as nucleus accumbens and amygdala. 
Oxytocin’s physiological functions include regulation of uterine contractility in pregnant 
women and milk ejection in lactating women. In the central nervous system (CNS), oxytocin 
is a mediator of pro-social behavior and fear response. Oxytocin is approved by the Food and 
Drug Administration (FDA) for intravenous use to induce labor in pregnant women as well 
as for the treatment of postpartum hemorrhage. Intranasal oxytocin is used in Europe for 
inducing labor in pregnant women and for enhancing milk production in lactating women.  
Oxytocin exerts analgesic effects when administered intrathecally in the rodent model. This 
effect appears to be receptor specific since it was blocked by an oxytocin antagonist 
(Tzabazis, et al., 2017). The therapeutic index of intrathecal oxytocin is large, i.e., 270-fold 
when considering analgesic versus severe side effects and 400-fold when considering 
analgesic effects versus lethality. Oxytocin is thought to mediate its analgesic action in part 
via the endogenous opioid system. Diverse CNS sites may be involved in mediating such 




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2 
STUDY OBJECTIVES 
• Evaluate the efficacy of 2 TNX-1900 (intranasal oxytocin) treatment regimens at 30 IU 
daily (QD) and 30 IU twice daily (BID) compared to placebo in chronic migraineurs. 
• Evaluate the safety and tolerability of 2 TNX-1900 (intranasal oxytocin) treatment 
regimens at 30 IU QD and 30 IU BID compared to placebo in chronic migraineurs. 


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3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
This is a double-blind, randomized, placebo-controlled, multicenter, 3 arm parallel Phase 2 
study. Men and women with a current diagnosis of CM according to the International 
Classification of Headache Disorders, 3rd edition (ICHD-3) and who meet the study entry 
criteria will enter a Screening Period followed by a Run-in Period. A Run-in Period is a 
prospective baseline observation in which patient’s migraine/headache activity will be 
recorded for at least 28 days. At the end of the Run-in Period, eligible patients will be 
randomized at a 1:1:1 ratio, to one of the 3 treatment arms: TNX-1900 at a fixed daily dose 
of 30 IU QAM / placebo QPM (Treatment Arm A), or fixed daily dose of 30 IU QAM / 30 
IU QPM (Treatment Arm B), or placebo QAM / placebo QPM (Treatment Arm C), for the 
duration of a 12-week Treatment Period. Randomization will be stratified by study site and 
preventive migraine medication (use of a single preventative vs. no preventative). All 
participants will administer study drug twice a day, mornings and evenings, in a double-blind 
design. Two vials of study drug are dispensed at each dispensing visit, one clearly marked for 
“MORNING” and one clearly marked for “EVENING”. 
The study will be conducted in 3 periods (Screening/Wash-Out/Run-In, Treatment, and 
Safety Follow-up) and will consist of at least 6 visits (Screening Visit, 
Randomization/Baseline Visit, 3 Treatment Visits, and a Safety Follow-up Visit). 
Screening/Washout/Run-In Period (Visit 1: Screening Visit) 
After providing written informed consent, patients will be assessed for eligibility 
(considering medical history, migraine headache history, medication use, physical exam, 
nasal exam, vital signs, clinical labs and electrocardiogram [ECG]).  
Eligible patients will be trained on the e-diary during the Screening Visit and will enter a 28-
day Run-In period which will last for at least 28 days. Patients who need to wash out 
excluded medications will have up to an additional 21 days in the Run-In period, but every 
effort should be made to minimize to the fewest days needed for the given washout period(s) 
in the protocol.  
During the Run-In, patients will be required to answer questions daily regarding headaches 
and rescue (abortive) medication use on an electronic diary (e-diary) regardless of whether 
patients experienced a headache on that day. It is a patient’s responsibility to be compliant 
with e-diary entries. Each patient’s headache frequency, as well as e-diary compliance, will 
be evaluated at the end of the Run-in Period to ensure the patient meets all required eligibility 
criteria for treatment randomization. The patient must not be informed of the minimum 
number of headache days and migraine headache days required to enter the study as this 
might bias entries to the e-diary during Run-in Period.  
It is important to note that the last 28 days of Run-In diary entries includes diary entries 
logged on morning of the Baseline Visit. Patients should be reminded to complete the 
required e-diary entries on the morning of the Baseline Visit. 


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During this period, if any test results come back and indicate a patient’s ineligibility for the 
study, the patient should be considered a SF and informed that they are not eligible for the 
study and can stop completing the e-diary. However, if the investigator determines that the 
patient should be brought back into the clinic for re-testing, the patient should continue 
completing the e-diary until a final determination regarding eligibility is made. 
Any patients not meeting the randomization criteria at the end of the Run-in Period will be 
considered a SF. 
Patients will need to receive instructions and a password that uniquely identifies them when 
they log into the diary system along with instructions about what to do if they have difficulty 
completing the diary. 
Double-blind Treatment Period (Visit 2: Randomization/Baseline; Visits 3, 4, 5: Treatment) 
The Treatment Period will last for about 84 days. At Visit 2, eligible patients will be 
randomized in a 1:1:1 ratio to one of 3 treatment arms (A, B or C) as summarized above. 
Randomization will be stratified by study site and concomitant migraine preventive 
medication (use of a single preventative vs. no preventative). Patients will be required to 
answer daily headache questions and study drug compliance on an e-diary during the 
Treatment Period regardless of whether a headache was experienced that day. 
All patients who withdraw early from the study will be encouraged to complete an Early 
Termination Visit for safety evaluations (Visit 5 [V5]) within 7 days of withdrawal from the 
study. Study end is after Visit 5/ET. A Safety Follow-up Visit (Visit 6 [V6]) will occur 14 
days after V5/ET.  
Safety Follow-up Period (Visit 6) 
Approximately 14 days (+4 days) after Visit 5 or End of Treatment (ET), all randomized 
patients will attend a Safety Follow-up Visit. 
A schema of the study design is provided in Figure 1. 


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Figure 1 
Study Schema 
 
 
3.2 
Rationale for Study Design and Placebo Group 
The formulation of TNX-1900 has been designed specifically for intranasal administration, 
and regimens of daily or twice daily administration of TNX-1900 are being investigated as 
potential preventive treatments for migraines in a population with CM. Additional details 
regarding the nonclinical studies supporting the mechanism of action in migraine and the 
clinical experience from early clinical studies carried out to date with intranasally-delivered 
oxytocin can be found in the Investigator’s Brochure. 
3.3 
Study Duration and Dates 
The study duration for each patient will be approximately 18-21weeks including the 14-day 
Safety Follow-up Period. 


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4 
STUDY POPULATION SELECTION 
4.1 
Inclusion Criteria for Enrollment 
1. Men and women aged 18 to 65 years, inclusive, at the time of Visit 1. 
2. History of migraine with or without aura for at least 1 year and onset at < 50 years of age. 
Patient must also have a history of chronic migraine > 3 months prior to Visit 1 as 
defined by IHS ICHD-3 (Appendix A) 
3. Able to differentiate migraine or probable migraine headache from other headaches. 
4. Patients can be on stable ≤ 1 preventive medication and any number of abortive migraine 
medications for 90 days prior to Screening and during the study. All treatments, other 
than the study drug, thought to have preventive efficacy in migraine should not be started 
or discontinued during the entire study period. Note: Up to approximately 30% of the 
patients randomized into the study can be on 1 preventative medication. Once this 
category is filled, only patients who are not on any preventative medications can be 
randomized into the study. From study start, sites should enroll patients into both 
categories in parallel until informed otherwise. 
5. If female, is either not of childbearing potential (defined as postmenopausal for at least 
1 year or surgically sterile [e.g., bilateral oophorectomy, or hysterectomy]) or will be 
practicing one of the following methods of birth control throughout the study: 
a. Hormonal methods such as oral, implantable, injectable, or transdermal 
contraceptives for a minimum of one full cycle (based on the patient’s usual 
menstrual cycle period) before study drug administration. 
b. Intrauterine device (IUD). 
c. Bilateral tubal ligation 
d. Double-barrier method (condoms, sponge, diaphragm, or vaginal ring with 
spermicidal jelly or cream). 
e. Partners of vasectomized (> 1 year ago) males in monogamous relationships. 
f. Females involved only in same sex relationships. 
g. Females practicing abstinence may have the birth control requirement waived only 
with Medical Monitor approval. 
6. If male, is either vasectomized (> 1 year ago) or will be practicing once of the following 
methods of birth control throughout the study: 
a. Partner in monogamous relationship with female practicing one of the methods in 5a 
or 5b above. 


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b. Double-barrier method (condoms, sponge, diaphragm, or vaginal ring with 
spermicidal jelly or cream.) 
c. Males involved only in same sex relationships. 
d. Males practicing abstinence may have the birth control requirement waived only with 
Medical Monitor approval. 
7. The patient is willing and able to comply with all protocol-specified requirements. 
8. Capable of reading and understanding English and able to provide written informed 
consent to participate.  
 
4.2 
Exclusion Criteria for Enrollment 
Patients who meet any of the following criteria will be excluded from the study. 
1. History of cluster headache. 
2. Presence of headaches more than 26 days a month on an average for the 6 months prior 
to Screening. 
3. Failed to benefit from an adequate dose and duration, in the investigator’s judgment 
(e.g., one month of β-blocker), of 3 or more migraine preventive medications. 
4. History of seizure disorder other than childhood febrile seizures. 
5. The patient is at increased risk of suicide based on the investigator’s judgment, or the 
results of the Columbia Suicide Severity Rating Scale (C-SSRS) conducted at 
Screening and Baseline (e.g., C-SSRS Type 3, 4 or 5 ideation during the preceding 6 
months and any suicidal behavior within the past 12 months). 
6. In general, chronic use of systemic steroidal or non-steroidal anti-inflammatory drugs 
(NSAIDs) and combination products containing NSAIDs for any indication will be 
prohibited during the Screening Period and during the study. The following instructions 
should be followed: 
a. Excepting topical usage, chronic use of systemic steroidal anti-inflammatory drugs is 
not allowed for any indication. 
b. Chronic use of NSAIDs on a daily basis is not allowed; therefore, those on daily 
NSAIDs necessary for treatment of other medical conditions, e.g., arthritis, should not 
be enrolled; NSAIDs may be used as needed (PRN) for headache pain only if they are 
part of patient’s typical migraine/headache abortive treatment regimen; other use of 
NSAIDs is allowed as needed for other acute pain syndromes, but daily use is not 
allowed. 


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7. Use of opiates or barbiturates more than 4 days for more than 3 consecutive months 
prior to Visit 1 and during the study. 
8. Use of the following non-pharmacological treatments for headache or any other 
indication, is prohibited within 90 days prior to Screening and throughout the entire 
study: any electrical or magnetic stimulating devices (e.g., non-invasive vagal nerve 
stimulation (GammaCore), transcranial magnetic stimulation (TMS Mini), or Remote 
Electrical Neuromodulation [REN or Nerivio]). Any types of psychotherapy, stress 
management, acupuncture, chiropractic manipulation, and physical therapy is 
prohibited within 90 days of Screening and throughout the entire study only if the 
treatment is specifically targeted for the relief of headaches, migraines, or any type of 
head and neck pain. Otherwise, such treatments must have been ongoing for at least 90 
days prior to Visit 1 with a plan to continue throughout the study to be eligible.  Also, 
occipital nerve blocks or botulinum toxin treatments for any indication are prohibited 
within 90 days of Screening and throughout the entire study 
9. Use of OTC nasal products (i.e., saline spray, Neti-Pot, Naväge®, etc.) during the 
study. 
10. History of unstable psychiatric illness requiring hospitalization in the 12 months prior 
to Visit 1. Coexisting conditions, such as depression and anxiety, may be included if 
they are stable on current treatment regimens (with no change in treatment regimen for 
the last 90 days) and no planned changes during the study. 
11. History of or evidence supporting a diagnosis of borderline personality disorder (BPD) 
based on a score of ≥ 7 on the McLean Screening Instrument for BPD (MSI-BPD) at 
Visit 1 (Screening) and/or the investigator’s opinion. 
12. Body Mass Index (BMI) > 40 kg/m2. 
13. Any clinically significant medical condition that, in the opinion of the investigator, 
would make the patient unsuitable for study participation and completion. 
14. Any use of intranasal corticosteroid medications or conditions in which use of 
intranasal corticosteroids may be indicated during the study, e.g., unstable allergic 
rhinitis that has previously required intranasal corticosteroids. Intranasal corticosteroid 
use is not allowed within 28 days of Baseline/Randomization/Visit 2 and during the 
treatment phase or follow-up period of the study. 
15. Clinically significant laboratory and ECG abnormality (in the investigator’s opinion) 
based on Screening laboratory tests, or any of the following: 
a. Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 2 times 
the upper level of normal (ULN) 
b. Creatinine > 1.2 times the ULN 
c. Thyroid stimulating hormone (TSH) > 1.5 times the ULN 


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d. HbA1c > 7.5% 
e. Resting heart rate ≤ 45 bpm or ≥ 100 bpm 
f. Clinically significant arrhythmia or heart block 
g. Corrected QT interval by the Fridericia formula (QTcF) > 470 ms for females; and > 
450 ms for males. 
 
16. History of chronic nasal obstruction or local pathology in nostril pathway which, in the 
opinion of the investigator, would prevent appropriate nasal administration of the study 
drug. 
17. Known allergy or hypersensitivity to oxytocin containing products. 
18. Positive results for illegal or abused substances other than cannabis/ 
tetrahydrocannabinol at Screening or Baseline. 
19. Women who are pregnant, planning to become pregnant, or nursing during the study. 
20. Currently enrolled in or have participated within the last 30 days in a clinical trial 
involving an investigational product prior to Visit 1 (does not apply to anti-CGRP agent 
studies covered in Exclusion 21). 
21. Patients who recently discontinued treatment with an anti-calcitonin-gene-related 
peptide (CGRP) antibody or participated in an anti-CGRP antibody clinical study must 
be at least 4 months from the last drug administration prior to Visit 1. Patients who are 
in an extended observational period from such an anti-CGRP antibody study and are at 
least 4 months from the last drug administration prior to Visit 1 are eligible. Small 
molecule anti-CGRP treatments, e.g., gepants, are treated similarly but only must be at 
least 1 month from last drug administration prior to Visit 1. 
22. History of clinically significant and currently relevant cardiovascular disease or 
vascular ischemia (including myocardial, cerebral, peripheral extremity or other 
ischemic event) or thromboembolic events (arterial or venous thrombotic or embolic 
events) such as cerebrovascular accident, deep vein thrombosis, or pulmonary 
embolism. Recent myocardial infarction (within the last 2 years). Diagnosed with heart 
failure. 
23. History of alcohol or drug abuse within the prior year, or alcohol or drug dependence 
within the prior 5 years, as defined by the Diagnostic and Statistical Manual of Mental 
Disorders, Fourth Edition (DSM-IV).  
 
4.3 
Eligibility Criteria for Randomization 
Up to approximately 30% of the patients randomized into the study can be on 1 migraine 
preventative medication. Once this category is filled, only patients who are not on any 


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preventative medications can be randomized into the study. From study start, sites should 
enroll patients into both categories in parallel until informed otherwise. 
For a patient to be eligible for randomization, the following should be observed during the 
last 28 days of the Run-in Period: 
1. Demonstrate an ability to properly use e-diary. 
2. Complete ≥ 82% of the e-diary daily entries (23 days out of 28-day period). 
3. At least 14 headache (migraine-like or tension-type-like) days  
4. At least 8 days  
• An attack lasting 4 hours or more and meeting the ICHD-3 criteria (diagnostic criteria 
C and D) for migraine without aura (Appendix A) 
• Migraine with aura 
• Probable migraine (a migraine subtype fulfilling all but one criterion (B-D) for 
migraine without aura) 
• An attack of any duration that was believed by the patient to be a migraine and was 
relieved by a triptan, ergot derivative, or other migraine-specific abortive medication. 
It is important to note that the last 28 days of Run-In diary entries includes diary entries 
logged on morning of the Baseline Visit. Patients should be reminded to complete the 
required e-diary entries on the morning of the Baseline Visit. 
Those patients who only miss the e-diary compliance requirement (i.e., compliance less than 
82%) and otherwise are qualified for randomization may be given the opportunity to either 
extend or repeat the Run-in Period. Any extension will be considered on a case-by-case basis 
and require medical monitor approval.  
On the day of the Baseline/Randomization Visit (V2), patients must still meet all inclusion 
criteria and none of the exclusion criteria and be in good general health, or with only stable 
and non-serious conditions that, in the opinion of the investigator, will not place the patient at 
risk. 
 
4.4 
Withdrawal of Patients 
Patients may be withdrawn from the Run-in Period prior to the end of 28-days if patients 
were determined mathematically to be unable to meet the headache criteria required by the 
protocol. 
The investigator may withdraw a patient from the trial for any of the following reasons: 
• A protocol violation occurs, 
• A serious or intolerable adverse event occurs, 
• A clinically significant change in a laboratory parameter occurs, 


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• The sponsor or investigator terminates the study, 
• The patient requests to be discontinued from the study. 
 
In addition, any patient has the right to withdraw from the study at any time for any reason. 
All patients who withdraw early from the study will be encouraged to complete the ET Visit 
for safety evaluations (Visit 5) within 7 days from withdrawal of study, followed by a Safety 
Follow-up Visit (Visit 6) approximately 14 days from the last study drug administration. 


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5 
STUDY TREATMENT(S) 
5.1 
Description of Treatment(s) 
5.1.1 
Study Drugs 
5.1.1.1 
TNX-1900 
TNX-1900 is provided as a preservative-free, aqueous, oxytocin containing solution for 
intranasal delivery. TNX-1900 will be supplied at a 150 IU/mL oxytocin concentration for 
this study. One dose of study drug administration requires 2 administration sprays into the 
nostrils (1 spray to each nostril). Given the 150 IU/mL concentration, each 0.10 mL spray 
delivers 15 IU of TNX-1900, respectively. Consequently, one dose (2 sprays- one spray per 
nostril) equates to a 30 IU oxytocin total dose. 
5.1.1.2 
Placebo 
Placebo is provided as a preservative-free, colorless aqueous solution containing the same 
excipients as TNX-1900, minus oxytocin. Administration instructions are identical to those 
for TNX-1900. Intranasal application bottles containing placebo will deliver 0.10 mL volume 
per spray. A dose of placebo will comprise 1 spray per nostril (2 sprays total). 
A brief training on placebo response will be given to patients at Visits V1, V2, V3, V4, and 
V5. 
5.2 
Treatments Administered 
During the double-blind Treatment Period, patients are instructed to self-administer ONE 
dose (2 sprays total, 1 spray per each nostril) of MORNING study drug at a fixed time in the 
morning and ONE dose (2 sprays total, 1 spray per each nostril) of EVENING study drug at a 
fixed time in the evening, with a minimum period of 6 hours between the morning and 
evening doses. Each patient will be dispensed 2 bottles of study drug at each visit at which 
study drug is dispensed. The nasal spray bottle of MORNING study drug will be clearly 
labeled ‘MORNING’, and the EVENING study drug will be clearly labeled ‘EVENING’.  
Study drug administration should occur as follows: 
Dose  
Treatment 
Administration 
30 IU QAM / 
Placebo QPM 
A 
1 dose from ‘MORNING’ nasal spray bottle = 1 spray each 
nostril of TNX-1900 (2 sprays total) 
1 dose from ‘EVENING’ nasal spray bottle = 1 spray each 
nostril of placebo (2 sprays total) 
30 IU QAM / 
30 IU QPM 
B 
1 dose from ‘MORNING’ nasal spray bottle = 1 spray each 
nostril of TNX-1900 (2 sprays total) 
1 dose from ‘EVENING’ nasal spray bottle = 1 spray each 
nostril of TNX-1900 (2 sprays total) 


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Dose  
Treatment 
Administration 
Placebo QAM / 
Placebo QPM 
C 
1 dose from ‘MORNING’ nasal spray bottle = 1 spray each 
nostril of placebo (2 sprays total) 
1 dose from ‘EVENING’ nasal spray bottle = 1 spray each 
nostril of placebo (2 sprays total) 
 
Patients will be trained in the use of the nasal applicator prior to home use and will receive an 
Instructions for Use document. 
Priming of each dispensed bottle should be conducted by site staff at V2, V3, and V4.  
Prior to leaving the clinic at Baseline/Randomization/Visit 2, the patient will take their first 
dose from the Morning dose bottle regardless of time of day. Also, on the night of Visit 2, 
patients should administer from the Evening dose bottle the same evening at home, with a 
minimum period between the two doses of at least 6 hours. 
At subsequent visits (V3, V4, V5), the patient should take their AM dose of study drug from 
their existing study drug bottle, prior to the site collecting it and dispensing new study drug 
bottles. Patients should be reminded to take the AM dose prior to arriving at the clinic if 
possible. 
5.3 
Method of Assigning Patients to Treatment Groups 
Approximately 300 eligible patients will be randomized at a 1:1:1 ratio, to one of the 
3 treatment arms receiving TNX-1900 at a fixed daily dose of 30 IU QD (Treatment Arm A) 
or fixed daily dose of 30 IU BID (Treatment Arm B) or receiving placebo (Treatment Arm 
C) for the duration of a 12-week Treatment Period. Randomization will be stratified by study 
site and use of one concomitant preventive migraine medication (vs. no concomitant 
preventive migraine medication). All participants will administer study drug twice a day 
(mornings and evenings) in a double-blind design. 
The randomization schedule will be computer generated using a permuted block algorithm 
and will randomly allocate study drug to randomization numbers. The randomization 
numbers will be assigned through a central interactive web response system (IWRS) as 
patients are entered into the study. 
5.4 
Blinding and Unblinding 
All patients, Investigators, and study personnel involved in the conduct of the study, 
including data management, will be blinded to treatment assignment except for a specified 
unblinded statistician and programmer from the study contract research organization (CRO) 
who will have access to the randomization code. The unblinded study personnel will not 
participate in study procedures or data analysis prior to unblinding of the study data to all 
study-related personnel after database lock and only upon written notification by the sponsor. 
If an interim analysis is conducted, then unblinded personnel who are not otherwise involved 
in the study will prepare the data for review. 


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Study personnel will make every effort 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 patient’s treatment assignment. 
Unblinding should be discussed in advance with the medical monitor, if possible. For 
emergency unblinding, study personnel will use the IWRS. If the investigator is not able to 
discuss treatment unblinding in advance, they must notify the medical monitor as soon as 
possible about the unblinding incident without revealing the patient’s treatment assignment. 
Unblinding for an individual patient will not result in unblinding the treatment assignments 
for the remaining patients in the study. Thus, the overall study blind will not be 
compromised. If a patient’s treatment assignment is unblinded, he/she may or may not be 
asked to withdraw from the study. The investigator will make this decision after consultation 
with the medical monitor. 
5.5 
Concomitant Therapy 
Patients can be on stable ≤ 1 preventive medication and any number of abortive migraine 
medications for at least 90 days prior to Screening. Up to approximately 30% of the patients 
randomized into the study can be on 1 preventative medication. Once this category is filled, 
only patients who are not on any preventative medications can be randomized into the study. 
From study start, sites should enroll patients into both categories in parallel until informed 
otherwise. 
All treatments, other than the study drug, thought to have preventive efficacy in migraine 
should not be started or discontinued during the entire study period. Other prescription or 
over the counter medication not specifically excluded by entry criteria may be continued 
during the study, provided that the patient has been on this medication for at least 30 days at 
a stable dose prior to the date of randomization, and usage is expected to remain stable 
throughout the study. In addition, certain other medications will also be prohibited and may 
require washout, or exclusion of the patient if washout is not appropriate. 
Chronic use of NSAIDs daily is not allowed, therefore those on daily NSAIDs necessary for 
treatment of other medical conditions (e.g., arthritis), should not be enrolled. NSAIDs may be 
used as needed for abortive migraine treatment only if they are part of the patient’s typical 
migraine/headache abortive treatment regimen. Other use of NSAIDs is allowed as 
needed for other acute pain syndromes, but daily use is not allowed. Use of ibuprofen for 
such PRN use of NSAIDs is preferred over longer acting NSAIDs, e.g., naproxen and 
celecoxib. Concomitant medications or other treatments must be recorded in the patient’s 
medical record and case report form along with the dose and dates of treatment. 
5.5.1 
Permitted Therapy 
The array of medications a patient typically uses for abortive treatment of a migraine should 
be established at the Screening Visit and recorded as PRN concomitant medications. 


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Although any number of abortive medications are permitted, no new abortive medications 
should be started at any time during participation in the protocol. As noted above, PRN use 
of NSAIDs as part of a patient’s typical migraine abortive regimen or for treatment of other 
acute pain syndromes is permitted. Ibuprofen is preferred for such PRN use of NSAIDs over 
longer acting NSAIDs, e.g., naproxen and celecoxib. 
5.5.2 
Prohibited Therapy 
Use of opioids or barbiturates for more than 4 days per month; systemic corticosteroids, 
intranasal corticosteroids, and chronic daily NSAIDs (except permitted uses outlined in 
Section 5.5.1), are prohibited. Additionally, use of intranasally administered over the counter 
products (Flonase) is also prohibited during this study. Any use of nasal irrigation, e.g., “neti 
pot” or similar, is prohibited during this study. 
5.6 
Restrictions 
5.6.1 
Prior Therapy 
Patients who are taking certain medications to manage their migraine are eligible for the 
study if they are willing and able (and it is medically reasonable for them) to be withdrawn 
from those medications that are specifically excluded by the protocol and they agree to 
refrain from further usage during this study. This applies to any patient who is taking greater 
than one migraine preventive medication. 
5.6.2 
Fluid and Food Intake 
There are no restrictions on fluid or food intake in this study. 
5.6.3 
Reproductive Restrictions 
All patients of childbearing potential who participate in the study should be counseled on the 
need to practice adequate birth control and on the importance of avoiding pregnancy during 
treatment. Patients should be instructed to contact the investigator or study staff immediately 
if pregnancy occurs or is suspected. 
Participants of reproductive potential must agree to use a highly effective method of 
contraception from the time of consent and for 28 days following his or her last dose of 
investigational product (IP). Highly effective methods of contraception are as follows: 
1. If female is either not of childbearing potential (defined as postmenopausal for at least 
1 year or surgically sterile [e.g., bilateral oophorectomy, or hysterectomy]): 
a. Hormonal methods such as oral, implantable, injectable, or transdermal 
contraceptives for a minimum of one full cycle (based on the patient’s usual 
menstrual cycle period) before study drug administration. 
b. Intrauterine device (IUD). 


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c. Bilateral tubal ligation 
d. Double-barrier method (condoms, sponge, diaphragm, or vaginal ring with 
spermicidal jelly or cream). 
e. Partners of vasectomized (> 1 year ago) males in monogamous relationships. 
f. Females involved only in same sex relationships. 
g. Females practicing abstinence may have the birth control requirement waived only 
with Medical Monitor approval.  
2. If male: 
a. Partner in monogamous relationship with female practicing one of the methods in a) 
or b) above. 
b. Double-barrier method (condoms, sponge, diaphragm, or vaginal ring with 
spermicidal jelly or cream.) 
c. Males involved only in same sex relationships. 
d. Males practicing abstinence may have the birth control requirement waived only with 
Medical Monitor approval. 
Pregnancy testing will be conducted prior to administration of the IP on every patient of 
childbearing potential. A patient who is found to be pregnant at the Screening Visit will be 
excluded from the study and considered to be an SF. A patient who becomes pregnant during 
IP treatment will be immediately discontinued from study participation. See Section 7.2.8.2 
for additional details. 
5.7 
Treatment Compliance 
Treatment compliance will be monitored via the e-diary. The e-diary will be used to log 
headaches and abortive medications, but once patients are randomized into the study and 
starts the study drug, they will also be required to report whether they have taken their 
morning dose and evening dose on a daily basis. Please refer to Section 6.8.5 for additional 
details on the e-diary.  
5.8 
Packaging and Labeling 
Study drug supplies will be packaged identically to maintain the integrity of the study blind. 
The study drug bottles will be labeled minimally with the following information: study 
protocol number, sponsor name and location, bottle number, storage conditions, usage 
instructions (intranasal use only), and caution statements for an investigational drug, i.e., 
“Caution: New Drug - Limited by Federal (or United States) law to investigational use”. 


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5.9 
Dispensing, Storage and Accountability 
The study drugs will be supplied by Tonix or a designee to be used exclusively in the clinical 
study according to the instructions in this protocol. The investigator is responsible for 
dispensing the study drugs according to the dosage scheme and for ensuring proper storage of 
the products. 
Until study drug is dispensed to the patients, it must be stored in a securely locked 
refrigerated area that is not generally accessible. The key to the storage area is to be kept by 
the investigator or designee responsible for the study drug. The storage will be accessible 
only to those persons authorized by the investigator to dispense the products. 
The investigator or designee must confirm the receipt of the IP with his or her signature. A 
copy of this receipt must be kept by the investigator and another copy will be stored at Tonix 
or its designee. 
The investigator or investigator designee must maintain adequate records showing the 
receipt, dispensing, return, or other disposition of study drugs, including the date, quantity, 
batch or code number, and identification of patients who received each bottle of study drug. 
The investigator will not supply study drugs to any person except those named as sub-
investigators on the FDA form 1572, designated study personnel, and patients in this study. 
The investigator will not dispense the study drugs from any study sites other than those listed 
on the FDA form 1572. Study drugs may not be relabeled or reassigned for use to other 
patients. If any of the study drug is not dispensed, or is lost, stolen, spilled, unusable, or 
received in a damaged container, this information must be documented and reported to the 
sponsor and appropriate regulatory agencies, as required. 
Upon completion of the study, all study drug (partly used, unused, and empty packaging, 
e.g., vials with intranasal applicators) must be left in the original packaging and shipped back 
to drug depot. 


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6 
STUDY PROCEDURES 
6.1 
Informed Consent 
Before the potential participant has undergone any study-related Screening procedures, 
including any down-titration or withdrawal of medications, the nature of the study and the 
potential risks associated with it will be explained to the patient, and the patient will be given 
an opportunity to ask questions to his or her satisfaction. After the questions are answered, 
but before proceeding further, the patient must read and sign a written informed consent 
form. This signed informed consent form will be retained in the investigator’s study file, and 
the date the patient signed the form will be entered into the CRF. The patient will be 
provided with a copy of his or her signed and dated informed consent form. The patient will 
be required to sign all updated informed consents. 
The patient will also be provided with the opportunity to sign a separate consent form for the 
optional pharmacogenomics blood draw and analysis. Participation in this optional portion of 
the study is not required. Ideally, the blood draw for the optional pharmacogenomics should 
be drawn at the Baseline visit; however, it can be drawn at a subsequent visit if needed. A 
patient can decide to decline the optional pharmacogenomics but still participate in the main 
study. 
6.2 
Medical, Psychiatric and Medication History 
Any clinically significant abnormal findings at Screening will be recorded in medical history. 
Any changes to the medication history obtained at Screening will be recorded at 
Baseline/Randomization/Visit 2. (For further details: Schedule of Assessments 
). A self-assessed MSI-BPD will be administered to rule out BPD, as per Exclusion 11 
(Section 4.2). 
6.3 
Physical Examination 
A complete physical examination will be performed at Visits V1, V2 and V5. The complete 
physical examination may exclude rectal, genitourinary, and breast examinations for female 
patients, and rectal and genitourinary examinations for male patients. Examination of male 
patients should include breast examination at Visits V1, V2, and V5 in order to monitor for 
the unlikely adverse event of gynecomastia. 
6.4 
Nasal Examination 
A nasal examination will be performed at Visit 1, Visit 2, Visit 3, Visit 4, and Visit 5. The 
nasal exam will be conducted using a nasal speculum and headlamp to view into each nostril 
in order to establish any baseline pathology and assess any clinically significant changes in 
the nasal passages. A nasal exam should only be conducted at Visit 6 if needed to follow up 
on unresolved findings from the Visit 5 examination. 


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6.5 
Vital Signs 
Vital signs (sitting blood pressure and heart rate, temperature) and weight will be assessed at 
Visits V1, V2, V3, V4, V5, and V6. Height will be measured without shoes at Visit 1 only. 
The BMI will be a derived variable, based on height and weight entries obtained at the 
Screening Visit. 
6.6 
Electrocardiogram (ECG) 
An ECG will be conducted at V1, V2, V3, V4, and V5. PR intervals, QRS intervals, QT 
interval, and QTcF will be collected. An investigator interpretation of the ECG will also be 
required: normal, abnormal- non-clinically significant, abnormal- clinically significant. 
6.7 
Clinical Laboratory Tests 
6.7.1 
Laboratory Parameters 
Patients will be in a seated or supine position during blood collection. Clinical laboratory 
tests will include the following: 
Table 1. 
List of Laboratory Tests 
Serum Chemistry 
Alkaline phosphatase 
Creatine kinase (CK) 
 Alanine aminotransferase (ALT; SGPT) 
Glucose 
 Aspartate aminotransferase (AST/SGOT) 
LDH 
 Blood urea nitrogen (BUN) 
Phosphorus 
 Bilirubin (direct and total) 
Potassium 
 Calcium 
Sodium 
(serum osmolality will also be tested if Sodium is 
below the lower limit of normal) 
 Carbon dioxide (CO2) 
Protein (total) 
 Chloride 
Triglycerides 
Creatinine 
Uric Acid  
 
 
Hematology 
Hematocrit (Hct) 
Mean corpuscular volume (MCV) 
Hemoglobin (Hgb) 
Platelet count 
Mean corpuscular hemoglobin (MCH) 
Red blood cell (RBC) count 


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Serum Chemistry 
MCH concentration (MCHC) 
WBC differential 
 
 
Other 
Thyroid Stimulating Hormone (TSH) 
Hemoglobin A1c (HbA1c) 
 
Urinalysis: 
Urinalysis will include assessment or measurement of the following: 
Appearance, Bilirubin, Color, Glucose, Ketones, Microscopic Examination, Nitrite, Occult 
blood, pH, Protein, Specific Gravity, Urobilinogen 
Urine Drug Test: 
Cocaine, phencyclidine (PCP), barbiturates, amphetamines, cannabis, and opiates. 
A centrally analyzed urine drug screen (UDS) will be performed at Visit 1. If the patient has 
a positive drug screen at Visit 1 due to a drug of abuse other than cannabis (e.g., cocaine, 
methamphetamine) or due to a nondisclosed opioid, amphetamine, or barbiturate, then he/she 
should be deemed an SF. 
Patients with a positive Screening UDS due to an allowed prescription drug (e.g., headache 
remedies containing butalbital) do not require further drug Screening. 
Serum Pregnancy Test: 
A test for serum human chorionic gonadotropin (hCG) (only for females who are not 
diagnosed as postmenopausal for greater than one year or not of childbearing potential) is 
sent to the central lab at the Screening Visit 1 only. 
Urine Pregnancy Test: 
Urine hCG, for females who are not diagnosed as postmenopausal or not of childbearing 
potential, is conducted on-site at all study visits after the Screening Visit. 
6.7.2 
Sample Collection, Storage, and Shipping 
With the exception of the urine pregnancy test or an ad hoc urine drug screen, all clinical 
laboratory evaluations will be analyzed via a central clinical laboratory, and information 
regarding appropriate sample volume, collection tubes, sample labeling and handling, and 
shipment will be provided in the Clinical Laboratory Manual. 


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6.7.3 
Abnormalities 
Each clinically significant abnormal laboratory value or other clinically meaningful 
abnormality should be followed until the abnormality resolves or until a decision is made that 
it is not likely to resolve. If such abnormalities do not return to normal within a reasonable 
period, their etiology should be identified and Tonix or its designee should be notified. 
Clinically significant abnormalities in laboratory values after the Screening will be recorded 
as AEs. 
NOTE: A Screening TSH level greater than 1.5 times higher than the ULN, or ALT or AST 
level > 2x ULN, is exclusionary; however, the patient may remain in Screening to undergo 
repeat liver function tests if a transient abnormality (e.g., viral illness; effects of a medication 
being discontinued, etc.) is thought to be responsible for their initial elevation. 
6.8 
Efficacy Assessments 
Many of the secondary and exploratory efficacy endpoints in this study are derived from 
patientive patient-completed assessments. Therefore, it is critical that these assessments are 
conducted in the specified order, according to specific instructions, and in a setting where the 
patient has minimal distractions and sufficient time to complete them. After completion of 
these assessments, the study coordinator should review the responses for completeness with 
the patient. 
6.8.1 
Patient Global Impression of Change 
The Patient Global Impression of Change (PGIC) is a validated instrument to gauge the 
patient’s assessment of change in condition. This form will be completed by the patient at 
Visits 3, 4 and 5. The patient will answer a single question: 
Since the start of the study Treatment Period, overall, my migraine condition is: 
1 = Very much improved 
2 = Much improved 
3 = Minimally improved 
4 = No change 
5 = Minimally worse 
6 = Much worse 
7 = Very much worse 
 
6.8.2 
Hospital Anxiety and Depression Scale 
The patient’s total score on the Hospital Anxiety and Depression Scale (HADS) will be 
assessed at Visits 2, 3, 4, and 5. The HADS is a self-rated scale developed to assess 
psychological distress in non-psychiatric patients. It consists of 2 subscales, Anxiety and 


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Depression. The HADS aims to measure symptoms of anxiety and depression and consists of 
14 items, 7 items for the anxiety subscale (HADS Anxiety) and 7 for the depression subscale 
(HADS Depression).  
Note that the HADS is considered both an efficacy and safety endpoint. 
6.8.3 
Migraine Disability Assessment Questionnaire 
The Migraine Disability Assessment Test (MIDAS) is a patient-reported test used to 
determine how severely migraines affect a patient's life. At Visits 2 and 5, patients are asked 
questions about the frequency and duration of their headaches, as well as how often these 
headaches limited their ability to participate in activities at work, at school, or at home. 
The questionnaire contains 5 scored questions and 2 supplemental questions: 
1. On how many days in the last 3 months did you miss work or school because of your 
headaches? 
2. How many days in the last 3 months was your productivity at work or school reduced by 
half or more because of your headaches? (do not include days you counted in question 1 
where you missed work or school.) 
3. On how many days in the last 3 months did you not do household work because of your 
headaches? 
4. How many days in the last 3 months was your productivity in household work reduced by 
half or more because of your headaches? (do not include days you counted in question 3 
where you did not do household work.) 
5. On how many days in the last 3 months did you miss family, social or leisure activities 
because of your headaches? 
A. On how many days in the last 3 months did you have any headache? (If a headache lasted 
more than one day, count each day) 
B. On a scale of 0 - 10, on average how painful were these headaches? (where 0 = no pain at 
all, and 10 = pain which is as bad as it can be) 
Only questions 1-5 contribute to the score of the assessment. The score obtained gives a 
measure of the extent of debilitation a patient’s migraines: 
0 to 5, MIDAS Grade I, Little or no disability 
6 to 10, MIDAS Grade II, Mild disability 
11 to 20, MIDAS Grade III, Moderate disability 
21+, MIDAS Grade IV, Severe disability 
 


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6.8.4 
Migraine-Specific Quality of Life Questionnaire v2.1 
At Visits 2, 3, 4, and 5, patients will be asked to complete the Migraine-Specific Quality of 
Life Questionnaire version 2.1 (MSQ). The MSQ has been shown to have good psychometric 
performance in measuring headache impact in migraine patients. The MSQ is a 14-item 
patient-reported outcome instrument that measures the impact of migraine across 3 essential 
aspects of a patient’s health-related quality of life over the past 4 weeks: role function-
restrictive, role function-preventive, and emotional function. Patients respond to items using 
a 6-point scale: “none of the time,” “a little bit of the time,” “some of the time,” “a good bit 
of the time,” “most of the time,” and “all of the time,” which are assigned scores of 1 to 6, 
respectively. Raw dimension scores are computed as a sum of responses and rescaled from a 
0 to 100 such that higher scores indicate better quality of life. 
6.8.5 
E-Diary Assessments 
The daily diary is an important aspect of this study, and all patients must receive training 
explaining what is being asked of them, when to complete the diary, and how to use the diary 
system effectively.  
On Visit 1, patients will be shown how to download the app to their iPhone or Android 
smartphone, will be provided with the credentials for opening the e-diary app, and assisted in 
entering the patient’s specific typically used abortive medications for migraines. In addition, 
the site should set up the e-diary notifications for the patient within the IRT and the ePRO 
application.  
On V2, V3, and V4, diary compliance should be reviewed, and patients should receive re-
training as needed. 
6.8.5.1 
Screening/Wash-Out/Run-In Period 
On a daily basis during the Screening/Wash-Out/Run-in and the Treatment phase, patients 
are to record in the e-diary information on presence of headache, duration of headache, 
headache characteristics and symptoms, peak pain severity, and use of any rescue (abortive) 
headache medication. Patients will complete the e-diary each morning for the previous day’s 
headache assessment and rescue medication use.  For evaluating randomization eligibility, 
the last 28 days of Run-In diary entries will be used, which includes diary entries logged on 
morning of the Baseline Visit. 
6.8.5.2 
Treatment Period 
During the Treatment phase, patients will continue to record the data that was being collected 
during the Screening/Wash-Out/Run-In Period; however, they will also record study 
medication use for the expected morning and evening doses.   


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6.8.5.3 
Diary Reminders and Site Responsibilities 
Patients will receive daily reminders to complete their diary entries. Patients will receive a 
reminder to complete their diary if they miss two or more diary entries. Patients will also 
receive reminders twice a day to take their study drug. 
Site staff will be alerted when diary entries are missed. If two days or more of e-diary entries 
are missed, the site should contact the patient for re-training and to instruct the patient on the 
importance of routine completion of their diary. The study staff will be expected to monitor 
patient adherence in completing the diary throughout the study and will be instructed to call 
the patient should any problems or significant nonadherence be observed. 
6.9 
Safety Assessments 
Safety will be assessed by evaluation of adverse events (AEs), vital signs, ECG, responses on 
the Columbia Suicide Severity Rating Scale, CSFQ-14, HADS, and by clinical laboratory 
and physical examination findings, including a nasal exam that includes visual inspection of 
the nasal passages. 
6.9.1 
Adverse Events Assessments 
Patients will be monitored for AEs throughout the study. Any clinically significant abnormal 
findings at Screening should be recorded in medical history. AEs will be recorded after the 
informed consent is signed. AEs that are spontaneously reported or elicited or observed are to 
be recorded on the CRF with the date, time of onset, date and time of resolution, severity, 
seriousness, causality (relationship to study drug), actions required, and outcome. 
If an AE occurs, the investigator will institute support and/or treatment as deemed 
appropriate. If an AE is unresolved on the last day of the study, an effort should be made to 
follow-up until the AE is resolved or stabilized, the patient is lost to follow-up, or there is 
some other resolution of the event. 
There are many symptoms associated with migraine that can vary in intensity and frequency 
over time. Only symptoms that worsen or become more frequent, and in the opinion of the 
patient are outside of their normal experience, should be reported as AEs. 
Additional information regarding definition and reporting requirements for AEs, serious AEs, 
and pregnancies is provided in Section 7. 
6.9.2 
Columbia- Suicide Severity Rating Scale  
The C-SSRS is a questionnaire developed by researchers at Columbia University to assess 
and track suicide risk and behavior. This scale is intended to be used by individuals who have 
received training in its administration. The questions contained in the Columbia Suicide 
Severity Rating Scale are suggested probes. Ultimately, the determination of the presence of 
suicidal ideation or behavior depends on the judgment of the individual administering the 
scale. 


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Two versions of this questionnaire will be utilized in this study. At Visit 1, the 
“Baseline/Screening” questionnaire will be administered, and the recall periods will be 
“lifetime” and “within the past 6 months” for suicidal ideation and “within the past 1 year” 
for suicidal behavior. Patients whose responses are indicative of suicidal ideation with any 
method, intent, and/or plan (e.g., Type 3, 4 or 5 suicidal ideation) within the past 6 months or 
a history of suicidal behavior within the past year will be excluded from participation, with 
recommended referral for intervention as appropriate. 
At all subsequent visits (Visits 2, 3, 4, 5, and 6), the “Since Last Visit” version of the 
questionnaire will be administered, and the recall period on this will be “since the last visit”. 
Note that if there has been an increase in suicidal ideation or suicidal behavior, appropriate 
intervention should be prescribed. 
6.9.3 
Assessments of Changes in Sexual Function: Changes in Sexual 
Functioning Questionnaire Short-Form (CSFQ-14) 
The Changes in Sexual Functioning Questionnaire Short-Form (CSFQ-14) (Keller, et al., 
2006) is validated scale with internal reliability designed to allow a patient to self-evaluate 
his or her sexual behaviors or problems in a number of areas. The CSFQ-14 will be 
administered at Baseline (Visit 2) and Week 12/EOT (Visit 5). It yields a total score, 
3 subscales corresponding to phases of the sexual response cycle (i.e., desire, arousal, 
orgasm), and 5 subscales corresponding to important dimensions of sexual functioning. It is 
considered a useful scale for assessing sexual side effects of medications. For all items, 
higher scores reflect higher sexual functioning. For 12 of the 14 items, higher sexual 
functioning corresponds to greater frequency or enjoyment/pleasure (e.g., 1 = never to 5 = 
every day). For 2 items (item 10, assessing loss of interest after arousal for women and 
priapism for men, and item 14, assessing painful orgasm), higher sexual functioning 
corresponds to lower frequency (e.g., 1 = every day to 5 = never). Items 10 and 14 are 
included in the total score but not in any scale score. Note: there is a male version and female 
version for the CSFQ-14. 
Note that the CSFQ is considered both an efficacy and safety endpoint.  
6.10 
Optional Pharmacogenomics 
For optional pharmacogenomic analyses, a blood sample will be obtained from each patient 
who provided separate written, signed informed consent for pharmacogenomic analysis.  
These samples may be obtained at any post-screening visit, including an ET visit; however, it 
is preferred that they are collected at Baseline/Visit 2 whenever possible.  
The purpose of this testing is to allow for whole genome sequencing and analysis for allelic 
polymorphisms related to treatment response to TNX-1900.  
Please refer to the Laboratory Manual (for pharmacogenomics) for additional details on the 
sample collection methods and materials used in this study. 
Unused extracted DNA may be stored up to 15 years and potentially utilized to develop a 
pharmacogenomic test for determining the likelihood of treatment response to TNX-1900.  


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A decision to not participate in optional pharmacogenomic testing will not affect the patient’s 
eligibility for the main study. Patients have the right to stop participating at any time during 
the study or during the time of sample storage, and, if a patient decides to withdraw from the 
pharmacogenomics portion of this study, any remaining sample will be destroyed and not 
used for further research. Data collected before a patient’s withdrawal from the 
pharmacogenomics portion of this study will remain in the research database and included in 
the sponsor’s analyses and reports. 


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7 
ADVERSE EVENTS 
7.1 
Adverse Events 
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
patient administered an IP that does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding, for example), symptom, or disease temporally associated with 
the use of a medicinal product, whether related to the medicinal product, or not. 
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. 
Events that occur in patients treated with placebo, or during treatment free periods of the 
study, are also considered AEs. 
7.1.1 
Unexpected Adverse Events 
An expected AE is one for which the nature or severity is consistent with the known AE 
profile of the product. For a pre-approval test product, the known information is contained in 
the Investigator's Brochure (IB). For a marketed product, the known information is contained 
in the current package insert for the product. 
An unexpected AE is one for which the nature or severity is not consistent with the 
applicable product information (e.g., IB for an unapproved IP or package insert/summary of 
product characteristics for an approved product). For example, hepatic necrosis would be 
unexpected (greater severity) if the IB only listed elevated hepatic enzymes or hepatitis. 
Likewise, 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.) 
7.1.2 
Treatment-Emergent Adverse Events 
An AE is defined as treatment-emergent if the first onset or worsening is during or after the 
first administration of IP and not more than 30 days after the last administration of study 
drug. 


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7.1.3 
Severity 
7.1.3.1 
Severity of Adverse Events 
The clinical severity of an AE will be classified as: 
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 patient. 
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 7.1.4. 
7.1.3.2 
Serious Adverse Events 
7.1.4 
Serious Adverse Events 
A serious adverse event (SAE) is defined by federal regulation as any AE occurring at any 
dose that results in any of the following outcomes: death, life-threatening AE, hospitalization 
or prolongation of existing hospitalization, a persistent or significant disability/incapacity, or 
a congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, 
they may jeopardize the patient and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in patient hospitalization, or the development of 
drug dependency or drug abuse. 
Any SAE that occurs at any time during the study, including a clinically significant abnormal 
laboratory test result that is considered serious, must be reported to Tonix or its designee(s) 
so that Tonix may comply with regulatory obligations. If the SAE is life-threatening or fatal, 
it must be reported to Tonix or its designee(s) immediately, by facsimile and telephone. For 
these and all other SAEs, an SAE Report Form must be completed and sent by facsimile or 
email to Tonix or its designee(s) within 1 working day of the site’s initial awareness of the 
event. These requirements apply equally to all patients, regardless of the study period or the 
at-risk patient’s treatment assignment or dosage. 
A SAE (experience) or reaction is any untoward medical occurrence that, at any dose: 
• Results in death, 


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• Is life-threatening, 
• Requires in-patient hospitalization or prolongation of existing hospitalization, 
• Results in persistent or significant disability/incapacity, 
• Is a congenital anomaly/birth defect, or 
• Is an important medical event. 
 
NOTE: The term “life-threatening” in the definition of “serious” refers to an event in which 
the patient was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe. 
Any death occurring during the study, during the per-protocol follow-up period, or reported 
to the investigator after study participation (no required post-study time limit) must be 
reported to Tonix or its designee(s) immediately, whether or not it is considered treatment-
related. Initial SAE reports must be followed by detailed descriptions. These should include 
copies of hospital case records and other documents when requested. Telephone and email 
reports must be confirmed promptly either by facsimile or by email. For reporting SAEs, 
Tonix’s designated medical monitor should be called, and the relevant forms submitted to 
 within 24 hours of the site’s awareness of the SAE. 
The investigator, or the sponsor or designee in the case of a central IRB, also must notify the 
ethics committee IRB of the occurrence of the SAE, in writing, as soon as is practicable and 
in accordance with local law. A copy of this notification must be provided to Tonix or its 
designee. In the event of an SAE that meets the criteria for expedited reporting, an 
investigational new drug (IND) Safety Report will be prepared for submission to the FDA. 
7.2 
Adverse Event Assessment 
The occurrence of an AE or SAE may come to the attention of study personnel during study 
visits and interviews of a study patient presenting for medical care or upon review by a study 
monitor. 
7.2.1 
Performing Adverse Events Assessments 
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 patient 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?” 


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Any clinically relevant observations made during the visit will also be considered AEs. 
7.2.2 
Reporting Serious Adverse Events 
The investigator or designee must report all SAEs promptly to sponsor or designated CRO 
within 24 hours of first becoming aware of the event by completing, signing and dating the 
SAE Report Form, verifying the accuracy of the information recorded in the form with the 
source documents and eCRF, and sending the SAE form to the study CRO. SAEs should be 
sent to:
 This written report should be submitted on the 
SAE form provided for this purpose. At the time of first notification, the investigator or 
designee should provide the following information, if available: 
• Protocol number 
• Reporter (study site and investigator) 
• Patient’s study number 
• Patient’s year of birth 
• Patient’s sex 
• Date of first dose of IP(s) 
• Date of last dose of IP(s), if applicable 
• Adverse event term 
• 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 medical history information 
• Relevant laboratory test findings 
• Investigator’s opinion of the relationship to IP(s) (“Is there a reasonable possibility that 
the IP caused the SAE? Yes or No?”) 
• Whether and when the investigator was unblinded as to the patient’s treatment 
assignment 
 
Any missing or additional relevant follow-up information concerning the SAE should be sent 
to the sponsor/sponsor representative via the same contact details above as soon as possible 
on a follow-up SAE Report Form, together with the following minimal information (initial 


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report, AEs, date of occurrence, patient identification (ID), study ID, IP, and site number); 
this will allow the follow-up information to be linked to the initial SAE report. 
Specific information may be requested by the study CRO using a follow-up request form or 
via email communication. 
The investigator is required to comply with applicable regulations (including local laws and 
guidance) regarding the notification of his or her health authorities, Institutional Review 
Board (IRB), principal and coordinating investigators, study investigators, and institutions. 
Each investigator is obligated to learn about the reporting requirements for investigators in 
his/her country. The study monitor can assist with this. 
7.2.3 
Documentation of Adverse Events 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be 
captured on the appropriate CRF. Information to be collected includes event description, time 
of onset, clinician’s assessment of severity, relationship to study product (assessed only by 
those with the training and authority to make a diagnosis), and time of resolution/stabilization 
of the event. All AEs occurring while on study must be documented appropriately regardless 
of relationship. All AEs will be followed to adequate resolution or stabilization. 
• 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 (hospitalization, death, etc.) 
• Actions taken 
• Outcome 
• Investigator opinion regarding the AE relationship to the IP 
 
The outcome at the time of last observation will be classified as: 
• Recovered/resolved 
• Recovered/resolved with sequelae 
• Recovering/resolving 
• Not recovered/not resolved 
• Fatal* 


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• Unknown 
*Fatal should only be selected as an outcome when the AE results in death. If more than one 
AE is judged to be possibly related to the patient’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. 
7.2.4 
Treatment of Adverse Events 
AEs 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 decision about whether the 
patient may continue in the study will be made by the sponsor after consultation with the 
investigator and/or medical monitor. 
If AEs occur in a patient that are not tolerable, the investigator must decide whether to stop 
the patient’s involvement in the study and/or treat the patient. Special procedures may be 
recommended for the study drug, such as the collection of a serum sample for determining 
blood concentrations of study drug, specific tapering procedures, or treatment regimens, as 
appropriate. 
For double-blinded studies, it is not necessary to unblind a patient’s treatment assignment in 
most circumstances, even if an SAE has occurred. If unblinding is necessary, see Section 5.4 
for a description of the unblinding procedures. 
Action(s) taken may consist of: 
IP interrupted 
IP schedule was modified by temporarily terminating the prescribed regimen 
of IP. 
IP withdrawn 
IP schedule was modified through termination of IP. 
Not applicable 
Determination of a value is not relevant in the current context. 
Unknown 
Not known, not observed, not recorded, or refused. 
 
7.2.5 
Adverse Event Relationship 
The investigator must assess each AE’s relationship to the IP. The investigator must carefully 
consider possible when assigning a relationship of specific AEs to study drug. The categories 
for classifying the investigator’s opinion of the relationship are as follows: 
 
Not Related 
This is an AE that is clearly not related to the study drug beyond a reasonable 
doubt.  That is, another cause of the event is more plausible; and/or a clinically 
plausible temporal sequence is inconsistent with the onset of the event and the 
administration of study drug and/or a causal relationship is considered 
biologically implausible. 


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Unlikely Related 
This is an AE that could reasonably be considered caused by something else, and 
where there is no known or expected response pattern to the suspect study drug.  
Possibly Related 
This category applies to an AE that follows a reasonable temporal sequence from 
administration of the study drug and that follows a known or expected response 
pattern to the suspected study drug, but that could readily have been produced by 
a number of other factors. 
7.2.6 
Expectedness 
An expected adverse drug reaction has a nature or severity that is consistent with the study 
intervention description as found in the Investigator Brochure (for unapproved 
investigational products). An adverse drug reaction is unexpected if it is not listed in the 
Investigator Brochure or is not listed at the specificity or severity that has been observed. 
Determination of expectedness is the responsibility of the sponsor and is necessary for 
determining if the event is a suspected unexpected serious adverse reaction which is reported 
to FDA and IRB in an expedited manner. The purpose of expedited reporting is to make 
regulators, investigators, and other appropriate personnel aware of new, important 
information on serious reactions. Such reporting will generally involve events previously 
unobserved or undocumented. 
7.2.7 
Clinical Significance 
An abnormal laboratory value or test result, e.g., ECG, is clinically significant if the 
abnormality suggests a disease and/or there is organ toxicity that is new or worsened from 
Baseline. 
7.2.8 
Special Considerations 
7.2.8.1 
Adverse Events of Special Interest 
Since IN administrations of agents can cause significant irritation of nasal mucosa, events of 
nasal irritation will be followed closely during the study and considered an AE of Special 
Interest. Investigators should monitor for tissue changes or lesions in the visualized nasal 
mucosa on nasal exam, and for pain or discomfort anywhere in the nasal cavity, sinuses or 
oropharynx. 
Because intranasal administration of oxytocin can result in a transient, albeit short-lived and 
minor, rise in systemic oxytocin levels, there will be specific monitoring for the potential 
adverse effects of supraphysiological levels of oxytocin in plasma. It should, however, be 
noted that with intranasal administration and the proposed oxytocin dosing regimens, 
sustained and clinically relevant plasma oxytocin levels are not expected. It is out of an 
abundance of caution that close monitoring for potential safety signals will be carried out. 


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Theoretically, if substantial and sustained concentrations in plasma are achieved, plasma 
oxytocin may activate off target vasopressin receptors leading to antidiuretic effects. Thus, 
AEs that may involve changes in blood volume, blood pressure, and specific electrolyte 
disturbances (hyponatremia) will be AEs of special interest, e.g., new onset edema, 
hypervolemia, increased blood pressure, ECG changes related to cardiac hypertrophy or 
arrhythmia.  
7.2.8.2 
Pregnancy 
All women of childbearing potential who participate in the study should be counseled on the 
need to practice adequate birth control 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 prior to administration of the IP 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 to be a SF. 
A woman who becomes pregnant during IP treatment or within 28 days of discontinuing the 
IP will be immediately discontinued from study participation. The investigator must report 
the pregnancy as if it were an SAE within 48 hours of learning of the pregnancy, to 
 
 using the Pregnancy Data Collection Form via the same fax 
number and/or email address as for SAE reporting. The investigator should contact the 
designated individual(s) who receive SAE notification and record information related to the 
pregnancy on a designated form provided by the sponsor 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. These findings must be reported on the designated form and forwarded to the 
designated individual(s). The event meets the SAE criterion only if it results in a spontaneous 
abortion after the first trimester or a congenital anomaly. 
7.2.8.3 
Overdosage 
The maximal dose of study drug should not be exceeded during the study. Overdose that 
occurs during the study will be treated and documented as an AE/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, patient identification, IP, 
dose, action taken (e.g., supportive measures or therapy), and any comments. 
As with any overdose, patients should be monitored closely and observed for expected and 
unexpected clinical and laboratory effects. 
No specific antidote to oxytocin exists, so treatment should be directed at supportive care. 


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7.2.8.4 
Abuse Potential 
Although no indications of abuse have been reported, oxytocin will still be monitored for 
abuse or misuse. 


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8 
STUDY ACTIVITIES 
8.1 
Screening Visit 1  
Informed Consent 
Before the potential participant has undergone any study-related Screening procedures, 
including any down-titration or withdrawal of medications, the nature of the study and the 
potential risks associated with it will be explained to the patient, and the patient will be given 
an opportunity to ask questions to his or her satisfaction. After the questions are answered, 
but before proceeding further, the patient must read and sign a written informed consent 
form. This signed informed consent form will be retained in the investigator’s study file, and 
the date the patient signed the form will be entered into the CRF. The patient will be 
provided with a copy of his or her signed and dated informed consent form.  
After providing written informed consent, patients will be assessed for study entry eligibility. 
Screening Assessments and Procedures: 
1. Obtain written informed consent to participate 
2. Inclusion/exclusion criteria 
3. Demographics 
4. Confirm chronic migraine diagnosis 
5. Medical, neurological, and medication history 
6. Physical examination 
7. Nasal cavity examination 
8. Vital signs 
9. 12-lead ECG 
10. Clinical laboratory tests (hematology, standard blood chemistry panel, TSH, HbA1C, 
and urinalysis) 
11. Serum pregnancy test (for women of childbearing potential [WoCBP]) processed at 
central lab 
12. Urine drug test 
13. “Screening/Baseline” version of the C-SSRS. Any patient exhibiting Type 3, 4, or 5 
suicidal ideation in the last 6 months or who has had suicidal behavior in the last 
12 months should be deemed a screen failure and assessed for appropriate follow-up 
care. Results of the C-SSRS should be reviewed to ensure the patient is not 
experiencing suicidal ideation or has had suicidal behavior that requires emergency 
intervention 
14. MSI-BPD 
15. Placebo response training 


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16. Provide the patient with the e-diary training.  Reminder notifications for diary 
completion should be set up in the IRT and in the ePRO app according to the patient’s 
preferences 
During this Screening/Wash-Out/Run-In Period, if any test results come back and indicate a 
patient’s ineligibility for the study, the patient should be considered a screen-failure (SF) and 
informed that they are not eligible for the study and can stop completing the e-diary. 
However, if the investigator determines that the patient should be brought back into the clinic 
for re-testing, the patient should continue completing the e-diary until a final determination 
regarding eligibility is made. 
In addition, any patients not meeting the randomization criteria will be considered a SF. 
Only those patients meeting all the inclusion and none of the exclusion criteria will be 
eligible to continue. 
 
8.2 
Baseline/Randomization Visit 2 (Day 1) 
If the patient meets randomization (randomization will be stratified by study site and 
concomitant migraine preventive medication) criteria, the patient will be authorized to 
continue in the study, will undergo several Baseline assessments at this visit, and will be 
randomized via the randomization system to receive double-blind study drug. If the patient 
does not satisfy randomization criteria, the patient has failed to qualify for this study and 
should be considered an SF, with the reason documented. There is no requirement for a 
follow-up visit for SFs; however, the investigator should advise patients who have washed 
off of medications for the study on next steps of treatment. 
If the patient meets randomization criteria, the following procedures will be completed at V2: 
• Eligible patients will be randomized in a 1:1:1 ratio to one of 3 treatment arms (A, B or 
C) as summarized in Section 5.2. Randomization will be stratified by study site and 
concomitant migraine preventive medication. 
• The patient should also be provided with the opportunity to sign a separate consent form 
for the optional pharmacogenomics blood draw and analysis. Participation in this optional 
portion of the study is not required. Ideally, the blood drawn for the optional 
pharmacogenomics should be drawn at the Baseline visit; however, it can be drawn at a 
subsequent visit if needed. A patient can decide to decline the optional 
pharmacogenomics but still participate in the main study. 
The following assessments and procedures are scheduled for this visit in the following 
general order: 
• Confirm patient’s eligibility. 
• Review completed diary data with the patient. Provide re-training. 


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• Update medical history (if any new information has been provided since the Screening 
Visit). 
• Assess occurrence of AEs. 
• Assess changes in medication history and concomitant medications. 
• Conduct a physical examination, including vital signs and weight. 
• Conduct a nasal cavity examination. 
• Conduct a 12-lead ECG 
• Obtain clinical laboratory tests (standard blood chemistry panel and urinalysis) 
• Perform urine pregnancy test (for WoCBP) 
• Obtain blood sample for optional pharmacogenomics (after the separate ICF has been 
signed for pharmacogenomic substudy) - if not drawn at a prior visit 
• Administer the “Since Last Visit” version of the C-SSRS. Any patient exhibiting Type 3, 
4, or 5 suicidal ideation or any suicidal behavior since the Screening Visit should be 
screen-failed and assessed for appropriate follow-up care. Results of the C-SSRS should 
be reviewed to ensure the patient is not experiencing suicidal ideation or has had suicidal 
behavior that requires emergency intervention. 
• Have the patient complete placebo response training. 
• Administer the HADS: Hospital Anxiety and Depression Scale 
• Have the patients complete the following rating scales: 
1. MIDAS: Migraine Disability Assessment questionnaire 
2. MSQ: Migraine-Specific Quality of Life Questionnaire v2.1 
3. CSFQ-14: Changes in Sexual Functioning Questionnaire Short-Form 
• Verify patient’s ability to use an intranasal device prior to leaving the clinic at 
Baseline/Randomization/Visit 2. Patient will also take their first study drug dose before 
leaving the clinic. 
• Once it has been confirmed that the patient remains eligible, randomize patient via 
interactive response technology (IRT) Randomization System 
• Dispense 2 unopened nasal applicators of double-blind study drug as assigned via the 
IRT (one is marked “MORNING” and the other is marked “EVENING”). Prime the two 
study drug bottles. Supervise the patient as they take one dose of study drug from the 
appropriate study drug bottle (AM or PM) depending on appointment time. 
• Each treatment bottle number should be recorded in the patient’s records. Review patient 
instructions regarding study drug dosing and diary completion  


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8.3 
Visits 3 (Week 4) and 4 (Week 8) 
Visits 3 and 4 are similar study visits that are scheduled to be conducted after 4 weeks, and 
8 weeks of treatment, respectively. The following assessments and procedures are scheduled 
for both of these visits in the following general order: 
• Assess changes in medication history and concomitant medications 
• Assess occurrence of AEs 
• Conduct nasal exam cavity examination 
• Obtain vital signs 
• Conduct a12-Lead ECG 
• Obtain clinical laboratory tests (standard blood chemistry panel and urinalysis) 
• Perform urine pregnancy test (for WoCBP). 
• Obtain blood sample for optional pharmacogenomics (after the separate ICF has been 
signed for pharmacogenomic substudy) - if not drawn already at a prior visit 
• Have the patient complete placebo response training. 
• Administer the “Since Last Visit” version of the C-SSRS. Results of the C-SSRS should 
be reviewed to ensure the patient is not experiencing suicidal ideation or has had suicidal 
behavior that requires emergency intervention 
• Have the patient complete: 
1. PGIC: Patient Global Impression of Change 
2. HADS: Hospital Anxiety and Depression Scale 
3. MSQ: Migraine-Specific Quality of Life Questionnaire v2.1 
• Review completed diary data and diary compliance with the patient. Provide re-training. 
• Assess study drug compliance and collect previously dispensed study drug and bottles 
• Dispense 2 unopened nasal applicators of double-blind study drug as assigned via the 
IRT (one is marked “MORNING” and the other is marked “EVENING”). Prime the two 
study drug bottles.  
• After all the assessments at each visit have been completed, the patient should be given 
an appointment to return to the clinic for the next scheduled visit, and be re-instructed, as 
necessary, in the completion of the diary, dosing instructions, and reminded to bring 
study drug back to the clinic at their next visit. 


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8.4 
Visit 5 (Week 12) or Early Termination Visit 
Visit 5 should occur after 12 weeks of double-blind study drug treatment. At this visit, the 
patient will return all study drug. The following assessments are completed: 
• Assess changes in medication history and concomitant medications 
• Assess occurrence of AEs 
• Conduct a physical examination, including vital signs, weight 
• Conduct a nasal cavity examination 
• Conduct a 12-lead ECG 
• Obtain blood for clinical laboratory tests (hematology, standard blood chemistry panel, 
urinalysis)  
• Perform in-clinic urine pregnancy test (for WoCBP) 
• Obtain blood sample for optional pharmacogenomics (after the separate ICF has been 
signed for pharmacogenomic substudy) - if not drawn at a prior visit 
• Have the patient complete placebo response training 
• Administer the “Since Last Visit” version of the C-SSRS. Results of the C-SSRS should 
be reviewed to ensure the patient is not experiencing suicidal ideation or has had suicidal 
behavior that requires emergency intervention 
• Have the patient complete: 
1. PGIC: Patient Global Impression of Change 
2. HADS: Hospital Anxiety and Depression Scale 
3. MIDAS: Migraine Disability Assessment questionnaire 
4. MSQ: Migraine-Specific Quality of Life Questionnaire v2.1 
5. CSFQ-14: Changes in Sexual Functioning Questionnaire Short-Form 
• Review completed diary data and diary compliance with the patient. Provide re-training 
as needed. 
• Assess study drug compliance and collect previously dispensed study drug and bottles 
• After all the assessments at each visit have been completed, the patient should be given 
an appointment to return to the clinic for the Follow-up visit. 
 
All patients who withdraw early from the study will be encouraged to complete the ET Visit 
for safety evaluations (Visit 5) within 7 days from withdrawal of study, followed by a Safety 
Follow-up Visit (Visit 6) approximately 14 days from the last study drug administration.  


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8.5 
Visit 6 (Week 14)/Safety Follow-up  
Visit 6 (Week 14) or Safety Follow-up in-person visit will occur 14 days after the final 
treatment (Visit 5). 
The following assessments are completed: 
• Assess AEs 
• Conduct nasal exam, only if there is any ongoing or new AE of the nasal cavity 
• Conduct vital signs 
• Obtain samples for clinical lab tests (hematology, blood chemistry, and/or urinalysis), 
only if there are any clinically significant findings from the V5 labs 
• Perform in-clinic urine pregnancy test (for WoCBP) 
• Optional blood draw for pharmacogenomics (after the separate ICF has been signed for 
pharmacogenomic substudy) - if not drawn at a prior visit 
• Administer the “Since Last Visit” version of the C-SSRS. Results of the C-SSRS should 
be reviewed to ensure the patient is not experiencing suicidal ideation or has had suicidal 
behavior that requires emergency intervention 
 
8.6 
Early Termination (After Randomization) 
In accordance with the Declaration of Helsinki, patients have the right to withdraw from the 
study at any time for any reason, and they will be advised of this right. The investigator and 
Tonix also have the right to remove patients from the study. Specific reasons for removal of a 
patient from the study could include, but are not limited to: 
• An AE 
• An illness that, in the judgment of the investigator or Tonix, might invalidate the study 
data or place the patient at risk 
• The request of the patient, investigator, or Tonix, whether for administrative or other 
reasons  
• Pregnancy 
 
Patients who wish to terminate their participation in the study should be instructed to come to 
the clinic for an ET Visit. The purpose of the ET Visit is to obtain critical information about 
the patient’s participation and should be scheduled preferably before there has been a 
substantial lapse in study drug usage. However, even if there has been a drug lapse, the 


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patient should be encouraged to return to the clinic for this visit and should be instructed to 
return all study drug and bottles. Additionally, the patient should be encouraged to also 
subsequently attend the Safety Follow-Up Visit (Visit 6). NOTE: These visit procedures are 
not intended for patients who fail to qualify for randomization or for patients who withdraw 
from the study prior to receipt of a dose of double-blind study drug.  
In addition to documenting the reason for ET during the ET visit, assessments and 
procedures should be completed according to the V5 schedule. For the Safety Follow-Up 
Visit (Visit 6), assessments and procedures should be completed according to the V6 
schedule.  
 


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9 
QUALITY CONTROL AND ASSURANCE 
Unless otherwise specified, procedures, data collection and evaluation will be conducted as 
per the standard operating procedures of the CRO. The investigator will assume the 
responsibility of ensuring the completeness and accuracy of the clinical data. All data will be 
verified for quality control and will also be patient to audits from Tonix or designee to ensure 
quality. 


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10 
PLANNED STATISTICAL METHODS 
10.1 
General Considerations 
All safety and efficacy data will be listed and summarized. Unless otherwise specified, 
Baseline is defined as the last observed measurement, whether scheduled or unscheduled, 
prior to study drug administration. Safety and efficacy endpoints will be summarized by 
treatment group. Continuous variables will be summarized using the number of patients with 
data (n), mean, SD, median, minimum, and maximum. Selected continuous variable 
summaries will also include the standard error. Categorical variables will be summarized 
using frequency counts and percentages. All values summarized will also be presented in 
listings. 
The statistical analysis plan (SAP) will provide further details for statistical methodology. 
All analyses will be performed using SAS® version 9.4 or higher, unless otherwise specified. 
10.1.1 
Estimand 
The primary efficacy endpoint is defined as the change in monthly migraine days from 
Baseline (last 28 days prior to randomization) to month 3 (last 28 days of treatment). For 
defining months, diary days will be divided into 28 day “months”; Days 1 to 28 will be 
Month 1; Days 29 to 56 will be Month 2; and Days 57 to 84 will be Month 3. The change in 
count of days with migraine vs the baseline will be compared between treatment groups. 
The target population is all patients in the mITT population with CMs as defined by the 
inclusion/exclusion criteria. 
A “while on treatment” policy strategy will be used for all intercurrent events. That is, the 
data will be considered independently from any intercurrent event, such as rescue medication 
usage and study discontinuation. The approach for partial and missing data is described in 
Section 10.1.3. 
The population-level summary will be the model-based least-squared means for each arm and 
differences between treatment arms (analyzed as randomized) at month 3.   
10.1.2 
Multiple Comparisons 
A multiplicity algorithm will maintain an overall alpha level of 0.05 across the two dose 
groups as well as the primary endpoint of change in monthly migraine days from Baseline to 
month 3, using the graphical method. Full details will be specified in the SAP. 
 
10.1.3 
Missing Data 
Every effort will be made to retain patients in the study; however, patients are free to 
withdraw from the study at any time for any reason. Patients that withdrawal early will be 


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asked to return to the clinic for an Early Termination Visit for completion of assessments 
(see Schedule of Assessments 
). 
The monthly migraine count will be calculated for patients that have at least 14 days of 
non--missing data for a given month. For patients with less than 28 days of data, the counts 
will be normalized to 28 days by taking 28* [migraine count] / [days of non-missing data]. 
If less than 14 days are available for a month, then the month will remain missing, but the 
patient’s other months will contribute to the estimation via a mixed-effects model of repeated 
measures. The mixed model repeated measures analysis will provide unbiased estimates 
under the assumption that data are missing at random (MAR). Sensitivity analyses will 
confirm the robustness of the results to deviations from this assumption.  
For responder analyses using the monthly migraine days, the values as imputed above will be 
utilized. If a month is missing, then the patient will be considered a non-responder for that 
month. 
For other responder analyses, patients with missing values will be treated as non-responders. 
10.2 
Determination of Sample Size 
The planned total number of randomized patients is approximately 300 and will be 
randomized 1:1:1 to TNX-1900 30 IU QAM, placebo QPM: TNX-1900 30 IU BID: or 
placebo BID. The sample size estimate was derived using a two-sided t-test with 90% power 
and 5% two-sided significance level to test the primary efficacy statistical superiority 
hypothesis of TNX-1900 30 IU BID over placebo. 
Based on a post-hoc analysis of a chronic migraine subgroup from a prior study, it is 
anticipated that a difference in mean change from Baseline to study end (last 28 days of 
double-blind) in migraine headache days between TNX-1900 30 IU BID and placebo BID 
would be approximately 1.84 with a common standard deviation of ± 3.95. As such the 
required sample size per group is approximately 100. 
Accounting for the multiplicity adjustment by applying an alpha of 2.5% to the first test 
yields power of approximately 85% with the above assumptions. 
10.3 
Analysis Populations 
The following populations will be utilized for the analyses of data. Disposition of patients 
will use the All Patients Population. The safety analyses will be conducted on the Safety 
Population. The modified intent-to-treat (mITT) Population will be used for the primary 
efficacy analyses. 


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10.3.1 
All Patients Population 
This includes all patients available in the electronic data capture system; patients will be 
presented by their randomized treatments (if applicable). 
10.3.2 
Modified Intent-to-Treat Population 
The mITT population will include all randomized patients who received at least one dose of 
study drug and had at least one post-Baseline evaluable month (that is, at least one of the 
three 28-day periods had at least 14 non-missing e-diary entries; see full details in SAP). This 
population will be used to summarize the primary and other efficacy data. Patients will be 
analyzed according to randomized treatment assignment. 
10.3.3 
Safety Population 
The Safety Population will include all patients who received at least one dose of study drug. 
This population will be used to summarize the safety data. Patients will be analyzed 
according to their treatment received; if an error in issuing IP occurs and a patient receives a 
mix of treatments, they will be analyzed under the treatment arm with the most IP issued to 
the patient. 
10.4 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics such as age, gender, race/ethnicity, height, weight, 
BMI, family status, education, employment status, smoking history, use of preventative 
migraine medications, and Migraine Diagnostic criteria will be summarized by treatment 
group (TNX-1900 and placebo) and overall using descriptive statistics. 
Medical History will be coded using the most current version Medical Dictionary for 
Regulatory Activities (MedDRA)® and summarized by System Organ Class and Preferred 
Term using frequency counts by treatment group. 
10.5 
Primary Endpoint(s) 
10.5.1 
Primary Safety Endpoint(s) 
Incidence of AEs, and changes in C-SSRS scores, HADS scores, physical examination and 
vital sign findings, clinical laboratory values, ECG parameters, and CSFQ-14 scores. 
10.5.2 
Primary Efficacy Endpoint(s) 
Mean change in the number of monthly migraine headache days from the last 28 days of 
Baseline to the last 28 days of treatment (i.e., month 3).  A migraine headache day is any 
calendar day (0:00 to 23:59) in which the patient records in the e-diary: 
• An attack lasting 4 hours or more and meeting the ICHD-3 criteria for migraine without 
aura (Appendix A), or 


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• A migraine with aura, or 
• An attack that meets ICHD-3 criteria for probable migraine, (a migraine subtype fulfilling 
all but one criterion (B-D) for migraine without aura), or 
• An attack of any duration that was believed by the patient to be a migraine and was 
relieved by a triptan, ergot derivative, or other migraine-specific abortive medication. 
10.6 
Secondary Endpoint(s) 
10.6.1 
Key Secondary Efficacy Endpoint(s) 
• Proportion of patients experiencing a ≥ 50% reduction in the number of migraine 
headache days from the last 28 days of Baseline to the last 28 days of treatment in each 
treatment group. 
• Mean change in the number of days using rescue medication (triptan, ergot derivative, or 
other migraine-specific acute medication) from the last 28 days of Baseline to the last 
28 days of treatment in each treatment group. 
• Proportion of patients with a PGIC rating of 1, “very much improved”, or 2, “much 
improved”, at Week 12. 
• Mean change in the number of moderate or severe headache days from the last 28 days of 
Baseline to the last 28 days of treatment in each treatment group. A moderate or severe 
headache day is defined as any calendar day wherein a patient records a headache or 
migraine of moderate or severe peak intensity in the e-diary. 
• Mean change in the number of migraine headache days from the last 28 days of Baseline 
to average number per 28 days over the entire 12-week duration of Treatment Period. 
• Mean change from Baseline in the Migraine-Specific Quality of Life Questionnaire 
(MSQ v2.1) at Week 12  
10.6.2 
Secondary Efficacy Endpoint(s) 
• Mean change from Baseline in the MIDAS Test total score at Week 12. 
• Mean change from Baseline in the HADS at Week 12. 
• Mean change from Baseline in patient-rated Changes in Sexual Functioning 
Questionnaire Short-Form (CSFQ-14) total score in males and in females, analyzed 
separately, at Week 12. 
 


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10.6.3 
Exploratory Endpoint(s) 
• Proportion of patients experiencing a ≥ 75% reduction in the number of migraine 
headache days from the last 28 days of Baseline to the last 28 days of treatment in each 
treatment group. 
• Proportion of patients with fewer than 14 headache days or fewer than 8 migraine 
headache days per 4 weeks over the 12-week period. 
• Mean change from Baseline in number of headache free days from the last 28 days of 
Baseline to the last 28 days of treatment. 
• PGIC rating (1-7) at Week 12 
 
10.7 
Analysis Methods 
10.7.1 
Disposition and Demographics 
The number and percentage of patients in each analysis population will be summarized. The 
number of patients screened, patients enrolled, and the number and percentage of patients 
completing the study, discontinuing from the study and reasons for discontinuation will also 
be reported. All percentages will be calculated using the number of patients enrolled as the 
denominator. 
Demographics and baseline characteristics will be reported for the efficacy and safety 
populations. Categorical items will be reported with counts and percentages; continuous 
items will be reported using summary statistics (mean, SD, median, minimum, maximum). 
10.7.2 
Efficacy Analysis 
10.7.2.1 
Primary Efficacy Analysis 
Summary statistics (mean, SD, median, minimum, maximum) for the primary efficacy 
endpoint will be reported for the change from the Baseline to month 3 for each of the 
treatment groups. The change from Baseline will be analyzed in a Mixed-Effects Model of 
Repeated Measures (MMRM) model with fixed effects of treatment, month, baseline value, 
treatment by month interaction, baseline by month interaction, site, and stratification factor 
(preventive medication use); an unstructured covariance matrix will be used. Least square 
means (LSMs), standard errors, and the LSM differences (each treatment vs placebo) will be 
reported for each month. Denominator degrees of freedom will use the Kenward Rogers 
approach. Should the model fail to converge, heterogeneous Toeplitz, heterogeneous first-
order autoregressive, Toeplitz, first order autoregressive and compound symmetric will be 
attempted in that order; in these cases, the sandwich estimator (Diggle and Kenward 1994) 
will be used to estimate the standard errors of the fixed effects parameters and the 
denominator degrees of freedom will utilize the DDFM=BETWITHIN option in SAS®. 
To account for the blinded interim sample size re-estimation (Section 10.8), data from the 
interim and post-interim cohorts will be combined using the inverse normal method to test 


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the null hypotheses that there is no difference in the change from Baseline to month 3 in 
number of migraine days per month between each of the active groups and placebo (Cui et al 
1999): 
𝑍𝑍1  = 𝛷𝛷−1(1 − 𝑝𝑝1)                                                 (1) 
𝑎𝑎𝑎𝑎𝑎𝑎 𝑍𝑍2  = 𝑤𝑤1𝑍𝑍1  + 𝑤𝑤2𝛷𝛷−1(1 − 𝑝𝑝2)   
Where: 
Z1 = the Z statistic for the first stage 
Z2 = the combination test statistic at the end of the second stage 
wi = the weighting applied for each associated Z statistic 
p1 = the first stage p-value 
p2 =the second stage p-value based on second stage participants 
The weights are defined prospectively according to the square-root of the planned proportion 
of participants in the two stages, relative to the preplanned total enrollment of 300 
participants, as w𝑖𝑖 = √0.5.  In order to control the type-I error, adaptive changes of the stage 
wise sample sizes will not lead to changes of the weights (Lehmacher and Wassmer 1999). 
For each difference of interest, the combined point estimate of the difference, and adjusted 
95% confidence interval will be provided (Lawrence and Hung 2003).  The formulas for the 
inferential statistics are given below. 
The combined point estimate of the treatment difference is provided in formula (2) and its 
adjusted confidence interval is provided in formula (3). 
𝛿𝛿̂ =
𝑟𝑟1𝛿𝛿෡(1)+ඥ1−𝑟𝑟1ඥ𝑁𝑁∗−𝑟𝑟1 𝛿𝛿෡(2)
𝑟𝑟1+ඥ1−𝑟𝑟1ඥ𝑁𝑁∗−𝑟𝑟1
    
  
 
 
(2) 
 
𝛿𝛿̂ ± ቀቚ
𝛿𝛿෡
𝑍𝑍2ቚ𝑧𝑧𝛼𝛼/2ቁ 
 
 
 
 
 
(3) 
Where: 
𝛿𝛿̂(1): LS Means difference from stage 1 analysis (interim cohort analysis) 
𝛿𝛿̂(2): LS Means difference from stage 2 analysis (post-interim cohort analysis) 
𝑟𝑟1: total number of patients planned to be included at the interim analysis divided by the 
total number of patients originally planned (planned sample size), i.e., 0.5 
𝑁𝑁∗: final total number of patients divided by the total number of patients originally 
planned 
     𝑍𝑍2: combination test statistic at the end of the second stage obtained in equation 1 
 
10.7.2.2 
Sensitivity Analyses 
Three sensitivity analyses will be performed: 


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• Multiple imputation methodology will be utilized to impute complete datasets with 
three monthly observations for all patients in the mITT population. This will be done 
within each treatment group conditioned on each patient’s non-missing data 
(including baseline), site, and the stratification factor.   
• A tipping point analysis will be performed using the above MI datasets and applying 
an increasing penalty to the active group until statistical significance is no longer 
achieved. 
• Finally, a missing-not-at-random multiple imputation approach will be utilized taking 
into account the reason for discontinuation; intermittent missing data will still be 
assumed to be missing at random. 
Full details of each analysis will be provided in the SAP. 
10.7.2.3 
Secondary Analyses 
Continuous endpoints will be analyzed in a manner parallel to the primary analysis. Daily 
diary measures will be aggregated to monthly values and analyzed in the MMRM. Visit-
based measures will use visit in place of month in the MMRM. 
For binary endpoints, the counts and percentages of responders in each treatment arm will be 
reported as well as the 95% CIs of those percentages.  Patients with missing data will be 
considered non-responders.  The difference in percentages in the active and placebo arms 
will be reported along with its 95% CI based on the Sato variance estimator.  Pairwise p-
values will compare each treatment arm to placebo based on a Cochran-Mantel-Haenszel 
(CMH) stratified by preventive medication use. 
Full details of the secondary analyses will be provided in the SAP. 
10.7.3 
Safety Analysis 
All safety analyses will be completed for the Safety Population. All safety data will be 
tabulated and listed. No formal statistics will be performed for the safety analysis. 
Adverse events that occur between the time written informed consent is provided and the 
start of study drug administration will be considered pretreatment AEs. Adverse events that 
start during or after study drug administration, or AEs with an onset prior to study drug 
administration that worsen after study drug administration will be considered TEAEs.   All 
AEs will be coded using MedDRA, and the incidence of TEAEs will be summarized overall 
and by preferred term and system organ class for each treatment group. Incidence of TEAEs 
will also be summarized by severity and relationship to study drug. Serious AEs, TEAEs 
involving the nasal passages, and TEAEs leading to discontinuation of study drug will also 
be summarized.  
Actual values and changes from Baseline for clinical laboratory test results, ECG parameters, 
vital signs, HADS scores, and CSFQ-14 scores will be summarized by treatment group and 


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visit using descriptive statistics (n, mean, SD, median, minimum, and maximum). The 
number of patients with baseline and treatment-emergent suicidal ideation and/or suicidal 
behavior, based on the C-SSRS, will be summarized by treatment group. For each laboratory 
test, individual patient values will be listed and values outside of the standard reference range 
will be flagged. 
 
10.8 
Interim Analysis 
An interim analysis will be performed once 50% of the planned patients have enrolled and 
those patients have either completed or discontinued the study. The purpose of the interim 
will be to potentially increase the sample size to maintain statistical power conditioned on the 
results of the first 50% of patients; or continue as planned if conditional probability of 
success at end of the Treatment Period is above a pre-specified threshold; or to stop the study 
early for futility if the conditional power is sufficiently low. The conditional power will be 
calculated based on the first cohort, using the following formula (Mehta and Pocock 2010): 
CP(Z1,ň2) = 1 - Φ൬
𝑍𝑍𝛼𝛼√𝑛𝑛2− 𝑍𝑍1√𝑛𝑛1
ඥň2
−
𝑍𝑍1ඥň2
√𝑛𝑛1 ൰ 
Where:  
Z1 is the value of the Z score at the interim  
n1 is the actual sample size at the interim 
n2 is the total planned sample size 
ň2 is the total planned sample size minus the actual sample size at the interim 
The study team will only be informed of the non-binding recommendation to maintain the 
original sample size, increase the sample size (by a fixed, pre-specified amount), or 
discontinue the study for futility. 
Full details of the interim analysis will be included in the SAP and finalized prior to 
execution of the interim analysis. 


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11 
ADMINISTRATIVE CONSIDERATIONS 
11.1 
Institutional Review Board or Ethics Committee Approval 
The EC/IRB must be a properly constituted board or committee operating in accordance with 
21 CFR Part 56, “Institutional Review Boards.” This protocol, any protocol amendments, the 
associated informed consent forms, and the informed consent procedures must be submitted 
to the EC/IRB for review and approved before the enrollment of any patient into the trial. All 
types of patient recruitment or advertising information must be submitted to Tonix or its 
designee and to the EC/IRB for review and approval prior to implementation. EC/IRB 
approval of any protocol amendments must be received before any of the changes outlined in 
the amendments are put into effect, except when the amendment has been enacted to 
eliminate a potential hazard to study patients. In such cases, the chair of the EC/IRB should 
be notified immediately, and the amendment forwarded to the EC/IRB for review and 
approval. 
11.2 
Ethical Conduct of the Study 
This protocol is written in accordance with the principles established by the 18th World 
Medical Assembly General Assembly (HelsinkiDeclaration, 2014) and amendments and 
clarifications adopted by subsequent General Assemblies. The investigator will make sure 
that the study described in this protocol is conducted in full conformance with those 
principles, the protocol, current FDA regulations, ICH Good Clinical Practices (GCP) 
guidelines, Good Laboratory Practices (GLP) guidelines, local ethical and regulatory 
requirements, including the Federal Food, Drug and Cosmetic Act, US applicable Code of 
Federal Regulations (title 21), any EC requirements relative to clinical studies. As required 
by the US FDA, the study drug may not be shipped to any participating investigator until the 
requisite study documentation has been submitted to the IND. 
Should a conflict arise, the investigator will follow whichever law or guideline affords the 
greater protection to the individual patient. The investigator will also make sure he or she is 
thoroughly familiar with the appropriate administration and potential risks of administration 
of the study drug, as described in this protocol and the Investigator’s Brochure, prior to the 
initiation of the study. 
11.3 
Patient Information and Consent 
It is the responsibility of the investigator to obtain signed written informed consent from each 
potential study patient prior to the conduct of any Screening or other study procedures. This 
written informed consent will be obtained after the methods, objectives, and potential risks of 
the study have been fully explained to the potential patient. The investigator must explain to 
each patient that he or she is completely free to refuse to enter the study or to withdraw from 
it at any time. The patient should also be asked in the informed consent form (ICF) for 
permission for the principal investigator or his designee to contact the patient’s other 
personal physicians, as appropriate, concerning participation in the study. 


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prohibited. 
The method of obtaining and documenting informed consent and the contents of the ICF will 
comply with ICH GCP guidelines, the requirements of 21 CFR Part 50, “Protection of 
Human Patients,” the Health Insurance Portability and Accountability Act (HIPAA) 
regulations, and all other applicable regulatory requirements. A properly executed written 
ICF shall be read, signed, and dated by each patient prior to entering the trial or prior to 
performing any study procedure. The original signed and dated ICF will be kept on file at the 
study site. Patients will be given a copy of the signed ICF and will be informed of any new 
developments during the study that might influence their continued participation in the study. 
The investigator or a qualified designee will be available to answer each patient’s questions 
throughout the study, and all questions must be answered to the patient’s satisfaction. If the 
protocol is amended and a revised ICF is introduced during the study, each patient’s further 
consent must be obtained. The new version of the ICF must be approved by the EC/IRB, 
prior to subsequently obtaining each patient’s consent. 
Receipt of written informed consent will be documented in each patient’s or potential 
patient’s CRF. The signed ICF must remain in each patient’s study file and must always be 
available for verification by study monitors. 
Separate written, signed informed consent must be obtained if the patient is to participate in 
the optional pharmacogenomic assessment. 
11.4 
Patient Confidentiality 
The investigator must make sure that each patient’s anonymity is maintained. On CRFs or 
other documents submitted to Tonix or its agent, patients should not be identified by their 
names or initials, nor by their date of birth (DOB), but rather by their assigned study 
identification numbers. The investigator should keep a separate record of the patient initials, 
DOB, randomization codes, patient names, address, and contact information. Documents that 
contain the names or initials or DOBs associated with these codes are not for submission to 
Tonix or its agents (e.g., written informed consent forms). These records should be 
maintained by the investigator in strict confidence except to the extent necessary to allow 
auditing by regulatory authorities, Tonix, or its agents. These records should be kept in 
compliance with HIPAA regulations. 
11.5 
Study Monitoring 
Monitoring and auditing procedures developed by Tonix and/or its designee will be 
implemented to ensure compliance with FDA and ICH GCP and GLP guidelines. 
Tonix’s designated representative (the monitor or auditor) will contact the investigator and 
conduct regular visits to the clinical site. In extenuating circumstances related to the 
COVID-19 pandemic, remote monitoring will be permissible. The monitor will be expected 
and allowed to verify the investigator’s qualifications, to inspect clinical site facilities, and to 
inspect study records, including proof of EC/IRB review, with the stipulation that patient 
confidentiality will be maintained in accordance with local and federal regulations, including 
HIPAA requirements. The monitor will also be responsible for confirming adherence to the 


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prohibited. 
study protocol, inspecting CRFs and source documents, and ensuring the integrity of the data. 
CRFs will be checked for accuracy, completeness, and clarity and will be cross-checked for 
consistency with source documents, including laboratory test reports and other patient 
records. Instances of missing or uninterpretable data will be resolved in coordination with the 
investigator. 
The monitor/auditor will also investigate any questions concerning adherence to regulatory 
requirements. Any administrative concerns will be clarified and followed. The monitor will 
maintain contact with the site through frequent direct communications with the study site by 
email, telephone, facsimile, and mail. The investigator and all other site personnel agree to 
cooperate fully with the monitor and will work in good faith with the monitor to resolve all 
questions raised, and difficulties detected by the monitor. 
11.6 
Case Report Forms and Study Records 
The investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each study 
patient. Data must be recorded on CRFs approved by Tonix or its designee. Data (including 
AEs) will be recorded on raw data sheets and/or electronic or paper source documents. If 
selected data is collected via paper (patient questionnaires, etc.), the data must be entered into 
the eCRF and verified that it has been transcribed correctly. 
11.7 
Protocol Violations/Deviations 
No protocol waivers will be allowed. 
A protocol deviation is any noncompliance with the clinical trial protocol or ICH GCP 
requirements. The noncompliance may be either on the part of the patient, the investigator, or 
the study site staff. As a result of deviations, corrective actions are to be developed by the 
site and implemented promptly. 
It is the responsibility of the site investigator to use continuous vigilance to identify and 
report deviations within 3 working days of identification of the protocol deviation, or within 
3 working days of the scheduled protocol-required activity. All deviations must be addressed 
in study source documents, reported to the sponsor’s designated CRO Protocol deviations 
must be sent to the reviewing IRB per their policies. The site investigator is responsible for 
knowing and adhering to the reviewing IRB requirements. Further details about the handling 
of protocol deviations will be included in the protocol deviation guidance plan. 
11.8 
Access to Source Documentation 
All documentation and material provided by Tonix for this study are to be retained in a 
secure location and treated as confidential material. 
Information recorded in the electronic data capture system should be supported by 
corresponding source documentation. Examples of acceptable source documentation include, 


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prohibited. 
but are not limited to, hospital records, clinic and office charts, laboratory notes, and 
recorded data from automated instruments, memoranda, and pharmacy dispensing records. 
11.9 
Data Management 
Tonix or 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
 standard operating procedures. A comprehensive data 
management plan (DMP) will be developed, including a data management overview, 
description of 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 
corrected and/or clarified data. Procedures for soliciting and documenting resolution to data 
queries will be described in the DMP. 
11.9.1 
Quality Assurance/Audit 
This study will be patient to audit by Tonix or its designee. Audits may be performed to 
check compliance with GCP guidelines and can include: 
• Site audits 
• Trial Master File audits 
• Database audits 
• Document audits (e.g., Clinical Study Protocol and/or Clinical Study Report) 
 
Tonix or its designee may conduct additional audits on a selection of study sites, requiring 
access to patient 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 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 Tonix immediately. 
11.10 
Retention of Data 
The investigator shall retain and preserve 1 copy of all data generated during the study, 
specifically including, but not limited to, those defined by GCP as essential until: 


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prohibited. 
• At least 2 years after the last marketing authorization for the IP has been approved or the 
sponsor has discontinued its research with the IP, or 
• At least 2 years have elapsed since the formal discontinuation of clinical development of 
the IP. 
 
These documents should be retained for a longer period, however, if required by the 
applicable regulatory requirement(s) or if needed by the sponsor. 
At the end of such period, the investigator shall notify the sponsor in writing of his or her 
intent to destroy all such material. The sponsor has 30 days to respond to the investigator’s 
notice, and the sponsor has further opportunity to retain such materials at the sponsor’s 
expense. 
11.11 
Financial Disclosure 
Trial TNX-OX-CM201 is funded in whole by the sponsor, Tonix Pharmaceuticals, Inc. 
Sites/institutions must ensure that investigators and all sub-investigators submit a completed 
financial disclosure form accompanied with a Form FDA 3454 or 3455, as applicable, prior 
to trial initiation, or as otherwise required in accordance with applicable law. 
11.12 
Publication and Disclosure Policy 
No presentations, abstracts (including meeting abstracts), or other publications based on the 
conduct or results of this study will be permitted without the express written permission of 
Tonix or its designated agent. All such presentations or publications will proceed only as 
collaborations between Tonix and the investigators. If the investigator wishes to publish the 
results of this study, a copy of the proposed manuscript or abstract (including meeting 
abstracts) will be provided to Tonix or its designee for review, revision, and approval at least 
60 days before the expected date of submission for publication, unless otherwise arranged 
with Tonix in writing. This will enable Tonix to protect its proprietary information and 
augment the publication with insights or information of which the investigator may not be 
aware. Patient names and other identifiers, such as photographs or audio or video recordings, 
may not be disclosed in any publication or public forum without prior written authorization 
from the patients involved or their legal guardians. 


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prohibited. 
12 
REFERENCE LIST 
Benemei S, De Cesaris F, Fusi C, Rossi E, Lupi C, Geppetti P. TRPA1 and other TRP 
channels in migraine. J Headache Pain. 2013;14:71. 
Benemei S, Fusi C, Trevisan G, Geppetti P. The TRPA1 channel in migraine mechanism and 
treatment. Br J Pharmacol. 2014;171(10):2552-2567. 
Cui L, Hung HM, Wang SJ. Modification of sample size in group sequential clinical trials. 
Biometrics. 1999; 55(3):853-7. 
Diggle P, Kenward M. Informative dropout in longitudinal data analysis (with discussion). 
Appl Stat. 1994;43:49-93 
Dussor G, Yan J, Xie JY, Ossipov MH, Dodick DW, Porreca F. Targeting TRP channels for 
novel migraine therapeutics. ACS Chem Neurosci. 2014;5(11):1085-1096. 
Edvinsson L. CGRP receptor antagonists and antibodies against CGRP and its receptor in 
migraine treatment. Br J Clin Pharmacol. 2015;80(2):193-199. 
Goadsby PJ, Holland PR, Martins-Oliveira M, Hoffmann J, Schankin C, Akerman S. 
Pathophysiology of Migraine: A Disorder of Sensory Processing. Physiol Rev. 
2017;97(2):553-622. 
Headache Classification Committee of the International Headache Society (IHS). The 
International Classification of Headache Disorders, 3rd edition. Cephalalgia. 2018 
Jan;38(1):1-211.  
Helsinki Declaration. World Medical Association General Assembly: Declaration of 
Helsinki: ethical principles for medical research involving human subjects. J Am Coll Dent. 
2014;81(3):14-18. 
Ho TW, Edvinsson L, Goadsby PJ. CGRP and its receptors provide new insights into 
migraine pathophysiology. Nat Rev Neurol. 2010;6(10):573-582. 
Keller A, McGarvey EL, Clayton AH. Reliability and construct validity of the Changes in 
Sexual Functioning Questionnaire short-form (CSFQ-14). J Sex Marital Ther. 
2006;32(1):43-52. 
Lawrence J and Hung HMJ. Estimation and confidence intervals after adjusting the 
maximum information. Biometrical Journal. 2003; 45(2):143-52. 
Lehmacher W, Wassmer G. Adaptive sample size calculations in group sequential trials. 
Biometrics. 1999; 55:1286-90.Mathew NT. Pathophysiology of chronic migraine and mode 
of action of preventive medications. Headache. 2011;51 Suppl 2:84-92. 
Mehta C, Pocock S. Adaptive increase in sample size when interim results are promising: A 
practical guide with examples. Statistics in Medicine. 2010; 30:3267–84.Moller M. 
Vasopressin and oxytocin beyond the pituitary in the human brain. Handb Clin Neurol. 
2021;180:7-24. 


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Clinical Trial Protocol TNX-OX-CM201 
 
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The contents of this document are confidential to Tonix. Unauthorized use, disclosure or reproduction is strictly 
prohibited. 
Natoli JL, Manack A, et al. Global prevalence of chronic migraine: a systematic review. 
Cephalalgia. 2010;30(5):599-609. 
Steiner TJ, Stovner LJ, Birbeck GL. Migraine: the seventh disabler. J Headache Pain. 
2013;14:1. 
Su M, Yu S. Chronic migraine: A process of dysmodulation and sensitization. Mol Pain. 
2018;14:1744806918767697. 
Tzabazis A, Kori S, et al. Oxytocin and Migraine Headache. Headache. 2017;57 Suppl 2:64-
75. 
WHO. Headache Disorders. In:2016. 
Yang, J. Intrathecal Administration of Oxytocin Induces Analgesia in Low Back Pain 
Involving the Endogenous Opiate Peptide System. Spine. 1994;19:867–871. 
 
 
 


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prohibited. 
APPENDIX A. ICHD-3 DIAGNOSTIC CRITERIA 
1.1 Migraine without Aura 
A. At least 5 attacks fulfilling criteria B through D 
B. Headache attacks lasting 4 to 72 hours (untreated or unsuccessfully treated) 
C. Headache has at least 2 of the following 4 characteristics: 
1. unilateral location 
2.  pulsating quality 
3. moderate or severe pain intensity 
4. aggravation by or causing avoidance of routine physical activity (e.g., walking or 
climbing stairs) 
D. During headache at least 1 of the following: 
1. nausea and/or vomiting 
2. photophobia and phonophobia 
E. Not better accounted for by another ICHD-3 diagnosis 
 
1.2 Migraine with Aura 
A. At least 2 attacks fulfilling criteria B and C 
B. One or more of the following fully reversible aura symptoms: 
1. visual 
2. sensory 
3. speech and/or language 
4. motor 
5. brainstem 
6. retinal 
C. At least 3 of the following 6 characteristics: 
1. at least one aura symptom spreads gradually over ≥5 minutes 
2. two or more aura symptoms occur in succession 


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3. each individual aura symptom lasts 5 to 60 minutes 
4. at least one aura symptom is unilateral 
5. at least one aura symptom is positive 
6. the aura is accompanied, or followed within 60 minutes, by headache 
D. Not better accounted for by another ICHD-3 diagnosis 
 
1.3 Chronic Migraine 
A. Headache (migraine-like tension-type-like) on ≥15 days/month for >3 months, and 
fulfilling criteria B and C 
B. Occurring in a patient who has had at least five attacks fulfilling criteria B-D for 1.1 
Migraine without aura and/or criteria B and C for 1.2 Migraine with aura 
C. On ≥8 days/month for >3 months, fulfilling any of the following: 
 
1. criteria C and D for 1.1 Migraine without aura 
 
2. criteria B and C for 1.2 Migraine with aura 
 
3. believed by the patient to be migraine at onset and relieved by a triptan or ergot 
 
derivative 
D. Not better accounted for by another ICHD-3 diagnosis 

SAP_001.pdf: 
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Statistical Analysis Plan: TNX-OX-CM201
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Version: 1.0 
 
STATISTICAL ANALYSIS PLAN 
 
STUDY TITLE: 
A Phase 2, Double-blind, Randomized, Multicenter, Placebo-controlled, Three Arm Parallel 
Study to Evaluate the Efficacy and Safety of TNX-1900 (Intranasal Oxytocin) in Patients with 
Chronic Migraine 
PROTOCOL NUMBER:  
TNX-OX-CM201 
 
SHORT TITLE: 
PREVENTION 
NCT#: 
NCT05679908 
CLIENT: 
Tonix Pharmaceuticals 
IND 
NUMBER(S): 
 
PREPARED BY: 
 
 
 
 
 
 
 
 
 
 
This document is confidential and proprietary to Tonix Pharmaceuticals. This study is being conducted in 
compliance with good clinical practice, including the archiving of essential documents. Acceptance of this 
document constitutes agreement by the recipient that no unpublished information contained herein will be 
reproduced, published, or otherwise disclosed without the prior written approval of Tonix Pharmaceuticals, 
except that this document may be disclosed to appropriate Institutional Review Boards under the condition that 
they keep the information confidential. 
 
 
 


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ACKNOWLEDGEMENT AND SIGNATURE SHEET


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VERSION HISTORY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS
1.
LIST OF ABBREVIATIONS.......................................................................................8
2.
PURPOSE OF THE ANALYSES ..............................................................................10
3.
PROTOCOL SUMMARY ..........................................................................................11
4.
ANALYSIS SAMPLES..............................................................................................14
4.1.
All Patients Population ...............................................................................................14
4.2.
Modified Intent-to-Treat Population ...........................................................................14
4.3.
Safety Population ........................................................................................................14
5.
ESTIMANDS FOR PRIMARY AND KEY SECONDARY EFFICACY 
ENDPOINTS ..............................................................................................................15
5.1.
Primary Efficacy .........................................................................................................15
5.2.
Key Secondary Efficacy .............................................................................................15
6.
STUDY PATIENTS ...................................................................................................18
6.1.
Disposition of Patients ................................................................................................18
6.2.
Demographic and Other Baseline Characteristics ......................................................18
6.3.
Prior and Concomitant Medications ...........................................................................18
6.4.
Medical History ..........................................................................................................19
7.
STUDY OPERATIONS .............................................................................................20
7.1.
Protocol Deviations ....................................................................................................20
7.2.
Randomization ............................................................................................................20
7.3.
Measures of Treatment Compliance ...........................................................................20
8.
GENERAL ANALYSIS AND REPORTING CONSIDERATIONS ........................21
8.1.1.
Study Success .............................................................................................................21
8.1.2.
Multicenter Studies .....................................................................................................21
8.1.3.
Assessment Time Windows ........................................................................................21
8.1.4.
Timing of Analyses .....................................................................................................22
8.1.5.
Multiple Comparisons/Multiplicity ............................................................................22
8.1.6.
Power and Sample Size ..............................................................................................23
9.
ENDPOINT EVALUATION .....................................................................................25
9.1.
Primary Endpoint ........................................................................................................25
9.1.1.
Computation of the Primary Endpoint ........................................................................25


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9.1.2.
Primary Analysis of the Primary Endpoint .................................................................25
9.1.3.
Sensitivity Analyses of the Primary Analysis ............................................................26
9.1.4.
Secondary Analyses of the Primary Endpoint ............................................................27
9.2.
Secondary Endpoints ..................................................................................................28
9.2.1.
Key Secondary Endpoints ...........................................................................................28
9.2.2.
Additional Secondary Endpoints ................................................................................30
9.2.3.
Exploratory Endpoints ................................................................................................30
10.
SAFETY EVALUATION ..........................................................................................32
10.1.
Overview of Safety Analysis Methods .......................................................................32
10.2.
Extent of Exposure .....................................................................................................32
10.3.
Adverse Events ...........................................................................................................32
10.4.
Deaths, Serious Adverse Events, and Other Significant Adverse Events ..................33
10.5.
Clinical Laboratory Evaluation ...................................................................................34
10.6.
Vital Signs, Electrocardiograms, Physical Findings, and Other Observations 
Related to Safety .........................................................................................................34
10.6.1.
Vital Signs ..................................................................................................................34
10.6.2.
Electrocardiograms (ECGs) ........................................................................................34
10.6.3.
Physical Examinations ................................................................................................34
10.6.4.
Other Safety Measures ................................................................................................34
11.
OTHER ANALYSES .................................................................................................36
12.
INTERIM ANALYSES ..............................................................................................37
13.
CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL .....................38
14.
REFERENCES ...........................................................................................................39
15.
APPENDIX.................................................................................................................40
15.1.
Schedule of Events .....................................................................................................40
15.2.
Random Seeds ............................................................................................................44
15.3.
AEs Potentially Related to Abuse...............................................................................44
15.4.
Electronic Diary Questions and Derivation of Migraines/Headaches ........................46
15.5.
Rescue Medications ....................................................................................................49
16.
ATTACHMENTS .......................................................................................................51
 


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LIST OF TABLES
Table 1:
List of Abbreviations ....................................................................................................8
 
LIST OF FIGURES 
Figure 1
Study Schema .............................................................................................................12
 


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1.
LIST OF ABBREVIATIONS
Table 1: 
List of Abbreviations 
Abbreviation 
Term 
AE 
adverse event 
AESI 
adverse event of special interest 
BID 
twice daily 
BMI 
body mass index 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CM 
chronic migraine 
CMH 
Cochran-Mantel-Haenszel 
CRF 
case report form 
CSFQ-14 
Changes in Sexual Functioning Questionnaire Short-Form 
CSR 
clinical study report 
C-SSRS 
Columbia Suicide Severity Rating Scale 
ECG 
electrocardiogram 
EMA 
European Medicines Agency 
ET 
early termination 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HADS 
Hospital Anxiety and Depression Scale 
ICHD-3 
International Classification of Headache Disorders, 3rd edition 
ICH 
International Council on Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IND 
Investigational New Drug  
IRB 
Institutional Review Board 
IP 
Investigational product 
IU 
international unit 
IWRS 
interactive web response system 
LOE 
lack of efficacy 
LS, LSM 
least square, least square means 
mITT 
modified intent-to-treat 
MedDRA 
Medical Dictionary for Regulatory Activities 


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Abbreviation 
Term 
MAR 
missing at random 
MCMC 
Markov Chain Monte Carlo 
MI 
multiple imputation 
MIDAS 
Migraine Disability Assessment questionnaire 
MMRM 
Mixed-Effects Model of Repeated Measures 
MSI-BPD 
McLean Screening Instrument for Borderline Personality Disorder 
MSQ 
Migraine-Specific Quality of Life Questionnaire 
NDA 
New Drug Application 
NSAIDs 
Non-steroidal anti-inflammatory drugs 
PGI-C 
Patient Global Impression of Change 
QAM 
Every morning 
QPM 
Every evening 
QD 
once daily 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SF 
screen failure 
SOC 
system organ class 
TEAE 
Treatment-Emergent Adverse Event 
US 
United States 
WHO-DD 
World Health Organization Drug Dictionary 
 


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2.
PURPOSE OF THE ANALYSES
This statistical analysis plan (SAP) describes the planned analysis and reporting for Protocol 
TNX-OX-CM201 (A Phase 2, Double-blind, Randomized, Multicenter, Placebo-controlled, 
Three Arm Parallel Study to Evaluate the Efficacy and Safety of TNX-1900 (Intranasal 
Oxytocin) in Patients with Chronic Migraine).  
The structure and content of this SAP provides sufficient detail to meet the requirements 
identified by the US Food and Drug Administration (FDA), European Medicines Agency 
(EMA), and International Council for Harmonisation (ICH) of Technical Requirements for 
Registration of Pharmaceuticals for Human Use: Guidance on Statistical Principles in Clinical 
Trials.  All work planned and reported for this SAP will follow internationally accepted 
guidelines for statistical practice, as published by the American Statistical Association and the 
Royal Statistical Society. 
The planned analyses identified in this SAP may be included in clinical study reports (CSRs), 
regulatory submissions, or future manuscripts.  Also, post-hoc exploratory analyses not 
necessarily identified in this SAP may be performed to further examine study data.  Any post-
hoc, or unplanned exploratory analysis performed will be clearly identified as such in the final 
CSR. 
 
 
 
  
 
 
 
 
 
 
The reader of this SAP is encouraged to also read the clinical protocol, and other identified 
documents, for details on the planned conduct of this study.  Operational aspects relating to 
collection and timing of planned clinical assessments are not repeated in this SAP unless they are 
relevant to the planned analysis. 


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3.
PROTOCOL SUMMARY
This is a double-blind, randomized, placebo-controlled, multicenter, 3 arm Phase 2 study. Men 
and women with a current diagnosis of chronic migraine (CM) according to the International 
Classification of Headache Disorders, 3rd edition (ICHD-3) and who meet the criteria for the 
study at Screening will enter a Run-in Period in which patient
be recorded for at least 28 days. At the end of the Run-in Period, eligible patients will be 
randomized at a 1:1:1 ratio, to one of the 3 treatment arms: TNX-1900 at a fixed daily dose of 30 
IU QAM / placebo QPM (Treatment Arm A), or fixed daily dose of 30 IU QAM / 30 IU QPM 
(Treatment Arm B), or placebo QAM / placebo QPM (Treatment Arm C), for the duration of a 
12-week Treatment Period. Randomization will be stratified by study site and preventive 
migraine medication (use of a single preventive vs. no preventive).  All participants will 
administer study drug twice a day, mornings and evenings, in a double-blind design.  
The study will be conducted in 3 periods (Screening/Washout/Run-in, Treatment, and Safety 
Follow-up) and will consist of at least 6 visits (Screening Visit, Randomization/Baseline Visit, 3 
Treatment Visits, and a Safety Follow-up Visit). 
Screening/Washout/Run-In (Visit 1: Screening Visit) 
After providing written informed consent, patients will be assessed for eligibility (including 
medical history, migraine headache history, medication use, physical exam, nasal exam, vital 
signs, clinical labs, and electrocardiogram [ECG]).  
 
Eligible patients will be trained on the e-diary during the Screening Visit and will enter a 28-day 
Run-In period which will last for at least 28 days. Patients who need to wash out excluded 
medications will have up to an additional 21 days in the Run-In period, but every effort should 
be made to minimize to the fewest days needed for the given washout period(s) in the protocol.   
 
During the Run-In, patients will be required to answer questions daily regarding headaches and 
rescue (abortive) medication use on an electronic diary (e-diary) regardless of whether patients 
lity to be compliant with e-diary 
-diary compliance, will be evaluated at 
the end of the Run-in Period to ensure a patient meets all required eligibility criteria for treatment 
randomization. A patient must not be informed of the minimum number of headache days and 
migraine headache days required to be randomized to study treatment as this might bias e-diary 
entries during Run-in Period. 
 
During this Screening and Run-
ineligibility for the study, the patient should be considered a screen-failure (SF) and informed 
that they are not eligible for the study and can stop completing the e-diary.  However, if the 
investigator determines that the patient should be brought back into the clinic for re-testing, the 
patient should continue completing the e-diary until a final determination regarding eligibility is 
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In addition, any patients not meeting the randomization criteria will be considered a failure. 
 
Double-blind Treatment Period (Visit 2: Randomization/Baseline; Visits 3, 4, 5: Treatment) 
The Treatment Period will last for about 84 days. At Visit 2, eligible patients will be randomized 
in a 1:1:1 ratio to one of 3 treatment arms (A, B or C) as summarized above. Randomization will 
be stratified by study site and concomitant migraine preventive medication (up to one is 
allowed). Patients will be required to answer daily headache questions and study drug 
compliance on an e-diary during the Treatment Period regardless of whether a headache was 
experienced that day. 
All patients who withdraw early from the study will be encouraged to complete an Early 
Termination Visit for safety evaluations (Visit 5 [V5]) within 7 days of withdrawal from the 
study. Study end is after Visit 5/ET. A Safety Follow-up Visit (Visit 6 [V6]) will occur 14 days 
after V5/ET.  
Safety Follow-up Period (Visit 6) 
Approximately 14 days (+4 days) after Visit 5 or End of Treatment (ET), all randomized patients 
will attend a Safety Follow-up Visit. 
A schema of the study design is provided in Figure 1. 
Figure 1: 
Study Schema 
 
 
 


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4.
ANALYSIS SAMPLES
The following populations will be utilized for the analyses of data. Disposition of patients will 
use the All Patients Population. The safety analyses will be conducted on the Safety Population. 
The modified intent-to-treat (mITT) Population will be used for the primary efficacy analyses.  
4.1. 
All Patients Population 
This includes all patients available in the electronic data capture system; patients will be 
presented by their randomized treatments (if applicable). 
4.2. 
Modified Intent-to-Treat Population 
The mITT population will include all randomized patients who received at least one dose of 
study drug and had at least one post-Baseline evaluable month (that is, at least one of the three 
28-day periods has at least 14 non-missing e-diary entries; see Section 9.1.1). This population 
will be used to summarize the primary and other efficacy data. Patients will be analyzed 
according to randomized treatment assignment. 
4.3. 
Safety Population 
The Safety Population will include all patients who received at least one dose of study drug. This 
population will be used to summarize the safety data. Patients will be analyzed according to their 
treatment received; if an error in issuing investigational product (IP) occurs and a patient 
receives a mix of treatments, they will be analyzed under the treatment arm with the most IP 
issued to the patient. 


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5.
ESTIMANDS FOR PRIMARY AND KEY SECONDARY 
EFFICACY ENDPOINTS 
5.1. 
Primary Efficacy 
The primary efficacy endpoint is defined as the mean change in monthly migraine days from 
Baseline (last 28 days prior to randomization) to month 3 (last 28 days of treatment). For 
Days 29 to 56 will be Month 2; and Days 57 to 84 will be Month 3. The change in count of days 
with migraine vs the baseline will be compared between treatment groups. 
The target population is all patients in the mITT population with CM as defined by the 
inclusion/exclusion criteria. 
In general, a 
the data will be considered independently from any intercurrent event, such as rescue medication 
usage and study discontinuation. One exception is that patients that report a headache believed to 
be a migraine that was resolved by a migraine-specific abortive rescue medication will be 
counted as a migraine (see section 9.1).The approach for partial and missing data is described in 
Section 9.1.1. 
The population-level summary will be the model-based least-squared means for each arm and 
differences between treatment arms (analyzed as randomized) at month 3.  The model is given in 
Section 9.1.2. 
5.2. 
Key Secondary Efficacy  
There are six key secondary efficacy endpoints.  For all, the target population is all patients in 
the mITT population with CMs as defined by the inclusion/exclusion criteria.  The key 
secondaries (in order) are: 
 Proportion of patient
days from the last 28 days of Baseline to the month 3 28-day normalized migraine headache 
days. The percent change from baseline will be calculated for each month as 100*[monthly 
count  baseline count] / [baseline count].  
 A composite strategy will be employed to handle missing data and discontinuation.  
Concomitant medications and all other intercurrent events will use a treatment policy 
strategy; data will be analyzed as observed.  For all missing data (whether or not due 
to discontinuation), they will be assumed to be non-responders; that is, failure to stay 
on-trial and provide data is assumed to reflect non-response to study treatment. 
 The population-level summary will be the percentages of responders in each arm and 
difference in percentages of responders between treatment arms (analyzed as 
randomized) at month 3.  See Section 9.1.4.2 for full details 


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 Mean change in the number of days using rescue medication (triptan, ergot derivative, or 
other migraine-specific acute medication) from the last 28 days of Baseline to the last 28 
days of treatment.  
 
strategy will be used for all intercurrent events. 
That is, the data will be considered independently from any intercurrent event, 
such as study discontinuation. The approach for partial and missing data is 
described in Section 9.1.1 (Missing data approach will be identical to that of the 
primary endpoint). 
 The population-level summary will be the model-based least-squared means for 
each arm and differences between treatment arms (analyzed as randomized) at 
month 3.  See Section 9.2.1.1 for details. 
 Proportion of patient
 
 A composite strategy will be employed to handle missing data and 
discontinuation.  Concomitant medications and all other intercurrent events will 
use a treatment policy strategy; data will be analyzed as observed.  For all missing 
data (whether or not due to discontinuation), they will be assumed to be non-
responders; that is, failure to stay on-trial and provide data is assumed to reflect 
non-response to study treatment. 
 The population-level summary will be the percentages of responders in each arm 
and difference in percentages of responders between treatment arms (analyzed as 
randomized) at month 3. See Section 9.2.1.2 for full details 
 Mean change in the number of moderate or severe headache days from the last 28 days of 
Baseline to the last 28 days of treatment. A moderate or severe headache day is defined as 
any calendar day wherein a patient records a headache or migraine of moderate or severe 
peak intensity in the e-diary. 
 
That is, the data will be considered independently from any intercurrent event, 
such as study discontinuation. The approach for partial and missing data is 
described in Section 9.1.1 (Missing data approach will be identical to that of the 
primary endpoint). 
 The population-level summary will be the model-based least-squared means for 
each arm and differences between treatment arms (analyzed as randomized) at 
month 3.  See Section 9.2.1.3 for details. 
 Mean change in the number of migraine headache days from the last 28 days of Baseline to 
average number per 28 days over the entire 12 week duration of Treatment Period. 
 
That is, the data will be considered independently from any intercurrent event, 
such as study discontinuation. The approach for partial and missing data is 


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described in Section 9.1.1 (Missing data approach will be identical to that of the 
primary endpoint). 
 The population-level summary will be the model-based least-squared means for 
each arm and differences between treatment arms (analyzed as randomized) at 
month 3.  See Section 9.1.4.1 for details. 
 Mean change from Baseline in the Migraine-Specific Quality of Life Questionnaire Role 
Function, Restrictive domain (MSQ v2.1) at Week 12. 
 
That is, the data will be considered independently from any intercurrent event, 
such as study discontinuation. 
 The population-level summary will be the model-based least-squared means for 
each arm and differences between treatment arms (analyzed as randomized) at 
month 3.  See Section 9.2.1.4 for details. 
 


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6.
STUDY PATIENTS
6.1. 
Disposition of Patients 
The number and percentage of patients in each analysis population will be summarized. The 
number of patients screened, patients enrolled, and the number and percentage of patients 
completing the study, discontinuing from the study and reasons for discontinuation will also be 
reported. All percentages will be calculated using the number of patients enrolled as the 
denominator. 
6.2. 
Demographic and Other Baseline Characteristics 
Demographic and baseline characteristics such as age, gender, race/ethnicity, height, weight, 
BMI, family status, education, employment status, smoking history, use of preventative meds, 
chronic migraine history, number of baseline headache days, number of baseline migraines, and 
baseline diary compliance (see section 7.3) will be summarized by treatment group (TNX-1900 
and placebo) and overall for the mITT and Safety populations. Categorical items will be reported 
with counts and percentages; continuous items will be reported using summary statistics (mean, 
standard deviation (SD), median, minimum, maximum). 
6.3. 
Prior and Concomitant Medications 
Prior medications are defined as medications or therapies initiated prior to the start of the study 
drug and terminated prior to the start of study drug.  Hence, these medications or therapies will 
have end dates prior to the first dose date of study drug.  Concomitant medications are defined as 
any medications other than the study drug that a patient receives concurrently with the study 
drug.  These medications will have end dates on or after the first dose date of the study drug if 
they have an end date. In the case of missing or partial dates, medications will be considered 
concomitant unless the available data excludes that possibility. 
All medications will be coded using the World Health Organization Drug Dictionary (WHO-
DD).  Prior and concomitant medications will be summarized by treatment group and by the 
number and percentage of patients taking each medication, classified by using WHO-DD 
Anatomical Therapeutic Chemical Level 3 and preferred term. 
Prior, but previously discontinued (prior to screening for the study), preventative migraine 
medications will be collected on a separate case report from (CRF) with additional information 
on the tolerability and efficacy of the medication.  These will be summarized by treatment group 
and by the number and percentage of patients taking each medication (grouped by preferred 
term) as well as the number and percentage for each level of the patient reports of effectiveness 
and tolerability.  Any preventative migraine medication used within 90 days of the Screening 
visit will be recorded on the Prior and Concomitant Medication CRF.    
Additionally, prior other treatments or devices used within 90 days of the Screening Visit (ie. 
acupuncture, electrical or magnetic stimulating devices, chiropractor, PT, etc.) will be collected 
and tabulated by type of therapy. 


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All medications and therapies will be presented in listings, with prior preventative migraine 
medications listed separately. 
6.4. 
Medical History 
Medical History will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) and summarized by system organ class (SOC) and Preferred Term using frequency 
counts and percentages by treatment group.  Nasal Exam findings will be summarized using 
frequency counts and percentages by treatment group. Physical examination and nasal exam 
findings will be presented in listings. 


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7.
STUDY OPERATIONS
7.1. 
Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol or ICH Good Clinical 
Practice (GCP) requirements. The noncompliance may be either on the part of the patient, the 
investigator, or the study site staff. As a result of deviations, corrective actions are to be 
developed by the site and implemented promptly. Protocol deviations will be logged and 
categorized as important or non-important prior to unblinding.  Protocol deviations will be 
summarized by type, status as important or non-important, and by treatment group for the Safety 
population. 
Individual protocol deviations will be listed by patient. 
7.2. 
Randomization 
This is a double-blind study; unless otherwise specified, all study personnel are to remain 
blinded to study drug prior to database lock and final analysis following study unblinding. 
Approximately 300 eligible patients will be randomized at a 1:1:1 ratio, to one of the 3 treatment 
arms receiving TNX-1900 at a fixed daily dose of 30 IU QD (Treatment Arm A) or fixed daily 
dose of 30 IU BID (Treatment Arm B) or receiving placebo (Treatment Arm C) for the duration 
of a 12-week Treatment Period. Randomization will be stratified by site and use of one 
concomitant preventive migraine medication (vs. no concomitant preventive migraine 
medication). All participants will administer study drug twice a day, mornings and evenings, in a 
double-blind design. Up to approximately 30% of the patients randomized into the study can be 
on 1 migraine preventative medication. 
The randomization schedule will be computer generated using a permuted block algorithm and 
will randomly allocate study drug to randomization numbers. The randomization numbers will 
be assigned through a central interactive web response system (IWRS) as patients are entered 
into the study. 
7.3. 
Measures of Treatment Compliance 
No direct measures of drug compliance will be captured via drug accountability.  Compliance via 
the diary will be reported for the post-baseline period.  Patients are asked to report whether they 
responses reported out of the total number of expected doses based on the dates the diary was 
issued and collected times 2 doses/day.  The compliance will be summarized with descriptive 
statistics. Additionally, the number and percentage of patients with <70% compliance, 70% to 
<80%, 80% to <90%, and 90 to 100% compliance will be reported. 
Additionally, compliance with diary completion will be reported and summarized with 
descriptive statistics.  Dairy compliance will be defined as the number of days which have ANY 
data entered (even if partial/incomplete) divided by the number of days they were expected to 
complete the diary.  This will be summarized for the baseline and post-baseline periods 
separately. 


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8.
GENERAL ANALYSIS AND REPORTING CONSIDERATIONS
Descriptive summaries will be provided where appropriate for each of the primary and secondary 
variables.  In general, tables will summarize data by treatment group and visit.  
Continuous, quantitative variable summaries will include the number of patients (N) with non-
missing values, mean, standard deviation, median, minimum, and maximum. 
Categorical, qualitative variable summaries will include the frequency and percentage of patients 
who are in the particular category.  In general, the denominator for the percentage calculation 
will be based upon the total number of patients in the study population for the treatment group 
unless otherwise specified. 
Unless otherwise specified, baseline values are defined as the last non-missing measurement 
prior to the first dose of study drug.  Change from baseline will be defined as the post-baseline 
visit value minus the baseline value. 
For continuous endpoints where treatment groups are compared via linear models with the 
difference in LS means, the effect size will be calculated and included as a summary statistic 
using the difference in LS means and its standard error, transformed to a standard deviation. 
Study day is defined as assessment date  first dose date +1 for dates after the first dose date and 
assessment date  first dose date for dates prior to the first dose. 
All analyses will be performed using SAS® Software version 9.4 or later. 
8.1.1. 
Study Success 
 
 
 
 
 
 
 
 
  
8.1.2. 
Multicenter Studies 
This is a multicenter study.  Unless otherwise specified, data from all study sites will be pooled 
for all analyses unless otherwise specified. 
8.1.3. 
Assessment Time Windows 
Patients who withdraw/drop out from the study will have the early termination (ET) data 
collected at their ET visit included in the analysis at the closest visit where a given assessment 
should be collected per the schedule of assessments (Week 4, 8, 12, 14), using midpoints 


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between visits to window the early termination.  If this results in two records for a given visit, 
then the one closest to the targeted date will be used. Visits beyond day 112 (two weeks past the 
target day for Week 14) will not be mapped and reported with Week 14; they may appear in the 
last observation analyses described for safety endpoints.   
9.1.1 for details. 
 
8.1.4. 
Timing of Analyses 
All final, planned analyses will be performed after the last participant has completed all study 
assessments, all relevant study data have been processed and integrated into the analysis 
database, and the database has been locked.  
Any post-hoc, exploratory analyses completed to support planned study analysis, which were not 
identified in this SAP, will be documented and reported in appendices to the CSR. Any results 
from these unplanned analyses (post-hoc) will also be clearly identified in the text of the CSR. 
8.1.5. 
Multiple Comparisons/Multiplicity 
key secondary 
endpoint comparisons between each dose level of active versus placebo using a graphical 
approach. Each of the dose comparisons to placebo will be assigned ½ the alpha for the primary 
endpoint of change in the number of migraine headache days from the last 28 days of Baseline to 
the last 28 days of treatment. The stronger of the p-values will be tested first 
and if 
significant, 100% of its alpha wil
 so that it is 
.   
If this is significant, then 
will be passed to the first secondary and split for the two 
dose comparisons to placebo on the endpoint of the proportion of patient
reduction in the number of migraine headache days from Baseline to month 3.  As above, the 
stronger of the p-values will be tested first 
and if significant, 100% of its alpha will 
 
. At each step, if a p-value 
fails to meet the alpha threshold for significance, the process will be halted and all subsequent 
comparisons declared non-significant. This will continue with the same pattern through the 
endpoints in the order listed below: 
The order of the key secondary analyses will be: 
 Proportion of patient
days from the last 28 days of Baseline to the last 28 days of treatment in each treatment 
group. 
 Mean change in the number of days using rescue medication (triptan, ergot derivative, or 
other migraine-specific acute medication) from the last 28 days of Baseline to the last 28 
days of treatment. 
 Proportion of patient
 


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 Mean change in the number of moderate or severe headache days from the last 28 days of 
Baseline to the last 28 days of treatment. A moderate or severe headache day is defined as 
any calendar day wherein a patient records a headache of moderate or severe peak intensity 
in the e-diary. 
 Mean change in the number of migraine headache days from the last 28 days of Baseline to 
average number per 28 days over the entire 12 week duration of Treatment Period. 
 Mean change from Baseline in the Migraine-Specific Quality of Life Questionnaire Role 
Function, Restrictive domain (MSQ v2.1) at Week 12. 
 
The order of the other secondary analysis will be: 
 Mean change from Baseline in the Migraine Disability Assessment (MIDAS) Test total score 
at Week 12. 
 Mean change from Baseline in the Hospital Anxiety and Depression Scale (HADS) total 
score at Week 12. 
 Mean change from Baseline in patient-rated Changes in Sexual Functioning Questionnaire 
Short-Form (CSFQ-14) total score in males and in females, analyzed separately, at Week 12. 
 
The exploratory analyses will be: 
 Proportion of patient
days from the last 28 days of Baseline to the last 28 days of treatment in each treatment 
group. 
 Proportion of patients with fewer than 14 headache days or fewer than 8 migraine headache 
days per 4 weeks over the 12-week period. 
 Mean change from Baseline in number of headache free days from the last 28 days of 
Baseline to the last 28 days of treatment 
Although all p-values will be non-significant following the first to fail to meet its alpha 
threshold, p-values will be reported for all the above endpoints; they will be noted as descriptive 
for those following the first non-significant p-value. 
8.1.6. 
Power and Sample Size 
The planned total number of randomized patients is approximately 300 and will be randomized 
1:1:1 to TNX-1900 30 IU QAM, placebo QPM: TNX-1900 30 IU BID: or placebo BID. 
 
 
 
 
 
 


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9.
ENDPOINT EVALUATION
9.1. 
Primary Endpoint 
The primary efficacy endpoint will be the change in the number of migraine headache days from 
the last 28 days of Baseline to the last 28 days of treatment (i.e. month 3). A migraine headache 
day is any calendar day (0:00 to 23:59) in which the patient records in the e-diary:  
 An attack lasting 4 hours or more and meeting the ICHD-3 criteria for migraine without aura, 
or 
 A migraine with aura, or 
 An attack that meets ICHD-3 criteria for probable migraine (a migraine subtype fulfilling all 
but one criterion (B-D) for migraine without aura), or 
 An attack of any duration that was believed by the patient to be a migraine and was relieved 
by a triptan, ergot derivative, or other migraine-specific abortive medication (see Appendix 
15.5) 
9.1.1. 
Computation of the Primary Endpoint 
The monthly migraine count will be calculated for patients that have at least 14 days of non-
missing data for a given month. For patients with less than 28 days of data for a month, the 
counts will be normalized to 28 days by taking 28* [migraine count] / [days of non-missing 
data].  The eDiary questions and derivation of migraine days are found in Appendix 15.4. 
If less than 14 days are available for a month, then the month will remain missing, but the 
patient
-effects model of repeated 
measures.  
Every effort will be made to retain patients in the study; however, patients are free to withdraw 
from the study at any time for any reason. Patients that withdrawal early will be asked to return 
to the clinic for an Early Termination Visit for completion of assessments (see Schedule of 
Assessments).  The mixed model repeated measures analysis will provide unbiased estimates 
under the assumption that data are missing at random (MAR).  
9.1.2. 
Primary Analysis of the Primary Endpoint 
Summary statistics (mean, SD, median, minimum, maximum) for the primary efficacy endpoint 
will be reported for the change from the Baseline to month 3 for each of the treatment groups. 
The change from Baseline will be analyzed in an MMRM model with fixed effects of treatment, 
month, baseline value, treatment by month interaction, and stratification factor (preventive 
medication use); an unstructured covariance matrix will be used. Least square means (LSMs), 
standard errors, and the LSM differences (each treatment vs placebo) with 95% CIs and p-values 
will be reported for each month. Denominator degrees of freedom will use the Kenward Rogers 
approach. Should the model fail to converge, heterogeneous Toeplitz, heterogeneous first-order 
autoregressive, Toeplitz, first order autoregressive and compound symmetric will be attempted in 
that order; in these cases, the sandwich estimator (Diggle and Kenward 1994) will be used to 


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estimate the standard errors of the fixed effects parameters and the denominator degrees of 
freedom will utilize the DDFM=BETWITHIN option in SAS®. 
Additionally, Kruskal-Wallis tests will be performed and reported for each month, in case the 
migraine days do not adhere to model assumptions. 
9.1.3. 
Sensitivity Analyses of the Primary Analysis 
Three sensitivity analyses may be performed if the primary analysis is positive (statistically 
significant or strongly trending in favor of active treatment): 
9.1.3.1. 
Missing at Random Multiple Imputation 
Multiple imputation (MI) methodology will be utilized to impute complete datasets with three 
monthly observations for all patients in the mITT population. Monthly migraine counts will be 
computed as described in Section 9.1.1.  This will yield 4 migraine count records per patient 
(baseline and 3 months follow-up).  The missing values will be imputed for all patients/records 
using MI within each treatment group conditioned on each patient
-missing data (including 
baseline), and the stratification factor.  The Markov Chain Monte Carlo (MCMC) method will be 
used to produce 20 repeats of the data and seeds are given in appendix 15.2.  LS means and 
differences across the twenty MI reps will be combined using SAS procedure MIANALYZE 
(Rubin, 1976). 
9.1.3.2. 
Multiple Imputation Tipping Point 
A tipping point analysis will be performed using the above MI datasets and applying an 
increasing delta (of higher migraine counts) to the active groups until statistical significance is no 
longer achieved.  The delta will only be applied to imputed values; this will be done in 0.5 
migraine day increments.  This will only be performed if the primary analysis is significant.  This 
will test the overall robustness of the primary analysis. 
9.1.3.3. 
Missing Not at Random Multiple Imputation 
Finally, a missing-not-at-random multiple imputation approach will be utilized taking into 
account the reason for discontinuation. 
Missing monthly migraine counts for participants in the mITT population will be imputed via 
multiple imputation (MI).  
 
 
 
 
 
 
 
 
 
 
 
 


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9.1.4. 
Secondary Analyses of the Primary Endpoint 
Two additional analyses of the number of headache days will be performed: 
9.1.4.1. 
Mean Change Over the Full 12 Week follow-up 
The mean change in the number of migraine headache days from the last 28 days of Baseline to 
average number per 28 days over the entire 12-week duration of Treatment Period will be 
compared among the treatment groups.  This will utilize the same model and output as the 
primary analysis, but will report model contrasts averaging the three follow-up months.  Least 
square means (LSMs), standard errors, and the LSM differences (each treatment vs placebo) will 
be reported for these averages. 
9.1.4.2. 
Patients E
50% Reduction in Migraine Headaches 
Finally, for each patient and month, patients will be flagged as responders if they experience a 
50% reduction in the number of migraine headache days from the last 28 days of Baseline to the 
-day normalized migraine headache days. The percent change from baseline 
will be calculated for each month as 100*[monthly count  baseline count] / [baseline count].   
The number and percentage of patients achieving 50% improvement will be reported as well as 
95% CIs for the percentages.  Patients with missing data will be considered non-responders/ not 
achieving either improvement threshold.  The difference in percentages in the active and placebo 
arms from the Cochran-Mantel-Haenszel (CMH) common risk difference estimator will reported 
along with its 95% CI based on the Sato variance estimator.  Pairwise p-values will compare 
each treatment arm to placebo based on a CMH stratified by preventive medication use. The 
primary time point of interest will be month 3, but each month will be summarized. 


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9.2.
Secondary Endpoints
All secondary efficacy analyses will be based on the mITT population.   
9.2.1. 
 Key Secondary Endpoints 
There will be six key secondary endpoints: 
 Proportion of patient
headache 
days from the last 28 days of Baseline to the last 28 days of treatment in each treatment 
group (described in Section 9.1.4.2 above). 
 Mean change in the number of days using rescue medication (triptan, ergot derivative, or 
other migraine-specific acute medication) from the last 28 days of Baseline to the last 28 
days of treatment. 
 Proportion of patient
 
 Mean change in the number of moderate or severe headache days from the last 28 days of 
Baseline to the last 28 days of treatment. A moderate or severe headache day is defined as 
any calendar day wherein a patient records a headache or migraine of moderate or severe 
peak intensity in the e-diary. 
 Mean change in the number of migraine headache days from the last 28 days of Baseline to 
average number per 28 days over the entire 12 week duration of Treatment Period (described 
in Section 9.1.4.1 above). 
 Mean change from Baseline in the Migraine-Specific Quality of Life Questionnaire Role 
Function, Restrictive domain (MSQ v2.1)  at Week 12. 
9.2.1.1. 
Rescue Medication Use 
The Mean change in the number of days using rescue medication from the last 28 days of 
Baseline to the last 28 days of treatment will be compared among the treatment groups. A rescue 
medication use day is any calendar day (0:00 to 23:59) in which the patient records the use of a 
triptan, ergot derivative, or other migraine-specific abortive medication (see Appendix 15.5).  
Calculation and analysis of this will be identical to the primary with the substitution of days 
using rescue medication for migraine days.   Least square means (LSMs), standard errors, and 
the LSM differences (each treatment vs placebo) will be reported for these averages. As with the 
primary endpoint, Kruskal-Wallis tests will be performed and reported. 
9.2.1.2. 
Patient Global Impression of Change 
The number and percentage and 95% CIs for the percentages will be reported for patients with a 
 for each treatment 
group. Patients with missing data will be considered non-responders. The difference in 
percentages in the active and placebo arms will reported along with its 95% CI (using the Sato 
estimator of variance).  Pairwise p-values will compare each treatment arm to placebo based on a 


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CMH stratified by preventive medication use. The primary time point of interest will be Week 
12, but each time point collected will be summarized. 
9.2.1.3. 
Mean Change in Moderate or Severe Headaches 
The mean change in the number of moderate or severe headache days from the last 28 days of 
Baseline to the last 28 days of treatment (i.e. month 3) will be compared among the treatment 
groups. A moderate or severe headache day is any calendar day (0:00 to 23:59) in which the 
patient records an attack of moderate or severe peak intensity in the e-diary. Calculation and 
analysis of this will be identical to the primary with the exception that only days with moderate 
or severe headache will be included in the tally.  Least square means (LSMs), standard errors, 
and the LSM differences (each treatment vs placebo) will be reported for these averages. As with 
the primary endpoint, Kruskal-Wallis tests will be performed and reported.
9.2.1.4. 
Mean Change in in the Migraine-Specific Quality of Life Questionnaire (MSQ) 
For the MSQ v2.1, items are scored 1-6; the total and three sub-domains will be calculated and 
scaled such that the resulting values will be scaled 0-100, with higher scores indicating better 
quality of life.  The Role Function, Restrictive domain will be a key secondary endpoint and the 
other items & total will be additional secondary endpoints. 
The total MSQ will be calculated as the sum of the 14 individual questions, minus 14, then 
scaled by 100/70. Missing values will be imputed with the means of the non-missing values, as 
long as there are at least 7 non-missing values.   
Role Function  Restrictive: Items 1-7 will be summed, then 7 subtracted from the value, and 
this scaled by 100/35.  Missing values will be imputed with the means of the non-missing values, 
as long as there are at least 4 non-missing values.  If there are less than 4 values, then the score 
will be set to missing. 
Role Function  Preventative: Items 8-11 will be summed, then 4 subtracted from the value, and 
this scaled by 100/20.  Missing values will be imputed with the means of the non-missing values, 
as long as there are at least 2 non-missing values.  If there are less than 2 values, then the score 
will be set to missing. 
Emotional Function: Items 12-14 will be summed, then 3 subtracted from the value, and this 
scaled by 100/15.  Missing values will be imputed with the means of the non-missing values, as 
long as there is at least 1 non-missing value.  If there are less than 2 values, then the score will be 
set to missing. 
Summary statistics (mean, SD, median, minimum, maximum) will be reported for the change 
from the baseline in each MSQ v2.1 score to each visit and for each of the treatment groups. The 
change from baseline will be analyzed in an MMRM model with fixed effects of treatment, visit, 
baseline value, treatment by visit interaction, and stratification factor (preventive medication 
use); an unstructured covariance matrix will be used. LSMs, standard errors, and the LSM 
differences (each treatment vs placebo) with 95% CIs and p-values will be reported for each visit 
(with week 12 being of primary interest). Denominator degrees of freedom will use the Kenward 
Rogers approach. Should the model fail to converge, heterogeneous Toeplitz, heterogeneous 
first-order autoregressive, Toeplitz, first order autoregressive and compound symmetric will be 


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attempted in that order; in these cases, the sandwich estimator (Diggle and Kenward 1994) will 
be used to estimate the standard errors of the fixed effects parameters and the denominator 
degrees of freedom will utilize the DDFM=BETWITHIN option in SAS®. 
9.2.2. 
Additional Secondary Endpoints 
Each of the following continuous endpoints will be summarized: 
 Mean change from Baseline in the Hospital Anxiety and Depression Scale (HADS) at Week 
12. 
 Mean change from Baseline in the Migraine Disability Assessment questionnaire (MIDAS) 
Test total score at Week 12. 
 Mean change from Baseline in patient-rated Changes in Sexual Functioning Questionnaire 
Short-Form (CSFQ-14) total score in males and in females, analyzed separately, at Week 12. 
For each, summary statistics (mean, SD, median, minimum, maximum) will be reported for the 
change from the baseline to each visit and for each of the treatment groups.  
For HADS the change from baseline will be analyzed in an MMRM model with fixed effects of 
treatment, visit, baseline value, treatment by visit interaction, and stratification factor (preventive 
medication use); an unstructured covariance matrix will be used. LSMs, standard errors, and the 
LSM differences (each treatment vs placebo) with 95% CIs and p-values will be reported for 
each visit (with week 12 being of primary interest). Denominator degrees of freedom will use the 
Kenward Rogers approach. Should the model fail to converge, heterogeneous Toeplitz, 
heterogeneous first-order autoregressive, Toeplitz, first order autoregressive and compound 
symmetric will be attempted in that order; in these cases, the sandwich estimator (Diggle and 
Kenward 1994) will be used to estimate the standard errors of the fixed effects parameters and 
the denominator degrees of freedom will utilize the DDFM=BETWITHIN option in SAS®. 
MIDAS and CSFQ are only collected at baseline and week 12, thus they will be modeled in a 
ANCOVA similar to the MMRM used for the repeated measures.  The model will include fixed 
effects for treatment, baseline, and stratification factor (preventive medication use). LSMs, 
standard errors, and the LSM differences (each treatment vs placebo) with 95% CIs and p-values 
will be reported. 
9.2.3. 
Exploratory Endpoints 
 Proportion of patient
days from the last 28 days of Baseline to the last 28 days of treatment in each treatment 
group. 
 Proportion of patients with fewer than 14 headache days or fewer than 8 migraine headache 
days per 4 weeks over the 12-week period. 
 Mean change from Baseline in number of headache free days from the last 28 days of 
Baseline to the last 28 days of treatment. 
 


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A headache day is any calendar day (0:00 to 23:59) in which the patient records an attack (a 
headache or a migraine) in the e-diary. 
For the first two exploratory endpoints, the difference in percentages in the active and placebo 
arms will reported along with its 95% CI (using the Sato estimator of variance).  Pairwise p-
values will compare each treatment arm to placebo based on a CMH stratified by preventive 
medication use.  Patients with missing data will be considered non-responders. 
Calculation and analysis of the number of headache free days will be identical to the primary 
with the exception that outcome of interest will be days without headaches.  Least square means 
(LSMs), standard errors, and the LSM differences (each treatment vs placebo) will be reported 
for these averages. As with the primary endpoint, Kruskal-Wallis tests will be performed and 
reported. 
 
 


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10.
SAFETY EVALUATION
10.1. 
Overview of Safety Analysis Methods 
All safety analyses will be completed for the Safety Population. All safety data will be tabulated 
and listed. No formal statistics or imputation will be performed for the safety analysis. The 
analysis of safety assessments in this study will include summaries of the following safety and 
tolerability data collected for each patient: 
 Extent of exposure 
 Incidence of Adverse Events 
 Changes from baseline in clinical laboratory results 
 Changes from baseline in vital signs 
 Changes from baseline in electrocardiograms 
 Monitoring suicidality using the Columbia Suicide Severity Rating Scale (C-SSRS) 
 Changes from baseline in the HADS scores 
 Changes from baseline in the CSFQ-14 
 
10.2. 
Extent of Exposure 
Duration of exposure will be calculated and summarized with descriptive statistics. The duration 
of exposure will be the date of last dose  date of the first dose +1, based on the first and last 
doses as recorded on the CRF.  
Exposure days (number of days on study drug) is defined as the total number days reported in the 
diary that the patient took study drug. If the first dose date or last dose date from the CRF is not 
among the diary-reported dates, that day is added to the tally. 
The duration of exposure and exposure days will be tabulated with summary statistics by 
treatment group. Additionally, the number of patients with duration of exposure 
4 
weeks, 
and >12 weeks) will be presented.  
10.3. 
Adverse Events 
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation patient administered an IP that does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding, for example), symptom, or disease temporally associated with the 
use of a medicinal product, whether related to the medicinal product, or not. 
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. 
Events that occur in patients treated with placebo, or during treatment free periods of the study, 
are also considered AEs.  


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An AE is defined as treatment-emergent if the first onset or worsening is during or after the first 
administration of IP and not more than 30 days after the last administration of study drug. In the 
case of missing or partial dates, an adverse event will be considered treatment-emergent unless 
the available data excludes that possibility. 
An AE summary table will present totals for the following: 
 All treatment-emergent adverse events (TEAEs) 
 TEAEs by severity 
 TEAEs leading to study drug discontinuation  
 TEAEs by relationship (not related, unlikely related, possibly related) 
 SAEs 
 AEs of Special Interest (AESIs [See below]) 
Summaries of incidence rates (frequencies and percentages) of individual AEs by MedDRA SOC 
and preferred term will be prepared.  Such summaries will be displayed for all TEAEs, TEAEs 
by maximum severity, and TEAEs by strongest relationship to study drug. 
Each patient will be counted only once within each summation level (SOC; preferred term).  If a 
patient experiences more than one TEAE within each summation level, the TEAE with the 
strongest relationship or the maximum severity, as appropriate, will be included in the 
summaries of relationship and severity. 
All AEs will be presented in a listing. 
These summaries will include SAEs; additionally, they will be presented separately (see below). 
10.4. 
Deaths, Serious Adverse Events, and Other Significant Adverse 
Events 
Summaries of incidence rates (frequencies and percentages) of individual SAEs by MedDRA 
SOC and preferred term will be presented.  Additionally, SAEs will be listed separately. 
Since intranasal administrations of agents can cause significant irritation of nasal mucosa, events 
of nasal irritation will be followed closely during the study and considered an AE of Special 
Interest (AESI); nasal cavity AEs will be identified on the CRF and additional information 
collected regarding the frequency, duration and temporal relationship to dosing.  This 
information will be tabulated for the nasal cavity AEs and presented in a listing. 
AESIs and TEAEs leading to discontinuation of study drug will be analyzed and presented in a 
manner identical to the SAEs. 
Adverse events potentially related to abuse will be presented in a separate listing; terms to be 
used are given in Appendix 15.3. These will be compared against the current coding dictionary 
and any related or similar terms will be included; additional terms may be added if they are 
thought to potentially be related to abuse. 
All deaths will be reported in a listing.  
 


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10.5.
Clinical Laboratory Evaluation
Laboratory data including Chemistry, Hematology, and urinalyses will be summarized by 
treatment and visit for the Safety Population.  Descriptive summaries of actual values and 
changes from baseline will be presented by study visit and last assessment for each clinical 
laboratory analyte and for each treatment group.  95% confidence intervals will be presented for 
change from baseline. 
Laboratory values will be displayed in the data listings with their corresponding normal ranges, 
and those values that are outside the normal range will be flagged.  For each laboratory analyte 
shifts in assessments of abnormality from baseline to each scheduled time point will be presented 
in shift tables. 
Results of urine drug screens and pregnancy tests will be presented in listings. 
  
10.6. 
Vital Signs, Electrocardiograms, Physical Findings, and Other 
Observations Related to Safety 
10.6.1. 
Vital Signs 
Descriptive summaries (mean, SD, median, minimum, and maximum) of actual values and 
changes from baseline at each assessment time point and last assessment will be calculated for 
vital signs including weight, body mass index, body temperature, pulse rate, systolic blood 
pressure and diastolic blood pressure. 95% confidence intervals will be presented for change 
from baseline. Vital sign values, including abnormal values, will be listed. 
10.6.2. 
Electrocardiograms (ECGs) 
Descriptive summaries (mean, SD, median, minimum, and maximum) of actual values and 
changes from baseline at each assessment time point and last assessment will be calculated for 
each electrocardiogram parameter. 95% confidence intervals will be presented for change from 
baseline. Additionally, the number and percentage of patients with normal, abnormal/not 
clinically significant, and abnormal/ clinically significant ECG interpretations will be 
summarized at each assessment time point and last assessment. Percentages will be out of the 
number of subjects in the safety population. Electrocardiogram values, including clinical 
interpretation values, will be listed. 
10.6.3. 
Physical Examinations 
Physical examination data will be presented in a data listing. 
10.6.4. 
Other Safety Measures 
10.6.4.1. Columbia Suicide Severity Rating Scale (C-SSRS) 
Based on the C-SSRS results, the overall number of patients with lifetime and/or current suicidal 
ideation (by item and category), suicidal behavior (by item and category), or self-injurious 


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behavior at the screening and baseline visit will be summarized by visit and treatment group.  
Additionally, the overall number of patients with any suicidal ideation or behavior (by type and 
in total) or self-injurious behavior while on-treatment will be provided by treatment group. 
Patients will only be counted once for on-treatment ideation and on-treatment behavior, at the 
worst-case response for each item. 
10.6.4.2. Changes from baseline in the HADS scores 
Descriptive summaries (mean, SD, median, minimum, and maximum) of actual values and 
changes from baseline at each assessment time point and last assessment will be calculated for 
both HADS domain scores.  Note that the HADS is considered both an efficacy and safety 
endpoint. 
10.6.4.3. Changes from baseline in the Sexual Functioning Questionnaire Short-Form 
(CSFQ-14) 
The CSFQ-14 will be analyzed by gender. Note: there is a male version and female version for 
the CSFQ-14. Descriptive summaries (mean, SD, median, minimum, and maximum) of actual 
values and changes from baseline at each assessment time point and last assessment will be 
calculated for each CSFQ domain score and the total. Note that the CSFQ is considered both an 
efficacy and safety endpoint. 
  
 


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11.
OTHER ANALYSES
N/A 


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12.
INTERIM ANALYSES
An interim analysis will not be performed in this study. 
 
 


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13.
CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL
 
 
 
 
 
 
 
 
 
 
 
 
 


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14.
REFERENCES
Diggle P, Kenward M. Informative dropout in longitudinal data analysis (with discussion). Appl 
Stat. 1994;43:49-93 
592. 
 


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15. 
APPENDIX 
15.1. 
Schedule of Events 
 
Study Phase 
Screening/Washout 
(Up to 21 days) 
 
Run-In 
(At least 28 days) 
 
Treatment 
84 days 
Follow-upb 
14 days 
Study Visit 
V1 
Screening  
V2 
Baseline/ 
Randomization 
V3 
V4 
V5 
Or Early 
Terminationa 
Visit 6 
End-of-
Study In-
Person  
Study Week 
 
 
 
Week 4 
Week 8 
Week 12 
Week 14 
Study Days 
1 Day 63 to -28 days 
Day -49 to Day -1 
Day 1 
Day 29 + 4d 
Day 57 + 4d 
Day 85 + 4d 
Day 99 + 4d 
Informed Consent 
X 
 
 
 
 
 
Inclusion/ Exclusion Criteria 
X 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Medical and Medication History 
X 
Xc 
 
 
 
 
Adverse Events Assessment 
 
X 
X 
X 
X 
X 
Concomitant Medication 
X 
X 
X 
X 
X 
 
Physical Exam 
X 
X 
 
 
X 
 
Nasal Exam 
X 
X 
X 
X 
X 
Xd 
Vital Signs 
X 
X 
X 
X 
X 
X 
12-Lead ECG 
X 
X 
X 
X 
X 
 
Blood Hematology-Central 
X 
 
 
 
X 
Xf 
Blood Chemistry-Central 
X e 
X e 
X e 
X e 
Xe 
Xe,f 


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Study Phase 
Screening/Washout 
(Up to 21 days) 
 
Run-In 
(At least 28 days) 
 
Treatment 
84 days 
Follow-upb 
14 days 
Study Visit 
V1 
Screening  
V2 
Baseline/ 
Randomization 
V3 
V4 
V5 
Or Early 
Terminationa 
Visit 6 
End-of-
Study In-
Person  
Study Week 
 
 
 
Week 4 
Week 8 
Week 12 
Week 14 
Study Days 
1 Day 63 to -28 days 
Day -49 to Day -1 
Day 1 
Day 29 + 4d 
Day 57 + 4d 
Day 85 + 4d 
Day 99 + 4d 
Urinalysis-Central 
X 
X 
X 
X 
X 
Xf 
Pregnancy Testg 
X 
X 
X 
X 
X 
X 
Urine Drug Testh (UDT)-Central 
X 
 
 
 
 
 
Thyroid Stimulating Hormone (TSH)-
Central 
X 
 
 
 
 
 
HbA1c 
X 
 
 
 
 
 
Optional Pharmacogenomics 
 
X 
*s 
* s 
* s 
* s 
C-SSRSi 
X 
X 
X 
X 
X 
X 
MSI-BPDj 
X 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
Placebo Response Training 
X 
X 
X 
X 
X 
 
E-diary Trainingk 
X 
X 
X 
X 
 
 
E-diary Assessmentl 
X 
X 
X 
X 
 
 
Dispense Study Drug 
 
Xm 
X 
X 
 
 


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Study Phase 
Screening/Washout 
(Up to 21 days) 
 
Run-In 
(At least 28 days) 
 
Treatment 
84 days 
Follow-upb 
14 days 
Study Visit 
V1 
Screening  
V2 
Baseline/ 
Randomization 
V3 
V4 
V5 
Or Early 
Terminationa 
Visit 6 
End-of-
Study In-
Person  
Study Week 
 
 
 
Week 4 
Week 8 
Week 12 
Week 14 
Study Days 
1 Day 63 to -28 days 
Day -49 to Day -1 
Day 1 
Day 29 + 4d 
Day 57 + 4d 
Day 85 + 4d 
Day 99 + 4d 
Return study drug and Perform 
Accountability  
 
 
X 
X 
X 
 
Review e-diary 
 
X 
X 
X 
X 
 
PGICn 
 
 
X 
X 
X  
 
HADSo 
 
X 
X 
X 
X 
 
MIDASp 
 
X 
 
 
X 
 
MSQq 
 
X 
X 
X 
X 
 
CSFQ-14r 
 
X 
 
 
X 
 
a 
An Early Termination Visit will be conducted approximately 7 days (+3 days) of withdrawing from study 
b 
Follow-up visit will be conducted approximately 14 days (+ 4 days) after Visit 5 
c 
Record any changes to the medication history obtained at Screening 
d 
Nasal exam will only be performed at Visit 6 if any abnormality on exam at Visit 5 or any report of a nasal cavity AE 
e 
Chemistry panel only: triggered serum osmolality will be measured from same specimen if sodium is below the lower limit of normal  
f 
Urinalyses, hematology and chemistry labs will only be repeated at Visit 6 if clinically significant findings were observed at Visit 5 
g 
Women of childbearing potential only: screening serum pregnancy test will be analyzed at Central laboratory; consecutive urine pregnancy tests will be 
conducted on-site at every subsequent study visit 
h 
Urine drug test: cocaine, phencyclidine (PCP), barbiturates, amphetamines, cannabis, and opiates 


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i 
C-SSRS: Columbia Suicide Severity Rating Scale 
j 
MSI-BPD: McLean Screening Instrument for Borderline Personality Disorder 
k 
E-diary training will be conducted at Visit 1 (Screening Visit) and Visit 2 (Treatment) and will be repeated at Visits 3 and 4. E-diary is collected at Visit 5 
l 
Patients will start completing their e-diary the day after their Screening Visit. 
m 
Study drug administration training performed at Visit 2 in addition to dispensation of study drug 
n 
PGIC: Patient Global Impression of Change 
o 
HADS: Hospital Anxiety and Depression Scale 
p 
MIDAS: Migraine Disability Assessment questionnaire 
q 
MSQ: Migraine-Specific Quality of Life Questionnaire v2.1  
r 
CSFQ-14: Changes in Sexual Functioning Questionnaire Short-Form 
s 
Pharmacogenomics should be drawn at Baseline but if it is not drawn, drawing at a subsequent visit is allowed. 
 


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15.2. 
Random Seeds 
The following list of numbers will be used for random seeds where required for MI processes: 
3954748 
5375852 
1235264 
2575945 
9454116 
2624285 
1783458 
6572845 
9458932 
7855785 
These will generally be used in order for the primary analysis, then secondary endpoints and 
sensitivity analyses.  For cases where identical code may be applied to more than one outcome or 
a sensitivity analysis that uses a minor variation on the primary code, the second to last digit will 
be incremented by 1 to produce new seeds for the subsequent outcome/analysis.  If a single 
dataset requires more than the 10 seeds above, additional seeds will be generated by 
incrementing the last digit by 1.  All seeds used will be documented in the programming 
specifications and the programs themselves. 
15.3. 
AEs Potentially Related to Abuse 
The following preferred terms will be used to identify AEs potentially related to abuse. 
 Euphoric mood 
 Elevated mood 
 Feeling abnormal 
 Feeling drunk 
 Feeling of relaxation 
 Dizziness 
 Thinking abnormal 
 Hallucination 
 Inappropriate affect 
 Psychosis 
 Aggression 
 Confusion 
 Disorientation 
 Drug tolerance 


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 Habituation 
 Drug withdrawal syndrome 
 
 


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15.4.
Electronic Diary Questions and Derivation of Migraines/Headaches
 
 
QUESTION 
RESPONSES 
Q1. Did you have a headache yesterday? 
Yes 
No 
Q2. Did you experience a migraine with aura yesterday? 
Yes 
No 
Q3. How long did your headache last? 
a. 4 hours or more 
b. at least 2 hours but 
less than 4 
c. less than 2 hours 
 
Q4. How severe was your headache pain yesterday at its peak? 
Mild 
Moderate 
Severe 
The following questions refer to yesterday: 
 
Q5. Was the headache throbbing, pulsating, or pounding? 
Yes 
No 
Q6. Was the headache pain on only one side of your head? 
Yes 
No 
Q7. Was the headache made worse by your usual daily activities 
such as walking or climbing stairs? 
Yes 
No 
Q8. Did light bother you (did you have photophobia)? 
Yes 
No 
Q9. Did sound and noise bother you (did you have 
phonophobia)? 
Yes 
No 
Q10. Did you have nausea or vomiting? 
Yes 
No
Q11. Did you take any headache medications yesterday? 
Yes 
No 
Q12. Please add medications taken. (drop down list name, 
route, dosage, and number of doses will be collected) 
 
Q13. Did you take any pain medications yesterday besides a 
medication for a headache or migraine? 
Yes 
No 
Q14. Please add medications taken for any issue other than a 
headache. (drop down list name, route, dosage, and number 
of doses will be collected)
 
Q15. Was your headache yesterday a migraine and was it 
relieved by the medication you took? 
Yes 
No 
For treatment phase only, log morning and evening doses. 


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15.5. 
Rescue Medications 
The following is a partial list of medications that will be considered migraine-specific abortive 
medications.   In general, triptans and ergot derivatives will be included; all medications will be 
reviewed and a final list will be documented prior to unblinding. 


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16.
ATTACHMENTS
N/A