Conditions: Migraine
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 71
Healthy volunteers: no

Brief summary:
This trial assesses the safety of TEV-48125 when subcutaneously self-administered in Japanese migraine patients using an autoinjector (AI) at home. Each subject will subcutaneously self-administer TEV 48125 at 225 mg/1.5 mL (150 mg/mL) once monthly for a total of 2 doses. The first dose will be self-administered at the trial site under the supervision of the investigator and the second dose will be self-administered at home.

Detailed description:

Arms:
arm 1: None

Interventions: intervention 1: Each subject will subcutaneously self-administer TEV 48125 at 225 mg/1.5 mL (150 mg/mL) once monthly for a total of 2 doses.
Intervention descriptions: intervention 1: Each subject will subcutaneously self-administer TEV 48125 at 225 mg/1.5 mL (150 mg/mL) once monthly for a total of 2 doses.

Protocol document:
Prot_000.pdf: 
 
 
CLINICAL STUDY PROTOCOL 
 
 
 
A multicenter, open-label trial to evaluate the safety of TEV-48125 when 
subcutaneously self-administered in migraine patients at the trial site and at home 
 
 
 
 
NCT Number: NCT04355117 
PRT NO.: 406-102-00005 
Version Date: 16 March 2020 (Amendment 1) 


Protocol 406-102-00005
1
Confidential - Proprietary Information
Amendment 1 Approval: 16 Mar 2020
(English Translation: 12 Aug 2020)
Otsuka Pharmaceutical Co., Ltd.
Investigational Medicinal Product
TEV-48125 (generic name: fremanezumab)
CLINICAL PROTOCOL
A multicenter, open-label trial to evaluate the safety of TEV-48125 when subcutaneously 
self-administered in migraine patients at the trial site and at home
A safety evaluation trial of TEV-48125 self-administered in migraine patients
Protocol No. 406-102-00005
CONFIDENTIAL PROPRIETARY INFORMATION
Clinical Development Phase:
III
Sponsor:
Otsuka Pharmaceutical Co., Ltd.
Immediately Reportable Event 
Clinical Safety and Pharmacovigilance
Otsuka Pharmaceutical Co., Ltd.
Email: IRE_PQC_406-102-00005@otsuka.jp
Amendment 1Approval:
16 Mar 2020
Original Approval:
15 Jan 2020


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(English Translation: 12 Aug 2020)
Table of Contents
Table of Contents...........................................................................................2
List of In-text Tables .....................................................................................8
List of In-text Figures....................................................................................9
1
Protocol Summary..............................................................................10
1.1
Synopsis.............................................................................................................10
1.2
Schema ..............................................................................................................14
1.3
Schedule of Assessments...................................................................................15
1.3.1
Screening Period.............................................................................................17
1.3.1.1
Date of Informed Consent...........................................................................17
1.3.1.2
Visit 1/Screening.........................................................................................18
1.3.2
Treatment Period ............................................................................................19
1.3.2.1
Visit 2/Baseline (Day 1): Self-administration at the Trial Site...................19
1.3.2.2
Pharmacokinetic Blood Sampling Visit 1 (PK1 Visit) ...............................20
1.3.2.3
Visit 3: Self-administration at Home ..........................................................21
1.3.2.4
Pharmacokinetic Blood Sampling Visit 2 (PK2 Visit) ...............................21
1.3.2.5
Visit 4/End of Treatment or at Withdrawal ................................................22
1.3.3
Unscheduled Visits .........................................................................................23
2
Introduction ........................................................................................23
2.1
Trial Rationale...................................................................................................23
2.2
Background .......................................................................................................24
2.3
Known and Potential Risks and Benefits ..........................................................25
3
Objectives and Endpoints..................................................................26
4
Trial Design.........................................................................................27
4.1
Type/Design of Trial .........................................................................................27
4.2
Scientific Rationale for Trial Design.................................................................27
4.3
Dosing Rationale...............................................................................................28
4.4
End of Trial Definition......................................................................................29
4.5
Definition of Completed Subjects.....................................................................29
5
Trial Population..................................................................................29
5.1
Subject Selection and Numbering.....................................................................29


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5.2
Eligibility Criteria..............................................................................................30
5.2.1
Inclusion Criteria ............................................................................................30
5.2.2
Exclusion Criteria...........................................................................................31
5.3
Lifestyle Considerations....................................................................................33
5.3.1
Meals and Dietary Restrictions.......................................................................33
5.3.2
Caffeine, Alcohol, and Tobacco .....................................................................33
5.3.3
Activity ...........................................................................................................33
5.4
Screen Failures ..................................................................................................33
6
Trial Treatments.................................................................................34
6.1
Trial Treatments Administered .........................................................................34
6.1.1
Visit 2/Baseline: Self-administration at the Trial Site....................................34
6.1.2
Visit 3: Self-administration at Home..............................................................35
6.1.3
Information Regarding Trial Treatment Administration................................35
6.1.4
Medical Devices .............................................................................................36
6.2
Management of Investigational Medicinal Product ..........................................36
6.2.1
Packaging and Labeling..................................................................................37
6.2.2
Storage ............................................................................................................37
6.2.3
Accountability.................................................................................................37
6.2.4
Returns and Destruction .................................................................................37
6.2.5
Reporting of Product Quality Complaints......................................................38
6.2.5.1
Eliciting and Reporting Product Quality Complaints .................................38
6.2.5.2
Information Required for Reporting Product Quality Complaints .............39
6.2.5.3
Return Process in Reporting Product Quality Complaints..........................39
6.2.5.4
Assessment/Evaluation ...............................................................................39
6.3
Measures to Minimize/Avoid Bias....................................................................39
6.4
Subject Compliance...........................................................................................39
6.5
Concomitant Medications or Therapies ............................................................40
6.5.1
Prohibited Medications (Preventive Migraine Medications)..........................40
6.5.2
Restricted Concomitant Medications (Preventive Migraine 
Medications) ...................................................................................................41
6.5.3
Prohibited Concomitant Therapies .................................................................41
6.5.4
Rescue Medications........................................................................................41
6.6
Intervention after the End of the Trial...............................................................41


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7
Stopping Rules, Withdrawal Criteria, and Procedures..................42
7.1
Entire Trial or Treatment...................................................................................42
7.2
Individual Site ...................................................................................................42
7.3
Individual Subject Discontinuation...................................................................42
7.3.1
Treatment Interruption....................................................................................42
7.3.2
Treatment Discontinuation .............................................................................42
7.3.3
Documenting Reasons for Treatment Interruption or Discontinuation..........43
7.3.4
Withdrawal of Consent or Assent...................................................................44
7.3.5
Procedures to Encourage Continued Trial Participation ................................45
7.4
Definition of Subjects Lost to Follow-up..........................................................45
8
Trial Procedures .................................................................................46
8.1
Efficacy Assessments........................................................................................46
8.2
Pharmacokinetic Assessments...........................................................................46
8.2.1
Plasma Drug Concentrations ..........................................................................46
8.3
Immunogenicity Assessments...........................................................................47
8.3.1
Serum Samples for Immunogenicity Assessments.........................................47
8.4
Pharmacodynamic Assessments........................................................................47
8.5
Pharmacogenomic Assessments........................................................................47
8.6
Biomarker Assessments ....................................................................................47
8.7
Future Biospecimen Research Samples ............................................................47
8.8
Safety Assessments ...........................................................................................47
8.8.1
Adverse Events ...............................................................................................47
8.8.2
Clinical Laboratory Assessments ...................................................................48
8.8.3
Physical Examination .....................................................................................48
8.8.4
Vital Signs ......................................................................................................49
8.8.5
Electrocardiogram...........................................................................................49
8.8.6
Suicidality Monitoring....................................................................................50
8.8.6.1
Columbia-Suicide Severity Rating Scale....................................................50
8.8.7
Other Safety Variables....................................................................................51
8.8.7.1
Height and Weight ......................................................................................51
8.8.7.2
Injection Site Reaction Assessment ............................................................51
8.9
Adverse Events..................................................................................................52


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8.9.1
Definitions ......................................................................................................52
8.9.2
Eliciting and Reporting Adverse Events.........................................................54
8.9.3
Immediately Reportable Events......................................................................55
8.9.4
Medical Device Incidents (Including Malfunctions)......................................55
8.9.5
Adverse Events of Special Interest.................................................................55
8.9.6
Potential Serious Hepatotoxicity ....................................................................56
8.9.7
Procedure for Breaking the Blind...................................................................56
8.9.8
Follow-up of Adverse Events .........................................................................56
8.9.8.1
Follow-up of Nonserious Adverse Events ..................................................56
8.9.8.2
Follow-up of Immediately Reportable Events ............................................56
8.9.8.3
Follow-up and Reporting of Immediately Reportable Events 
Occurring After Last Scheduled Contact....................................................57
8.10
Treatment of Overdose......................................................................................57
8.11
Subject Assessment Recording .........................................................................58
8.11.1
Electronic Headache Diary.............................................................................58
8.11.2
Recording Information on Self-administration at Home................................58
8.12
Other Assessments ............................................................................................59
8.12.1
Assessment of Self-administration at Home...................................................59
9
Statistical Considerations ..................................................................59
9.1
Sample Size.......................................................................................................59
9.2
Datasets for Analysis.........................................................................................59
9.3
Handling of Missing Data for Primary Endpoint Analysis ...............................59
9.4
Statistical Analyses............................................................................................59
9.4.1
Efficacy Analyses ...........................................................................................59
9.4.2
Safety Analysis ...............................................................................................59
9.4.2.1
Adverse Events............................................................................................59
9.4.2.2
Execution Status of Self-administration and Subject Compliance 
With Self-administration Procedure............................................................60
9.4.2.3
Deficiencies With the Autoinjector Device ................................................60
9.4.2.4
Clinical Laboratory Data.............................................................................60
9.4.2.5
Physical Examination and Vital Signs Data................................................60
9.4.2.6
Electrocardiogram Data ..............................................................................60
9.4.2.7
Other Safety Data........................................................................................61


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9.4.2.7.1
Weight .....................................................................................................61
9.4.2.7.2
Injection Site Reactions...........................................................................61
9.4.2.7.3
Columbia-Suicide Severity Rating Scale ................................................61
9.4.3
Other Analyses................................................................................................61
9.4.3.1
Analysis of Demographic and Baseline Characteristics .............................61
9.4.3.2
Pharmacokinetic Analysis...........................................................................61
9.4.3.3
Pharmacodynamic Analysis........................................................................61
9.4.3.4
Pharmacokinetic/Pharmacodynamic Analysis............................................61
9.4.3.5
Immunogenicity ..........................................................................................61
9.4.3.5.1
Immunogenicity Analysis........................................................................61
9.4.3.6
Pharmacogenomic Analysis........................................................................61
9.4.3.7
Exploratory Endpoint Analysis...................................................................61
9.4.3.8
Plasma Drug Concentrations.......................................................................62
9.5
Interim Analysis and Adaptive Design .............................................................62
9.5.1
Data Monitoring Committee...........................................................................62
10
Supporting Documentation and Operational Considerations .......63
10.1
Appendix 1: Regulatory, Ethical, and Trial Oversight Considerations.............63
10.1.1
Ethics and Responsibility ...............................................................................63
10.1.2
Informed Consent ...........................................................................................63
10.1.3
Confidentiality................................................................................................64
10.1.4
Quality Control and Quality Assurance..........................................................65
10.1.4.1
Monitoring ..................................................................................................65
10.1.4.2
Auditing ......................................................................................................65
10.1.5
Protocol Deviations ........................................................................................65
10.1.6
Records Management .....................................................................................66
10.1.6.1
Source Documents ......................................................................................66
10.1.6.2
Data Collection............................................................................................66
10.1.6.3
File Management at the Trial Site...............................................................67
10.1.6.4
Records Retention at the Trial Site .............................................................67
10.1.6.5
Publication Authorship Requirements ........................................................67
10.2
Appendix 2: Clinical Laboratory Tests .............................................................69
10.3
Appendix 3: Contraceptive Guidance and Collection of Pregnancy 
Information........................................................................................................70


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10.4
Appendix 4: ICHD-3 beta Diagnostic Criteria..................................................72
10.5
Appendix 5: Guidance on Safety Monitoring ...................................................73
10.6
Appendix 6: Columbia-Suicide Severity Rating Scale (Baseline)....................76
10.7
Appendix 7: Columbia-Suicide Severity Rating Scale (Since Last Visit)........79
10.8
Appendix 8: Clinical Criteria for Diagnosing Anaphylaxis..............................82
10.9
Appendix 9: Abbreviations ...............................................................................83
10.10
Appendix 10: Protocol Amendments ................................................................85
10.10.1
Protocol Amendment(s)/Administrative Change(s) .......................................86
11
References............................................................................................88


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List of In-text Tables
Table 1.3-1
Schedule of Assessments.............................................................. 15
Table 3-1
Trial Objectives and Endpoints..................................................... 26
Table 6.5.1-1
List of Prohibited Concomitant Medications (Preventive 
Migraine Medications).................................................................. 40
Table 6.5.2-1
List of Restricted Concomitant Medications (Preventive 
Migraine Medications).................................................................. 41
Table 8.8.7.2-1
Severity Grading of Pain for Injection Site Assessment............... 52
Table 10.2-1
Clinical Laboratory Assessments.................................................. 69


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List of In-text Figures
Figure 1.2-1
Trial Design Schematic................................................................. 14


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1
Protocol Summary
1.1
Synopsis
Name
Otsuka Pharmaceutical Co., Ltd.
Name of Investigational Medicinal Product:
TEV-48125
Protocol No.:
406-102-00005
Protocol Title:
A multicenter, open-label trial to evaluate the safety of TEV-48125 when subcutaneously 
self-administered in migraine patients at the trial site and at home
Protocol Lay Person Short Title:
A safety evaluation trial of TEV-48125 self-administered in migraine patients
Clinical Phase/Trial Type:
Phase 3/Dose-tolerance trial
Treatment/Indication:
Migraine
Objectives and Endpoints:
The primary objective is to assess the safety of TEV-48125 (generic name: 
fremanezumab) when subcutaneously self-administered in Japanese migraine patients 
using an autoinjector (AI) at home.
The primary endpoint of the trial is the occurrence of adverse events (AEs), and the 
safety of the investigational medicinal product (IMP; combination product of TEV-48125 
and the AI) will be assessed based on the occurrence of AEs. Other endpoints will 
include evaluation of the execution status of self-administration at home and subject 
compliance with the self-administration procedure, and an overall evaluation of the 
feasibility of self-administration of TEV-48125 at home. In addition, as the IMP is a 
combination product, any deficiencies with the AI device will also be evaluated.


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As exploratory endpoints, efficacy parameters including the number of migraine days, the 
number of headache days, and the number of headache days of at least moderate severity
will be evaluated.
Trial Design:
This trial is a multicenter, open-label trial in migraine patients and will consist of a 
4-week screening period and an 8-week treatment period.
Trial Population:
A total of 50 migraine patients age 18 to 70 years, inclusive, with a history of migraine 
(according to International Classification of Headache Disorders [ICHD-3] criteria*), or 
who have been clinically diagnosed with migraine and whose medical history is not 
better accounted for by another ICHD-3 diagnosis for 12 months prior to giving 
informed consent
*The International Classification of Headache Disorders, third edition (ICHD-3), 
Headache Classification Committee of the International Headache Society, 2018
Key Inclusion/Exclusion Criteria:
Key Inclusion Criteria:
1) Patient has a history of migraine (according to the ICHD-3 criteria) or clinical 
judgment suggests a migraine diagnosis (not better accounted for by another 
ICHD-3 diagnosis) for ≥12 months prior to giving informed consent.
2) Patient fulfills any of the following criteria on ≥4 days in baseline information 
collected during the 28-day screening period.

ICHD-3 diagnostic criteria C and D for 1.1 Migraine without aura

ICHD-3 diagnostic criteria B and C for 1.2 Migraine with aura

Probable migraine (a migraine subtype where only 1 migraine criterion is 
missing)

The patient used a triptan or ergot derivative to treat an established headache.
3) Not using preventive migraine medications for migraine or other medical 
conditions (ie, at least 5 half-lives have passed since last use) or using no more 
than 2 preventive migraine medications (restricted medications, see Table 6.5.2-1) 
for migraine or other medical conditions (eg, propranolol used for hypertension) if 
the dose and regimen have been stable for at least 2 months prior to screening 
examination (Visit 1/Screening).
4) Patient demonstrates compliance with the electronic headache diary (eDiary) 
during the screening period by entry of headache data on a minimum of 24 of 
28 days (≥85% diary compliance) and the entered data is judged appropriate by 
the investigator.


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5) At the time of informed consent, patient whom the investigator judges fit for self-
administration of the IMP
Key Exclusion Criteria:
1) Hematological, cardiac, renal, endocrine, pulmonary, gastrointestinal, 
genitourinary, neurologic, hepatic, or ocular disease considered clinically 
significant in the judgment of the investigator
2) History of hypersensitivity reactions to injected proteins, including monoclonal 
antibodies
3) Prior exposure to a monoclonal antibody targeting the calcitonin gene-related 
peptide (CGRP) pathway meeting the following conditions:

Less than 5 months has passed since the final administration of AMG334, 
LY2951742, or ALD304.

Less than 1 year has passed since the final administration of TEV-48125 
(prefilled syringe). (Even if 1 year has passed since the final administration, 
patient cannot be enrolled if assessment of anti-drug [TEV-48125] antibody 
[ADA] due to the previous administration is positive or inconclusive.)
4) The patient cannot participate or successfully complete the trial for other reasons 
in the opinion of the investigator.
Trial Site(s):
Approximately 10 trial sites are planned in Japan.
Investigational Medicinal Product(s), Dose, Dosage Regimen, Treatment Duration, 
Formulation, Mode of Administration:
In this trial, each subject will subcutaneously self-administer TEV-48125 at 
225 mg/1.5 mL (150 mg/mL) once monthly for a total of 2 doses. The first dose will be 
self-administered at the trial site under the supervision of the investigator and the second 
dose will be self-administered at home. The injection site may be the back of the upper 
arm, the abdomen, or the front of the thigh. To the extent possible, the injection site 
should be the same for both doses (but not exactly in the same location).
The IMP is to be removed from the refrigerator and left to stand at room temperature for 
30 minutes before administration.
Trial Assessments:
Assessments for safety: adverse event, clinical laboratory tests, 12-lead 
electrocardiogram (ECG), physical examination findings, vital signs, weight, injection 
site reaction (erythema, induration, ecchymosis, and/or pain), Columbia-Suicide Severity 
Rating Scale (C-SSRS), prior medication, concomitant medication, prior and concomitant 
therapy, and plasma drug concentration


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Screening/Other: Subject demographics, eDiary data (headache data), and serum ADA 
assessment
Data Monitoring Committee: None
Statistical Methods:

Safety analysis
The incidence of treatment-emergent AEs (TEAEs) will be summarized. Other 
safety endpoints will be summarized using descriptive statistics, shift tables, or 
frequency distributions.

Sample size
The statistically required sample size based on power was not calculated. The 
sample size for evaluating the safety of TEV-48125 when subcutaneously 
self-administered at the trial site and at home was set at 50 subjects.
Trial Duration:

Expected duration of trial participation for each individual subject: 85 days

Screening period: 4 weeks (28 days)

Treatment period: 8 weeks (57 days)
The expected overall trial duration from the time informed consent is obtained from the 
first subject to completion of final examination of the last subject is 7 months.


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1.2
Schema
Figure 1.2-1
Trial Design Schematic 


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1.3
Schedule of Assessments
Table 1.3-1
Schedule of Assessments
Item
Period
Screening 
Period
Treatment Period
Visit
V1/
Screening
V2/Baseline
Self-
administration 
at Trial Site
PK1 Visit
(PK Blood 
Sampling After
Administration 
at Trial Site)
V3a
Self-
administration 
at Home
PK2 Visit 
(PK Blood 
Sampling After 
Administration 
at Home)
V4/End of 
Treatment
At 
Withdrawal
Trial Dayb
Day −28
Day 1
Day 4 to 
Day 11
Day 29
Day 32 to 
Day 39
Day 57
Acceptable 
Window
−3
±3
±3
Day of 
Withdrawal 
Decision + 7c
Informed Consentd
X
Enrollmente
X
Demographics
X
Inclusion/Exclusion 
Criteria
X
X
Instruction on IMP
Handling and Self-
administration Procedure
X
X
X
Assessment/Confirmation 
That Self-administration 
Is Possible
X
X
IMP Self-administrationf
X
Xa
Confirmation of Self-
administration Execution 
Statusf
X
X
X
Confirmation of
Compliance With Self-
administration Proceduref
X
X
X
Injection Site Reaction 
Assessmentg
X
X
Physical Examination
X
X
X
X
X
Height
X
Weight
X
X
X
X
X
12-Lead ECG
X
X
X
X
X
Vital Signs (systolic and 
diastolic pressure, pulse 
rate, temperature, 
respiratory rate)
X
X
X
X
X
Clinical Laboratory Tests 
(chemistry, hematology, 
coagulation, urinalysis)
X
X
X
X
X
Urine hCG Testh
X
X
X
X
X


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Table 1.3-1
Schedule of Assessments
Item
Period
Screening 
Period
Treatment Period
Visit
V1/
Screening
V2/Baseline
Self-
administration 
at Trial Site
PK1 Visit
(PK Blood 
Sampling After
Administration 
at Trial Site)
V3a
Self-
administration 
at Home
PK2 Visit 
(PK Blood 
Sampling After 
Administration 
at Home)
V4/End of 
Treatment
At 
Withdrawal
Trial Dayb
Day −28
Day 1
Day 4 to 
Day 11
Day 29
Day 32 to 
Day 39
Day 57
Acceptable 
Window
−3
±3
±3
Day of 
Withdrawal 
Decision + 7c
Adverse Eventsi
Medication and Therapy 
Inquiry
AI Device Deficiency j
X
X
X
C-SSRSk
X
X
X
X
Blood Sampling for 
Plasma Drug 
Concentrationl
X
X
X
X
X
Blood Sampling for 
Serum ADA 
Assessmentm
X
X
X
X
eDiary Device Provided 
and Explainedn
X
Data Entry in eDiaryo
Review of eDiary
X
X
X
X
Return of eDiary Device
X
X
hCG = human chorionic gonadotropin; IMP = combination product of TEV-48125 and AI; PK = 
pharmacokinetic; V = visit.
aAfter completion of the specified items and reconfirmation that self-administration at home is possible 
at Visit 3, the subject will perform self-administration at home. Visit 3 and the day of self-
administration at home do not have to be the same day, but self-administration at home must be 
performed within 3 days from the day of Visit 3 (including the day of Visit 3) and also must be 
performed within the acceptable window for Visit 3.
bTrial Day is indicated on the basis of Visit 2/Baseline being Day 1 and self-administration at home 
being performed on Day 29.
cWithdrawal examination will not be performed for subjects withdrawn prior to self-administration at 
the trial site. For subjects withdrawn after self-administration, withdrawal examination is to be 
performed within 7 days from the day of the withdrawal decision.
dInformed consent can be obtained prior to the day of Visit 1/Screening.
eThe investigator will confirm that each subject meets all of the inclusion criteria and does not fall under 
any of the exclusion criteria and enroll subjects who are judged to be eligible.
fFollowing self-administration, the execution status of self-administration and compliance with the self-
administration procedure will be recorded. For self-administration at the trial site, the investigator 
will record the information after completion of self-administration. For self-administration at home, 
the subject will record the information using a check sheet and when the subject visits the trial site the 


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investigator will perform a confirmation based on an interview and the information recorded by the 
subject.
gAssessment of injection site reaction will be performed immediately after administration and at 1 hour 
postdose. If a subject has severe injection site erythema, induration, and/or ecchymosis and/or grade 3 
(severe) or grade 4 (worst possible) injection site pain at 1 hour after completion of IMP 
administration, the subject will be reassessed hourly thereafter until the reaction and/or pain is of 
moderate or less severity. The investigator will perform the assessment after completion of self-
administration at the trial site. For self-administration at home (Visit 3/Self-administration at Home), 
the subject will assess and record injection site reaction and at PK blood sampling visit 2 at 3 to 10 
days after self-administration at home the investigator will perform a confirmation based on an 
interview and the information recorded by the subject.
hWomen of childbearing potential only. If the result of urine hCG test at screening is positive, serum 
hCG will be tested to confirm that the result is negative. If the result of urine hCG test is positive at 
Visit 2 or Visit 3, the subject is to be withdrawn from the trial.
iInquiries about AEs will be made before and after IMP administration. Postdose inquiries following 
self-administration at the trial site will be made before the subject leaves the trial site. For self-
administration at home, when the subject visits the trial site the investigator will perform assessment 
based on an interview and the information recorded by the subject.
jDeficiencies with the AI device occurring from the time the IMP is provided to the subject to the 
completion of self-administration are to be recorded in the electronic case report form (eCRF). 
kThe C-SSRS Baseline Version will be completed at Visit 2/Baseline, and the C-SSRS Since Last Visit 
Version will be completed at all subsequent visits.
lBlood sampling for plasma drug concentration determination at Visit 3 will be performed before 
administration. The following blood sampling timepoints are also set:
Visit 2 (self-administration at trial site):
One timepoint between 3 to 10 days postdose (PK1 visit) and one timepoint at 28 days (± 3 days) 
postdose (Visit 3), for a total of 2 timepoints
Visit 3 (self-administration at home):
One timepoint between 3 to 10 days postdose* (PK2 visit) and one timepoint at 28 days 
(± 3 days)** postdose (Visit 4/End of Treatment), for a total of 2 timepoints
*Taking into consideration the acceptable window and using the day of self-administration at home at 
Visit 3 as the starting point, blood sampling will be performed between Day 29 and Day 42. 
**Taking into consideration the acceptable window and using the day of self-administration at home 
at Visit 3 as the starting point, blood sampling will be performed between Day 51 and Day 63. 
mBlood sampling for serum ADA assessment at Visit 2/Baseline will be performed before 
administration. Blood sampling for ADA assessment will also be performed if severe hypersensitivity 
reaction (eg, anaphylaxis) is suspected.
nSubjects who meet the inclusion criteria will be provided with the eDiary device at Visit 1/Screening, 
instructed on how to use it, and given an explanation of the compliance requirements.
oSubjects are to enter headache data in the eDiary every day from Visit 1/Screening until the day before 
Visit 4/End of Treatment or withdrawal.
1.3.1
Screening Period
1.3.1.1
Date of Informed Consent
The screening period is from the day of informed consent until trial enrollment.


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The investigator will obtain an appropriately signed and dated informed consent form 
before commencing any screening procedures. The following information will be 
recorded in the electronic case report form (eCRF):

Informed consent

Date of informed consent

Subject identification number
1.3.1.2
Visit 1/Screening
The start of Visit 1/Screening is 28 days before Visit 2/Baseline. In order to confirm that 
the subject meets all of the inclusion criteria and does not fall under any of the exclusion 
criteria, the following assessments, tests, and observations are to be performed and the 
information recorded in the eCRF.

Visit date

Result of eligibility assessment

Demographics

Date of investigation

Birthdate, age (at the time of informed consent), and sex

Childbearing potential (reason for nonchildbearing potential, or 
contraceptive methods)

Race, ethnicity, and country

Medical history and complications (at the time of informed consent)

Medical history for migraine

History of medications and therapies (within 5 months before the start of 
IMP administration)

Vital signs (systolic and diastolic blood pressure, pulse rate, temperature, and 
respiratory rate)

12-Lead ECG 

Physical examination

Height and weight (Body mass index [BMI] will be calculated using height 
and weight at Visit 1/Screening.)

Clinical laboratory tests

Chemistry, hematology, coagulation, and urinalysis

Urine human chorionic gonadotropin (hCG) test (women of childbearing 
potential [WOCBP] only) (If the result of urine hCG test is positive at 
screening, serum hCG test will be performed to confirm that the result is 
negative.)

eDiary (Subjects will be provided with the eDiary device, instructed on how 
to use it, and given an explanation of the compliance requirements.)


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
AEs

Instruction on IMP* handling and the self-administration procedure
*The IMP is a combination product of TEV-48125 and the AI.
Twelve-lead ECG and clinical laboratory test results measured by the central laboratory, 
which cannot be assessed at the start of Visit 1/Screening, should be checked against the 
inclusion and exclusion criteria as soon as they become available to confirm the subject’s 
eligibility.
For headache data on each day from Visit 1/Screening through the day before 
Visit 2/Baseline, subjects are to enter headache information for the previous day in the 
eDiary. The eDiary data of the most recent 28 days prior to Visit 2/Baseline will be used 
to determine whether inclusion criteria 5 is met.
1.3.2
Treatment Period
1.3.2.1
Visit 2/Baseline (Day 1): Self-administration at the Trial Site
The treatment period is from the time of trial enrollment until Visit 4/End of treatment or 
the time of withdrawal. On each day during the treatment period, subjects are to enter 
headache data for the previous day in the eDiary.
The investigator will confirm that each subject meets all of the inclusion criteria and does 
not fall under any of the exclusion criteria, and enroll subjects who are judged to be 
eligible. Subjects who are judged to be ineligible will be handled as screen failures. 
For subjects who are judged to be eligible, prior to IMP administration the following 
assessments, tests, and observations are to be performed and the information recorded in 
the eCRF.  

Visit date

Result of eligibility assessment

Use of preventive migraine medications

eDiary

Vital signs (systolic and diastolic blood pressure, pulse rate, temperature, and 
respiratory rate)

12-Lead ECG

Physical examination

Weight

Clinical laboratory tests

Chemistry, hematology, coagulation, and urinalysis

Urine hCG test (WOCBP only)


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
Blood sampling for serum ADA assessment

C-SSRS (Baseline Version)

History of medications and therapies (within 5 months before the start of IMP 
administration)

AEs

Instruction on IMP handling and the self-administration procedure  

Judgment on whether self-administration at the trial site is possible
After the above predose assessments, tests, and observations are completed, subjects 
whom the investigator judges fit for self-administration will perform self-administration 
at the trial site under the supervision of the investigator (see Section 6.1). After self-
administration by the subject, the investigator will perform the following assessments and 
observations and record the information in the eCRF. Additional assessments may be 
performed based on the severity of abnormal injection site reaction (erythema, induration, 
ecchymosis, and/or pain).

Execution status of self-administration

Date, time, injection site, confirmation of the amount of drug solution 
remaining in the AI, and leakage of drug solution on the skin after 
subcutaneous injection

Occurrence of injection site reaction (erythema, induration, ecchymosis, 
and/or pain) and its severity (immediately after administration and at 1 hour 
postdose)

Compliance with self-administration procedure

Judgment on whether self-administration at home is possible

Deficiency with the AI device

AEs
The investigator will assess the subject’s compliance with the procedure for self-
administration at the trial site. If it is judged that self-administration by the subject at 
home is not possible, the subject will be withdrawn from the trial.
1.3.2.2
Pharmacokinetic Blood Sampling Visit 1 (PK1 Visit)
At 3 to 10 days after IMP administration at Visit 2/Baseline, the following assessments, 
tests, and observations will be performed and the information recorded in the eCRF.

Visit date

Blood sampling for plasma drug concentration measurement

AEs


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1.3.2.3
Visit 3: Self-administration at Home
Prior to IMP administration, the following assessments, tests, and observations will be 
performed and the information recorded in the eCRF.

Visit date

eDiary

Vital signs (systolic and diastolic blood pressure, pulse rate, temperature, and 
respiratory rate) 

12-Lead ECG

Physical examination

Weight

Clinical laboratory tests

Chemistry, hematology, coagulation, and urinalysis

Urine hCG test (WOCBP only)

Blood sampling for serum ADA assessment

Blood sampling for plasma drug concentration measurement

C-SSRS (Since Last Visit Version)

Concomitant medications and therapies

AEs

Instruction on IMP handling and the self-administration procedure

Reconfirmation that self-administration at home is possible
After the above predose assessments, tests, and observations are completed, subjects who 
understand the instructions on IMP handling and the self-administration procedure and 
for whom it is reconfirmed that self-administration at home is possible will perform self-
administration at home according to “Procedure for TEV-48125 AI Self-administration” 
(see Section 6.1). Self-administration at home must be performed within 3 days from the 
day of Visit 3 (including the day of Visit 3) and must also be performed within the 
acceptable window for Visit 3 (± 3 days: Day 26 to Day 32).
The investigator will contact the subject via telephone or other means on the day of self-
administration at home, or as soon as possible thereafter if contact on the day of self-
administration is not possible, and confirm whether self-administration was performed. If 
occurrence of an AE or any incidence is reported, the subject will be requested to 
promptly visit the trial site as needed. 
1.3.2.4
Pharmacokinetic Blood Sampling Visit 2 (PK2 Visit)
At 3 to 10 days after IMP administration at Visit 3 (self-administration at home), the 
investigator will confirm the execution status of self-administration at home and 


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compliance with the self-administration procedure recorded by the subject, perform the 
following assessments, and record the information in the eCRF (to be performed by 
Visit 4/End of Treatment at the latest).

Visit date

Execution status of self-administration at home

Date, time, injection site, confirmation of amount of drug solution 
remaining in the AI, and leakage of drug solution on the skin after 
subcutaneous injection

Occurrence of injection site reaction (erythema, induration, ecchymosis, 
and/or pain) and its severity (immediately after administration and at 1 hour 
postdose)

Compliance with self-administration procedure

Deficiency with the AI device

AEs

Blood sampling for plasma drug concentration measurement
1.3.2.5
Visit 4/End of Treatment or at Withdrawal 
As the final evaluation (Visit 4/End of Treatment), the following assessments, tests, and 
observations will be performed. For withdrawals, the following assessments, tests, and 
observations will be performed wherever possible within the acceptable window. The 
results of the assessments, tests, and observations will be recorded in the eCRF.

Visit date

Completion of trial

Trial completion date or withdrawal date

In the case of withdrawal, reason for withdrawal 

eDiary (Subject is to return the eDiary device.)

Vital signs (systolic and diastolic blood pressure, pulse rate, temperature, and 
respiratory rate) 

12-Lead ECG

Physical examination

Weight

Clinical laboratory tests

Chemistry, hematology, coagulation, and urinalysis

Urine hCG test (WOCBP only)

Blood sampling for serum ADA assessment

Blood sampling for plasma drug concentration measurement

C-SSRS (Since Last Visit Version)


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
Concomitant medications and therapies

AEs
1.3.3
Unscheduled Visits
An unscheduled visit may be performed at any time during the trial, at the subject’s 
request or as deemed necessary by the investigator, and assessments, tests, and 
observations will be performed. The date of the unscheduled visit and the results of the 
assessments, tests, and observations (only those performed according to the procedures 
specified in the protocol) will be recorded in the eCRF. Other procedures may be 
performed at the discretion of the investigator.
2
Introduction
TEV-48125 (generic name: fremanezumab) is a monoclonal antibody that potently and 
selectively binds to calcitonin gene-related peptide (CGRP). By blocking the binding 
activity of the CGRP receptor,1,2 TEV-48125 is expected to be effective in preventing 
migraine attacks and is currently undergoing clinical development.
Refer to the fremanezumab (TEV-48125) Investigator’s Brochure (IB) for more detailed 
information.
2.1
Trial Rationale
In foreign countries, based primarily on the results of 2 double-blind, placebo-controlled
trials (Trials TV48125-CNS-30049 and TV48125-CNS-30050) and a long-term trial 
(Trial TV48125-CNS-30051) in chronic and episodic migraine (CM and EM) conducted 
as multinational phase 3 trials evaluating the efficacy and safety of subcutaneous 
administration of TEV-48125 for the preventive treatment of migraine, use of 
TEV-48125 as a prefilled syringe (PFS) preparation capable of being self-administered 
was approved for the preventive treatment of migraine in the US in September 2018 and 
in the EU in March 2019. Regarding self-administration, in a foreign human factor 
validation study of a TEV-48125 autoinjector (AI) preparation, most of the participating
healthcare professionals, patients, and caregivers were able to use the AI appropriately 
according to the instructions, and in a post-study survey more than 80% of the 
participants reported that the AI was easy to use and that they could use it with 
confidence.3 Bioequivalence between the TEV-48125 AI preparation and the PFS 
preparation was then demonstrated in a bioequivalence study (TV48125-BE-10145), and 
registration applications for the AI preparation capable of self-administration as an 
additional fremanezumab preparation were filed in the US in March 2019 and in the EU 


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in May 2019. Those applications are currently under review in both regions as of 
September 2019.
In Japan, as of September 2019, as phase 2b/3 trials evaluating the efficacy and safety of 
subcutaneous administration of TEV-48125 for the preventive treatment of migraine, 2 
double-blind, placebo-controlled trials (Trials 406-102-00001 and 406-102-00002) and a 
long-term trial (Trial 406-102-00003) are being conducted using the PFS preparation (not 
intended for self-administration). Although Otsuka’s initial submission for approval of 
TEV-48125 is planned only for the PFS preparation (not intended for self-
administration), as there is a strong medical need for treatment by self-administration at 
home, an additional application for an AI preparation capable of self-administration (at 
home) is also being planned with the aim of increasing patient convenience.
The AI device to be used in the present trial is pre-filled with a single dose of 225 mg.
The drug is administered by removing the protective cap and pressing the AI against the 
skin at the injection site. The injection needle is concealed behind a shield, and when the 
AI is lifted away from the skin after injection the shield returns to its original position and 
the needle is again concealed, thus preventing accidental needle injury. This is the same 
mechanism as the device used in the foreign human factor validation study. 
Based on the above, it is considered appropriate to conduct the present trial to assess the 
safety of TEV-48125 when subcutaneously self-administered at home using an AI in 
Japanese migraine patients.
2.2
Background
Migraine is a recurrent headache disorder manifesting in attacks lasting 4 to 72 hours. 
The headaches are unilateral and/or pulsating and of moderate or severe intensity and 
aggravated by routine physical activity. Migraine attacks associated with nausea and/or 
photophobia and phonophobia4 are reported to impose a considerable burden on the daily 
and social lives of affected individuals.5,6,7 Migraine affects more than 10% of adults 
worldwide8 and in a 1997 nationwide survey of the population aged 15 years or older, the 
prevalence of migraine in Japan was reported to be 8.4%, with a female/male ratio of 3.6. 
The highest prevalence (approximately 20%) was in women age 30 to 39.9 In a treatment 
status survey of physicians conducted in 2019 by INTAGE Healthcare Inc, the number of 
migraine patients under medication in Japan was estimated to be 666,000.10
The prevalence of migraine in Japanese age 20 to 59, the majority of the school or 
working age population, is approximately 3% to 7% for males and 11% to 20% for 
females, with the highest prevalence in the 20 to 39 age groups.9 As the daily lives of 


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people in this age range are predominantly occupied by school, work, or housework, the 
need for long-term regular clinical visits for medication administration is a time and 
mental burden, and this burden may lead to decreased treatment adherence.11,12,13
Decreased adherence is generally considered to be one cause of poor disease control, and 
in migraine patients, insufficient treatment efficacy increases the risk of progression from 
EM to CM.14 This would suggest that there is strong medical need for treatment by self-
administration of TEV-48125 at home. From the perspective of treatment continuation, it 
is considered meaningful to minimize the number of clinical visits and alleviate the 
impact on daily life by adding self-administration of TEV-48125 using an AI as a 
treatment option tailored to patients’ lifestyles.
2.3
Known and Potential Risks and Benefits
Identified risks (adverse drug reactions) of TEV-48125 include injection site induration, 
injection site erythema, injection site pruritus, and injection site rash. Being a protein 
injection, there is a potential risk that TEV-48125 could cause severe hypersensitivity 
reactions such as type I hypersensitivity or allergic reaction and type III hypersensitivity
reaction. Neither anaphylaxis nor severe hypersensitivity reactions to TEV-48125 were 
reported in placebo-controlled, double-blind, phase 2b trials evaluating the efficacy and 
safety of subcutaneous administration of TEV-48125 (Trials LBR-101-021 and LBR-
101-022) and Trials TV48125-CNS-30049, TV48125-CNS-30050, and TV48125-CNS-
30051 in CM and EM patients. Likewise, these events did not occur in healthy subjects. 
Among all subjects who participated in placebo-controlled trials, 2 placebo-treated 
subjects (< 1%) and 2 TEV-48125-treated subjects (< 1%) experienced drug 
hypersensitivity (moderate and mild in severity in 1 subject each). Aside from these 
events, among all TEV-48125-treated subjects, 3 subjects experienced an adverse event
(AE) of drug hypersensitivity (moderate in 2 subjects and mild in 1 subject). All drug 
hypersensitivity events reported in this clinical development program were non-serious; 
they all resolved after corticosteroid and/or antihistamine therapies, with the outcome 
classified as recovery.
In efficacy evaluation in 2 completed phase 2b trials and 2 completed phase 3 trials 
conducted thus far, statistically significant and clinically meaningful improvement from 
baseline was demonstrated in TEV-48125-treated subjects vs placebo-treated subjects.
Based on the above safety profile and the demonstrated efficacy of subcutaneous 
TEV-48125 administration, the benefits of TEV-48125 are expected to outweigh the 
risks.


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Trial sites will receive updated versions of the IB, when available, and trial sites should 
refer to the most current version as needed.
3
Objectives and Endpoints
The primary objective is to assess the safety of TEV-48125 when subcutaneously self-
administered in Japanese migraine patients using an AI at home.
The primary endpoint of the trial is the occurrence of AEs, and the safety of the 
investigational medicinal product (IMP) will be assessed based on the occurrence of AEs. 
Other endpoints will include evaluation of the execution status of self-administration at 
home and subject compliance with the self-administration procedure, and an overall 
evaluation of the feasibility of self-administration of TEV-48125 at home. In addition, as 
the IMP is a combination product, any deficiencies with the AI device will also be 
evaluated.
As exploratory endpoints, efficacy parameters including the number of migraine days, the 
number of headache days, and the number of headache days of at least moderate severity
will be evaluated.
Table 3-1
Trial Objectives and Endpoints
Objectives
Endpoints
To assess the safety of TEV-48125 when 
subcutaneously self-administered in 
migraine patients at home
Primary Endpoint:

Safety (occurrence of AEs)
Other Endpoints:

Execution status of self-
administration at home

Subject compliance with the self-
administration procedure

Deficiencies with the AI device
Exploratory Endpoint:

Efficacy (number of migraine days, 
number of headache days, and 
number of headache days of at least 
moderate severity)
Section 9.4 describes the statistical analysis of the endpoints.


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4
Trial Design
4.1
Type/Design of Trial
This trial is a multicenter, open-label trial in migraine patients. The schematic of the trial 
design is shown in Figure 1.2-1 and trial assessment time points are summarized in Table 
1.3-1.
The trial will consist of a 4-week screening period and an 8-week treatment period.
After obtaining written informed consent from each subject, the investigator will screen 
the subject for eligibility (Visit 1/Screening). On each day during the screening and the 
treatment periods, subjects are to enter headache data in the eDiary provided for use in 
this trial.
By Visit 2/Baseline, the investigator will provide subjects who have been diagnosed with 
migraine and who meet all the inclusion criteria and do not fall under any of the 
exclusion criteria with sufficient instruction on self-administration using the “Procedure 
for TEV-48125 AI Self-administration.” At Visit 2/Baseline subjects for whom the 
investigator judges self-administration to be possible in compliance with the procedure 
will perform self-administration using the AI at the trial site under the supervision of the 
investigator.
The investigator will confirm whether the subject is able to perform self-administration in 
compliance with the procedure, and judge whether self-administration at home is 
possible. Subjects for whom the investigator judges self-administration at home to be 
possible will perform self-administration using the AI at home after performing protocol-
specified procedures at Visit 3. Subjects will be asked to visit the trial site for blood 
sampling for plasma drug concentration measurement at 3 to 10 days after IMP 
administration at Visit 2/Baseline and Visit 3. At 4 weeks after final IMP administration 
(self-administration at home) subjects will visit the trial site for the final evaluation (Visit 
4/End of Treatment). For subjects who are withdrawn from the trial, a withdrawal 
examination will be performed wherever possible.
4.2
Scientific Rationale for Trial Design
In order to apply for marketing approval of TEV-48125 in Japan as a drug that can be 
self-administered at home, it is necessary to demonstrate in a clinical trial that self-
administration of TEV-48125 using an AI at home can be performed without any 
problem in clinical practice in Japan. In an attempt to demonstrate the safety of self-
administration of TEV-48125 using an AI at home, the present trial will evaluate the 
safety of TEV-48125 based on the occurrence of AEs and comprehensively assess the 


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feasibility of self-administration of TEV-48125 using an AI at home by evaluating the 
execution status of self-administration at home and subject compliance with the self-
administration procedure. The trial will also assess any deficiencies with the AI device.
Currently, clinical trials of the PFS preparation of TEV-48125 (not intended for self-
administration) are ongoing in CM and EM patients. Once the trials demonstrate 
superiority of TEV-48125 to placebo, an application for marketing approval will be made 
for the indication of “preventive treatment of migraine” in patients with migraine (EM 
and CM). The planned target patients for self-administration of TEV-48125 using an AI 
are the same patients population enrolled in the trials using the PFS preparation. The 
present trial will therefore include male and female migraine patients (age 18 to 70 years, 
inclusive), who have a history of migraine (according to the International Classification 
of Headache Disorders, third edition [ICHD-3] criteriaa) or for whom clinical assessment
suggests a migraine diagnosis (not better accounted for by another ICHD-3 diagnosis) for 
≥12 months prior to giving informed consent, and who meet the inclusion criteria based 
on the baseline information collected during the 28-day screening period. In addition, as 
this trial is designed to evaluate efficacy in an exploratory manner, eligible subjects must 
have migraine attacks on ≥4 days during the screening period.
Considering the use for self-administration at home, it is appropriate that the subject 
should perform self-administration only after the investigator has given adequate training 
to the subject and only if it has been confirmed that the subject is able to perform self-
administration appropriately. In this trial, the investigator will first instruct the subject on 
the self-administration procedure, and then subjects will self-administer the initial dose of 
TEV-48125 using the AI under the supervision of the investigator at the trial site. Only 
subjects who are judged by the investigator to be able to perform self-administration at 
home according to the procedure will be allowed to subcutaneously self-administer the 
second dose of TEV-48125 using the AI at home.
In conclusion, the sponsor considered that this trial in Japanese migraine patients will be 
able to show the safety of self-administration using an AI at home.
4.3
Dosing Rationale
The dosing regimen in the trial is 225 mg of TEV-48125 administered once monthly (2 
doses in total). 
                                                
a Diagnosis in accordance with the International Classification of Headache Disorders, third 
edition (ICHD-3) diagnostic criteria (Headache Classification Committee of the International 
Headache Society 2018)


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Each AI to be used in the trial contains 225 mg/1.5 mL (150 mg/mL) of TEV-48125. The 
dose of TEV-48125 in the trial is 225 mg, which is the dosing unit.
The safety of TEV-48125 administered at 225 mg once monthly (except for an initial 
dose of 675 mg in CM subjects) was demonstrated in multinational phase 3 trials (Trials 
TV48125-CNS-30049 and TV48125-CNS-30050) in CM and EM patients (including 
Japanese patients), the data from which were included in the dossier submitted upon 
application for marketing approval in the EU and US. Therefore, administering the dose 
of 225 mg once monthly for 2 months is considered appropriate.
4.4
End of Trial Definition
The end of trial date is defined as the last date of contact or examination or the date of 
final contact attempt as recorded on the electronic case report form (eCRF) page for the 
last subject completing or withdrawing from the trial.
4.5
Definition of Completed Subjects
The treatment period is defined as the time period during which subjects are evaluated for 
primary and/or exploratory objectives of the trial irrespective of whether or not the 
subject actually subcutaneously self-administered all doses of the IMP. Subjects who are 
evaluated at the last scheduled visit during the treatment period will be defined as trial 
completers. For purposes of this trial, subjects who complete assessment at Visit 4/End of 
treatment will be defined as trial completers.
5
Trial Population
Migraine patients age 18 to 70 years, inclusive, who have a history of migraine (ICHD-3 
criteria [see Section 10.4]) or for whom clinical judgment suggests a migraine diagnosis 
(not better accounted for by another ICHD-3 diagnosis) for ≥12 months prior to giving 
informed consent.
Subjects who are using preventive migraine medications (see Table 6.5.2-1 List of 
Restricted Concomitant Medications (Preventive Migraine Medications)) will be 
permitted to continue using no more than 2 preventive migraine medications only if the 
dose and regimen have been stable for at least 2 months prior to screening examination 
(Visit 1/Screening).
5.1
Subject Selection and Numbering
After giving informed consent, subjects will be assigned a unique subject identification 
number (site number [3 digits] + S + subject number [5-digit in-site serial number]). The 
site number (3 digits) will be designated by the sponsor. The subject number (5-digit in-


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site serial number) will be given at each trial site in the chronological order informed 
consent is obtained in, starting at 00001. Following screening, subjects who fail to meet 
the eligibility criteria will be handled as screen failures. Trial sites will prepare and retain 
a list of all consented subjects and their subject identification numbers.
5.2
Eligibility Criteria
Exceptions for eligibility criteria will not be permitted by the investigator during the trial.
5.2.1
Inclusion Criteria
Subjects are required to meet the following inclusion criteria at the time points described
in the schedule of assessments (Table 1.3-1).
1) Males or females age 18 to 70 years, inclusive, at the time of informed consent
2) Patient with migraine onset at ≤50 years of age
3) Patient signs the informed consent document before start of the trial
4) Patient has a history of migraine (according to the ICHD-3 criteria) or clinical 
judgment suggests a migraine diagnosis (not better accounted for by another 
ICHD-3 diagnosis) for ≥12 months prior to giving informed consent.
5) Patient fulfills any of the following criteria on ≥4 days in baseline information 
collected during the 28-day screening period.

ICHD-3 diagnostic criteria C and D for 1.1 Migraine without aura (see 
Section 10.4)

ICHD-3 diagnostic criteria B and C for 1.2 Migraine with aura (see 
Section 10.4)

Probable migraine (a migraine subtype where only 1 migraine criterion is 
missing)

The patient used a triptan or ergot derivative to treat an established headache.
6) Not using preventive migraine medications (prohibited or restricted medications, 
see Table 6.5.1-1, List of Prohibited Concomitant Medications (Preventive 
Migraine Medications), and Table 6.5.2-1, List of Restricted Concomitant 
Medications (Preventive Migraine Medications)) for migraine or other medical 
conditions (ie, at least 5 half-lives have passed since last use) or using no more 
than 2 preventive migraine medications (restricted medications, see Table 6.5.2-1, 
List of Restricted Concomitant Medications (Preventive Migraine Medications)) 
for migraine or other medical conditions (eg, propranolol used for hypertension) if 
the dose and regimen have been stable for at least 2 months prior to screening 
examination (Visit 1/Screening).
7) Body mass index (BMI) between 17.5 to 37.5 kg/m2 and a total weight between 
35.0 and 120.0 kg, inclusive
8) Patient demonstrates compliance with the electronic headache diary (eDiary) 
during the screening period by entry of headache data on a minimum of 24 of 


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28 days (≥85% diary compliance) and the entered data is judged appropriate by 
the investigator.
9) At the time of informed consent, patient whom the investigator judges fit for self-
administration of the IMP
10) Patient is willing and able to comply with trial restrictions and to remain at the 
trial site for the required duration, as specified in this protocol.
[Rationales for inclusion criteria]
1), 6), 8), and 10): These criteria were set to appropriately evaluate efficacy and safety.
2), 4), and 5): These criteria were set to identify patients with migraine.
3): This criterion was set to ensure conduct of the trial in an ethically appropriate manner.
7) and 9): These criteria were set to ensure appropriate and safe administration of the 
IMP.
5.2.2
Exclusion Criteria
Subjects will be excluded if they meet any of the following exclusion criteria at the time 
points described in the schedule of assessments (Table 1.3-1).
1) Patient has received onabotulinumtoxin A for migraine or for any medical or 
cosmetic reason requiring injection in the head, face, or neck within 4 months 
prior to Visit 1/Screening.
2) Patient is using medication containing opioids (including codeine) or barbiturates 
(including butalbital/aspirin/caffeine, butalbital/paracetamol/caffeine, or any other 
combination containing butalbital) on more than 4 days during the screening 
period for the treatment of migraine or for any other reason.
3) Patient has used an intervention/device (eg, scheduled nerve blocks or transcranial 
magnetic stimulation) for migraine within 2 months prior to Visit 1/Screening.
4) Patient suffers from unremitting headaches, defined as having headaches for more 
than 80% of the time that he/she is awake, and less than 4 days without headache 
per month. Daily headache is acceptable if the patient has headaches 80% or less 
of the time they are awake on most days.
5) Hematological, cardiac, renal, endocrine, pulmonary, gastrointestinal, 
genitourinary, neurologic, hepatic, or ocular disease considered clinically 
significant in the judgment of the investigator
6) Evidence or medical history of clinically significant psychiatric issues, including 
any suicide attempt in the past, or suicidal ideation with a specific plan in the past 
2 years
7) History of cardiovascular disease or vascular ischemia (such as myocardial, 
neurological [eg, cerebral ischemia], or peripheral extremity ischemia, or other 
ischemic event) or thromboembolic events (arterial or venous thrombotic or 


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embolic events), such as cerebrovascular accident (including transient ischemic 
attacks), deep vein thrombosis, or pulmonary embolism, considered clinically 
significant in the judgment of the investigator
8) Known infection or history of human immunodeficiency virus (HIV), 
tuberculosis, or hepatitis B virus (HBV) or hepatitis C virus (HCV) infection
9) Past or current history of cancer in the past 5 years, except for appropriately 
treated skin carcinoma other than malignant melanoma
10) History of hypersensitivity reactions to injected proteins, including monoclonal 
antibodies
11) Participation in a clinical trial of another drug or medical device within 2 months 
or 5 half-lives of the other drug, whichever is longer, prior to IMP administration 
in the present trial
12) Prior exposure to a monoclonal antibody targeting the CGRP pathway meeting 
the following conditions:

Less than 5 months has passed since the final administration of AMG334,
LY2951742, or ALD403.

Less than 1 year has passed since the final administration of TEV-48125 
(PFS). (Even if 1 year has passed since the final administration, patient cannot 
be enrolled if assessment of anti-drug [TEV-48125] antibody [ADA] due to 
the previous administration is positive or inconclusive.)
13) Any finding in the screening or baseline 12-lead electrocardiogram (ECG)
considered clinically significant in the judgment of the investigator
14) Any finding that, in the judgment of the investigator, is a clinically significant 
abnormality, including in chemistry, hematology, coagulation, and urinalysis test 
values
15) Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline 
phosphatase (ALP) more than 1.5 × the upper limit of the normal range (ULN) 
after confirmation in a repeat test or suspected hepatocellular damage that fulfills 
criteria for Hy’s law at screening
16) Serum creatinine more than 1.5 × ULN, clinically significant proteinuria, or 
evidence of renal disease at screening
17) History of alcohol or drug abuse during the past 2 years, or alcohol or drug 
dependence during the past 5 years
18) Females who are breast-feeding at the time informed consent is obtained and/or 
who have a positive pregnancy test result at screening or baseline
19) Sexually active males or females of childbearing potential (FOCBP) who do not 
agree to practice 2 different methods of birth control or remain abstinent during
the trial and for 225 days after the final dose of IMP. If employing birth control, 2 
of the following precautions must be used: vasectomy, tubal ligation, intrauterine 
device, oral contraceptive, condom (all of which are approved or certified in 
Japan).
20) The patient cannot participate or successfully complete the trial for other reasons 
in the opinion of the investigator.


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A definition of childbearing potential can be found in Section 10.3.
Subjects must agree to restrictions to medications described in Section 6.5.1 and
Section 6.5.2.
[Rationales for exclusion criteria]
1) through 4): These criteria were set to appropriately evaluate efficacy.
5) through 9), 11), 17), and 20): These criteria were set to appropriately evaluate efficacy 
and safety.
10) and 13) through 16): These criteria were set to appropriately evaluate safety.
12): This criterion was set in consideration of the potential effect on the measurement of 
blood concentration of the drug.
18) and 19): These criteria were set because the safety of the IMP in pregnant or nursing 
females had not been established.
5.3
Lifestyle Considerations
Not applicable.
5.3.1
Meals and Dietary Restrictions
Not applicable.
5.3.2
Caffeine, Alcohol, and Tobacco
Not applicable.
5.3.3
Activity
Not applicable.
5.4
Screen Failures
A screen failure is a subject from whom informed consent is obtained and who signs an 
informed consent form (ICF), but who is judged to be ineligible based on the inclusion 
and exclusion criteria.
If the subject meets the definition of a screen failure in this trial, the following 
information will be recorded in the eCRF:

Date of informed consent

Visit date (screening visit)


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
Demographics (collection date, birth date, sex, race, ethnicity, country)

Height and weight

eDiary

Result of eligibility assessment

Screen failure date

Reason for screen failure
Subjects who sign an ICF but who are judged to be ineligible based on the inclusion and 
exclusion criteria are permitted to be re-screened. In the event that the subject is re-
screened for trial participation, a new ICF must be signed, and a new subject 
identification number must be assigned to the subject prior to performing the rescreening 
examination.
6
Trial Treatments
6.1
Trial Treatments Administered
In this trial, each subject will subcutaneously self-administer TEV-48125 at 
225 mg/1.5 mL (150 mg/mL) once monthly for a total of 2 doses. The first dose will be 
self-administered at the trial site under the supervision of the investigator and the second 
dose will be self-administered at home. The injection site may be the back of the upper 
arm, the abdomen, or the front of the thigh. To the extent possible, the injection site 
should be the same for both doses (but not exactly in the same location).
Prior to administration, the IMP is to be removed from the refrigerator and left to stand at 
room temperature for 30 minutes. The IMP can be used for up to a cumulative total of 8
hours after it has reached room temperature.
For the self-administration procedure and the treatment period, see Section 4.1.
6.1.1
Visit 2/Baseline: Self-administration at the Trial Site

By Visit 2/Baseline, the investigator will instruct the subject on self-
administration via the AI using the “Procedure for TEV-48125 AI Self-
administration.”

Using a check sheet, the investigator will determine whether self-administration at 
the trial site is possible.

Subjects for whom the investigator judges self-administration to be possible will 
perform self-administration at the trial site under the supervision of the 
investigator.

Using a check sheet, the investigator will confirm the execution status of self-
administration, the subject’s compliance with the self-administration procedure, 


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and any deficiencies with the AI device, and judge whether self-administration at 
home is possible.
6.1.2
Visit 3: Self-administration at Home

When the subject visits the trial site for Visit 3, the investigator will instruct the 
subject on IMP handling and the self-administration procedure and use a check 
sheet to reconfirm that self-administration at home is possible.

Subjects for whom the investigator judges self-administration at home to be 
possible will perform self-administration at home according to the “Procedure for 
TEV-48125 AI Self-administration.”

After self-administration at home the subject will use a check sheet to record the 
execution status of self-administration at home, compliance with the procedure 
for self-administration, any injection site reaction, and any deficiencies with the 
AI device, and submit the check sheet to the investigator at the next trial site visit.

When the subject visits the trial site for PK blood sampling (PK visit 2), the 
investigator will review the check sheet recorded by the subject and conduct an 
interview to confirm the execution status of self-administration at home, the 
subject’s compliance with the self-administration procedure, and any deficiencies 
with the AI device.
6.1.3
Information Regarding Trial Treatment Administration
The investigator will record the date and time of IMP self-administration and the 
injection site in the eCRF. The amount of drug solution remaining in the AI and any 
leakage of drug solution on the skin after subcutaneous injection will be recorded based 
on the following criteria, as information regarding the amount of IMP administered.
[Amount of drug solution remaining in the AI]
Check the plunger viewing window to confirm whether or not all of the drug solution has 
been injected and select the appropriate description of the amount of drug solution 
remaining from the following 0 to 4.
0 All drug solution has been injected
1 Approximately 1/4 of the drug solution remaining
2 Approximately 1/2 of the drug solution remaining
3 Approximately 3/4 of the drug solution remaining
4 Almost all of the drug solution remaining


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[Leakage of drug solution on the skin after subcutaneous injection]
Observe the injection site for any leakage of the drug solution and select the appropriate 
description from the following 0 to 4.
0 No sign of drug solution on the skin
1 Slight wetness on the skin (mist)
2 Approx. 1/5 (0.3 mL) of the drug solution observed on the skin (most of the drug 
solution subcutaneously administered)
3 Approx. 1/2 (0.75 mL) of the drug solution observed on the skin (ie, approx. 1/2 
of drug solution subcutaneously administered)
4 Almost all of the drug solution observed on the skin (ie, little or no drug solution 
subcutaneously administered)
If any deficiencies are found with the AI device provided to the subject, the following 
information are to be recorded in the eCRF.
[Status of problem with AI device] 

Description of problem

Date on which problem was observed

Lot No.

Whether or not self-administration was performed using this AI device

Occurrence of any AEs related to the deficiency with the AI device
Any deficiencies with the AI device should be reported as specified in Section 6.2.5
“Reporting of Product Quality Complaints.”
6.1.4
Medical Devices
In this trial, the injector prefilled with TEV-48125 (combination product of TEV-48125 
and AI) will be handled as the IMP. The administration method is described in 
Section 6.1, Trial Treatments Administered.
6.2
Management of Investigational Medicinal Product
For full details on IMP management, please refer to the fremanezumab (TEV-48125) IB.
The IMP is a combination product. Each AI for single-use administration contains 
TEV-48125 225 mg/1.5 mL (150 mg/mL).


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The investigator will provide the IMP only to the subjects considered able to perform 
self-administration at home and instruct them on how to handle the IMP according to the 
protocol-specified procedure.
Unused IMPs will be collected by the sponsor and used IMPs will be discarded at the trial 
site.
6.2.1
Packaging and Labeling
The IMP will be provided to the person in charge of IMP management (IMP manager) by 
the sponsor or designated agent. The IMP will be supplied as packages each containing 
one AI prefilled with TEV-48125. Each package used in the dosing period will be labeled 
to clearly disclose the compound code, protocol number, sponsor’s name and address, 
instructions for use, route of administration, and appropriate precautionary statements.
6.2.2
Storage
The IMP will be stored in a securely locked cabinet or enclosure. Access will be limited 
to the IMP manager. 
The IMP will be stored at 2°C to 8°C, protected from light.
The clinical site staff will maintain a temperature log in the IMP storage area to record 
the temperature.
For self-administration at home, the subject will take home the IMP in a cool bag and 
store it in the refrigerator, avoiding freezing.
6.2.3
Accountability
The IMP manager must maintain an inventory record of IMP received, dispensed, 
administered, and returned. The IMP manager must not provide the IMP to any subject 
not participating in this protocol.
6.2.4
Returns and Destruction
Subjects must return unused or used IMP to the trial site.
Upon completion or termination of the trial, all unused IMP must be returned to the 
sponsor or a designated agent. All IMP returned to the sponsor must be accompanied by 
the appropriate documentation and be clearly identified by protocol number and trial site 
number on the outermost shipping container. All IMP to be returned should be in the 
original containers. The assigned trial monitor will facilitate the return of unused IMP.


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6.2.5
Reporting of Product Quality Complaints
A Product Quality Complaint (PQC) is any written, electronic, or verbal communication 
by a healthcare professional, consumer, subject, medical representative, Competent 
Authority, regulatory agency, partner, affiliate or other third party that alleges 
deficiencies or dissatisfaction related to identity, quality, labeling, packaging, reliability, 
safety, durability, tampering, counterfeiting, theft, effectiveness, or performance of a drug 
product or medical device after it is released for distribution. Examples include, but are 
not limited to, communications involving:

Malfunction/failure of a product to meet any of its specifications

Incorrect or missing labeling

Packaging issues (eg, damaged, dirty, crushed, missing product)

Syringe defects

Product defect (eg, odor, chipped, broken, embossing illegible)

Loss or theft of product
6.2.5.1
Eliciting and Reporting Product Quality Complaints
The investigator or designee must record all PQCs identified through any means from the 
receipt of the IMP from the sponsor or sponsor’s designee, through and including 
reconciliation and up to destruction, including subject dosing. The investigator or 
designee must notify the sponsor (or sponsor’s designee) (destination’s e-mail address:
IRE_PQC_406-102-00005@otsuka.jp) by e-mail immediately after becoming aware of 
the PQC of the information indicated in Section 6.2.5.2, Information Required for 
Reporting Product Quality Complaints.
Identification of a PQC by the subject should be reported to the site investigator, who 
should then follow one of the reporting mechanisms above.
PQCs relating to the occurrence of or the risk of causing a serious adverse event due to 
deficiency with the AI device will be handled as immediately reportable events (IREs) in 
accordance with Section 8.9.3, Immediately Reportable Events, and only PQCs relating 
to the occurrence of a serious adverse event will be handled in accordance with
Section 8.9.2, Eliciting and Reporting Adverse Events.
A deficiency with the AI device (AI device deficiency) is defined as any defect in the 
quality, safety, or performance of the device, such as mechanical breakage and 
malfunction, no matter whether it is caused by design, manufacture, dispensing, storage, 
or use.


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6.2.5.2
Information Required for Reporting Product Quality Complaints

Description of complaint

Reporter identification (eg, subject, investigator, site, etc.)

Reporter contact information (eg, address, phone number, e-mail address)

Identifier of material (product/compound name, lot number)

Clinical protocol reference (number and/or trial name)

Dosage form/strength (if known)

Pictures (if available)

Availability for return of the complaint sample
6.2.5.3
Return Process in Reporting Product Quality Complaints
Indicate during the report of the PQC if the complaint sample is available for return. The 
sponsor may indicate the procedure for returning the sample, as appropriate.
It must be documented in the site accountability record that a complaint sample for a 
dispensed kit has been forwarded to the sponsor for complaint investigation.
6.2.5.4
Assessment/Evaluation
Assessment and evaluation of PQCs will be handled by the sponsor.
6.3
Measures to Minimize/Avoid Bias
This is an open-label trial.
6.4
Subject Compliance
Prior to performing self-administration at the trial site and home, the subject will be given 
instructions on the self-administration procedure by the investigator using “Procedure for 
TEV-48125 AI Self-administration.” The subject must fully understand the procedure 
before performing self-administration according to the “Procedure for TEV-48125 AI 
Self-administration.” After self-administration at home, the subject will use a check sheet 
to record the execution status of self-administration at home, any injection site reaction
and its severity, compliance with the self-administration procedure, and any deficiencies 
with the AI device, and submit the check sheet to the investigator at the next trial site 
visit.
The subject will appropriately store the IMP according to the storage method specified in 
“Procedure for TEV-48125 AI Self-administration.” In the event that the IMP has not 
been stored as specified or any IMP defect has been found, the subject will promptly 
notify the person in charge at the trial site and will be given an instruction about how to 


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deal with the situation, such as replacing the IMP. If the subject decides to change the 
scheduled date of self-administration, the subject will promptly notify the investigator.
6.5
Concomitant Medications or Therapies
The investigator will record all medications and therapies taken by the subject from 5 
months before the start of IMP administration (Visit 2/Baseline) through the end of the 
evaluation period (defined as the time period during which subjects are evaluated for 
primary and exploratory objectives) on the eCRF. 
For concomitant medications, the following will be recorded in the eCRF: medication
name, purpose of use, dose per administration, frequency, route of administration, start 
date and end date of administration. For concomitant therapy, the following will be 
recorded in the eCRF: therapy name, purpose of use, start date and end date.
Subjects will be allowed to use acute headache medication only at the time of occurrence 
of a headache attack, as needed, but will not be allowed to use it as preventive 
medication.
Use of other medications that belong to the same classes as those of prohibited or 
restricted medications but are not included in Table 6.5.1-1 or Table 6.5.2-1 are allowed.
6.5.1
Prohibited Medications (Preventive Migraine Medications)
Use of any preventive migraine medications other than the IMP (see Table 6.5.1-1) will 
be prohibited.
Table 6.5.1-1
List of Prohibited Concomitant Medications (Preventive 
Migraine Medications)
Drug Class
Drug Name
Remarks
Antiepileptic medications
Carbamazepine
Angiotensin receptor blockers/
angiotensin converting enzyme 
inhibitors
Candesartan and lisinopril
Onabotulinumtoxin A
Botox
Triptans/ergot derivatives
Any drug in this class
Should not be used as 
preventive therapy for 
migraine
NSAID
Any drug in this class
Should not be used as 
preventive therapy for 
migraine or on a daily basis 
for other indications
NSAID = nonsteroidal anti-inflammatory drug.
Any of the medications listed above are allowed if given as a topical preparation or eye 
drops.


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6.5.2
Restricted Concomitant Medications (Preventive Migraine 
Medications)
Subjects will be allowed to use no more than 2 concomitant preventive migraine 
medications (see Table 6.5.2-1) at a stable dose and regimen during the trial if the 
medications were previously prescribed for migraine or for another indication. However, 
such subjects on preventive medication must be on a stable dose and regimen for at least 
2 months of consecutive use prior to screening examination (Visit 1/Screening). Subjects 
will be allowed to discontinue the use of preventive medication if discontinuation is 
considered clinically necessary by the investigator (for reasons such as they are no longer 
needed or they are associated with safety concerns).
In principle, use of medicines (including Chinese herbal medicines) or supplements that 
are regarded as effective for preventing migraine will be allowed if they were previously
used before screening examination (Visit 1/Screening). Subjects on such medicines or 
supplements should be on a stable dose and regimen in so far as possible.
Table 6.5.2-1
List of Restricted Concomitant Medications (Preventive 
Migraine Medications)
Drug Class
Drug Name
Beta-blockers
Atenolol, propranolol, metoprolol, nadolol, and timolol
Calcium channel blocker
Lomerizine
Antidepressants
Amitriptyline, venlafaxine, nortriptyline, and duloxetine
Antiepileptic medications
Topiramate and valproate
Any of the medications listed above are allowed irrespective of restriction conditions if 
given as a topical preparation or eye drops.
6.5.3
Prohibited Concomitant Therapies
Use of an intervention/device (eg, scheduled nerve blocks and transcranial magnetic 
stimulation) for treating migraine will be prohibited.
6.5.4
Rescue Medications
Not applicable.
6.6
Intervention after the End of the Trial
Not applicable.


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7
Stopping Rules, Withdrawal Criteria, and Procedures
7.1
Entire Trial or Treatment
If the sponsor decides to terminate or suspend the trial for any reason, prompt notification 
will be given to the head of the trial site and regulatory authorities in accordance with 
regulatory requirements.
7.2
Individual Site
Individual trial site participation may be discontinued by the sponsor, the investigator, or 
the institutional review board (IRB) if judged to be necessary for medical, safety, 
regulatory, ethical or other reasons consistent with applicable laws, regulations, and Good 
Clinical Practice (GCP). The head of the trial site will notify the sponsor promptly if the 
trial is terminated by the investigator or the IRB at the site.
7.3
Individual Subject Discontinuation
7.3.1
Treatment Interruption
Not applicable.
7.3.2
Treatment Discontinuation
After being enrolled in the trial following eligibility assessment based on the inclusion 
and exclusion criteria, a subject may stop treatment permanently for a variety of reasons. 
Treatment discontinuations may be initiated by a subject who is not satisfied with 
treatment or may become medically necessary due to AEs, required treatment with a 
disallowed medication or therapy, or other issues, as determined by the investigator. 
However, each investigator must comprehensively review the circumstances and offer the 
subject options for continuing his/her trial participation wherever possible as described in 
Section 7.3.5, Procedures to Encourage Continued Trial Participation.
If any of the following withdrawal criteria is met and it is decided to discontinue 
treatment for a subject, the withdrawal examination specified in Section 1.3.2.5, Visit 
4/End of Treatment or at Withdrawal, will be performed, and the date and reasons for 
discontinuation (see Section 7.3.3, Documenting Reasons for Treatment Interruption or 
Discontinuation) will be recorded in the source documents and eCRF.
1) The subject’s (or the subject’s legal representative if he/she is a minor) requests 
withdrawal
2) Occurrence of an AE making continuation of IMP administration difficult
3) The subject meets any of the discontinuation criteria specified in the Guidance on 
Safety Monitoring (see Section 10.5).


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4) The subject is unable to perform self-administration as determined by the 
investigator.
5) The subject is found not to have met one or more of the inclusion criteria or to 
have fallen under any of the exclusion criteria.
6) A significant deviation relating to IMP administration
7) A female subject becomes pregnant, or is suspected of being pregnant, or desires 
to become pregnant (see Section 10.3).
8) Other cases where the investigator thinks that the subject should discontinue 
treatment for reasons such as a difficulty in complying with the protocol
7.3.3
Documenting Reasons for Treatment Interruption or 
Discontinuation
If any of the following criteria is met and it is decided to discontinue a subject’s 
treatment, the investigator will perform the withdrawal examination specified in 
Section 1.3.2.5 and record the date and following reasons for discontinuation in the 
source documents and eCRF:

The subject’s (or the subject’s legal representative if he/she is a minor) requests 
withdrawal

AE

Subject decides to discontinue because of annoyance or discomfort due to a 
nonserious AE which is not otherwise determined to be an undue hazard.

Continuing IMP administration places the subject at undue risk as determined by 
the investigator (eg, a safety concern that is possibly, probably, or likely related to 
the IMP).

The subject meets any of the discontinuation criteria specified in the Guidance on
Safety Monitoring (see Section 10.5).

The subject is unable to perform self-administration as determined by the 
investigator.

Prior to Visit 2/Baseline (self-administration at the trial site), the investigator 
decides that the subject is unable to perform self-administration as specified in the 
procedure.

Following Visit 2/Baseline (self-administration at the trial site), the investigator 
decides that the subject is unable to perform self-administration at home as 
specified in the procedure.

Protocol deviation

The subject is found not to have met one or more of the inclusion criteria or to 
have fallen under any of the exclusion criteria.

Noncompliance with IMP administration (including a failure to self-administer 
the IMP at home within the acceptable window for treatment)

Site terminated by sponsor


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
Study terminated by sponsor

Deficiency with the AI device

Lost to follow-up

Pregnancy (see Section 10.3)

Other
If the subject discontinues IMP administration due to an AE, the investigator, or other 
trial personnel, will make every effort to follow the event until it has resolved or 
stabilized. Follow-up procedures in Section 7.3.2, Treatment Discontinuation, must be 
followed.
7.3.4
Withdrawal of Consent or Assent
All subjects have the right to withdraw their consent from further participation in the trial 
at any time without prejudice. Subjects cannot withdraw consent for use of data already 
collected as part of the trial, but only for future participation. The investigator can also 
discontinue a subject’s participation in the trial at any time if medically necessary. Unless 
the subject provides their written withdrawal of consent or there is other written 
documentation by the investigator confirming the subject’s verbal intent to completely 
withdraw from the trial, subjects should be followed for all protocol-specified evaluations 
and assessments, if possible.
Complete withdrawal of consent requires a subject’s refusal of ALL of the following 
methods of follow-up:

Participation in all follow-up procedures specified in the protocol (whether in-clinic, 
by telephone, or by an in-home visit).

Participation in a subset of protocol-specified follow-up procedures (a part of follow-
up procedures for which the subject withdraws his/her permission, as agreed by 
subject and trial personnel).

Contact of the subject by trial personnel, even if only by telephone, to assess current 
medical condition, and obtain necessary medical or laboratory reports relevant to the 
trial’s objectives.

Contact of alternative person(s) who have been designated in source records as being 
available to discuss the subject’s medical condition, even if only by telephone, mail, 
or e-mail (eg, family, spouse, partner, legal representative, friend, neighbor, or 
physician).

Access to medical information from alternative sources (eg, hospital/clinic medical 
records, referring doctor’s notes, public records, dialysis, transplantation or vital 
registries, social media sources).


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Withdrawal of consent is a critical trial event and, therefore, should be approached with 
the same degree of importance and care as is used in initially obtaining informed consent. 
The reasons for a subject’s intended withdrawal need to be completely understood, 
documented, and managed to protect the rights of the subject and the integrity of the trial. 
A subject may initially express their desire to discontinue IMP administration, which is 
not equivalent to a complete withdrawal of consent for further participation (see 
Section 7.3.2, Treatment Discontinuation). A subject may, however, indicate that further 
trial participation is creating a burden on their work, school, or social schedule. 
Therefore, the investigator should follow the procedures outlined in Section 7.3.3, 
Documenting Reasons for Treatment Interruption or Discontinuation, to determine if the 
subject can continue participation in the trial if modifications to his/her treatment and/or 
schedule of assessments can be accommodated. Only subjects who withdraw their 
permission for all of the above methods of follow-up are considered to have completely 
withdrawn their consent to participate in the trial.
7.3.5
Procedures to Encourage Continued Trial Participation
In all cases of impending IMP discontinuation or consent withdrawal, investigators will 
be instructed to meet and discuss with the subject their options of continuing in the trial, 
preferably on therapy. The investigator should ensure understanding and document the 
reasons for the subject subject’s desire to withdraw consent.
7.4
Definition of Subjects Lost to Follow-up
Subjects who cannot be contacted on or before Visit 4/End of treatment during the 
treatment period, who do not have a known reason for discontinuation (eg, withdrew 
consent or AE), and for whom survival status at the end of the trial cannot be determined 
will be classified as “lost to follow-up.” Survival status can be determined from a variety 
of sources, either by obtaining acceptable documentation for death (ie, death certificate, 
medical records, public records, statement by a family member or primary care 
physician) or acceptable documentation for life (ie, direct contact with the subject, 
medical records, successful telephone contact with the subject, statement by a family 
member or primary care physician, or public records).
The trial site will make 3 documented attempts to contact the subject by telephone and in 
the event the site is unable to reach the subject by telephone, the site will attempt to 
contact the subject via certified mail or an alternative similar method, where appropriate, 
before assigning a “lost to follow-up” status.


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If the subject is classified as “lost to follow-up,” “Were you able to contact the subject?,” 
“Date of contact/Date of final contact attempt,” and “Contact method” will be recorded in 
the source documents and eCRF.
8
Trial Procedures
The assessments to be conducted during the trial are summarized in Section 1.3, Schedule 
of Assessments.
8.1
Efficacy Assessments
Efficacy parameters will be evaluated, as exploratory endpoints, based on the following 
headache information collected from the eDiary:

Number of migraine days

Number of headache days

Number of headache days of at least moderate severity
8.2
Pharmacokinetic Assessments
For safety reasons, this trial will analyze plasma drug concentrations after self-
administration for a marked decrease or increase.
8.2.1
Plasma Drug Concentrations
Blood samples (6 mL) will be collected via venipuncture in vacutainers containing 
dipotassium ethylenediaminetetraacetic acid (EDTA) and processed into plasma to 
determine the concentrations of TEV-48125. Additional metabolites that are not 
identified in the protocol may also be analyzed, if needed. In addition, samples for 
determination of drug concentrations may be used for the investigation of a bioanalytical 
method, if needed.
Blood samples for determination of drug concentrations will be collected at the time 
points as shown in Table 1.3-1 (schedule of assessments).
Blood sampling status for determination of drug concentrations and the actual date and 
time of blood sampling will be recorded in the eCRF. The results of measurements will 
be reported directly to the sponsor from the bioanalytical laboratory; therefore, recording 
of the results in the eCRF is not needed.
After processing into plasma, aliquots will be placed into appropriately labeled tubes and 
will be placed in a freezer set at −70°C or −20°C, unless otherwise instructed in the 
Operations Manual.


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Plasma samples will be shipped to the bioanalytical laboratory for analysis. Additional 
information will be provided in the Operations Manual.
8.3
Immunogenicity Assessments
8.3.1
Serum Samples for Immunogenicity Assessments
Blood samples (5 mL) will be collected via venipuncture in vacutainers not containing 
anticoagulant (but containing procoagulant) and processed into serum to analyze ADA.
Blood samples for immunogenicity assessment will be collected at the time points as 
shown in Table 1.3-1 (schedule of assessments).
Blood sampling status for immunogenicity assessment and the actual date and time of 
blood sampling will be recorded in the eCRF. The results of analysis will be reported 
directly to the sponsor from the ADA analytical laboratory; therefore, recording of the 
results in the eCRF is not needed.
After processing into serum, aliquots will be placed into appropriately labeled tubes and 
will be placed in a freezer set at −70°C or −20°C, unless otherwise instructed in the 
Operations Manual.
Serum samples will be shipped to the ADA analytical laboratory for analysis. Additional 
information will be provided in the Operations Manual.
8.4
Pharmacodynamic Assessments
Not applicable.
8.5
Pharmacogenomic Assessments
Not applicable.
8.6
Biomarker Assessments
Not applicable.
8.7
Future Biospecimen Research Samples
Not applicable.
8.8
Safety Assessments
8.8.1
Adverse Events
In this trial, AEs related to TEV-48125 as well as those related to the AI device (ie, AEs
attributable to device manipulation during self-administration or to the AI device itself) 
will be collected.


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Details pertaining to the definitions, collection, reporting, and follow-up of AEs are 
described in Section 8.9, Adverse Events.
8.8.2
Clinical Laboratory Assessments
Clinical laboratory samples will be collected at the time points described in the schedule 
of assessments (Table 1.3-1) to perform the clinical laboratory assessments. The total 
volume of blood to be collected for each subject is 87 mL, including 15 mL (5 mL × 3) 
for serum ADA assessment and 24 mL (6 mL × 4) for determination of plasma drug 
concentrations in addition to blood samples for clinical laboratory tests.
All clinical laboratory tests in this trial, excluding urine hCG tests, will be performed 
using the central laboratory selected by the sponsor. The investigator will assess the 
eligibility of each subject based on clinical laboratory values measured by the central 
laboratory. 
Any additional clinical laboratory tests, if required apart from those performed at 
scheduled time points of blood/urine collection for reasons such as AEs, will also be 
performed by the protocol-specified central laboratory. Samples will be collected, treated, 
stored, and shipped as described in a separate operational procedure. 
For WOCBP, a urine or serum pregnancy test (hCG test) will be performed. If a urine test 
at screening is positive, an hCG test will be performed with a serum sample collected for 
biochemistry during screening.
The central laboratory will report clinical laboratory test results to the investigator, who
will then review the results promptly and date and sign the clinical laboratory test report 
as an official document. The date and time of blood/urine collection and whether during 
menses or not will be recorded in the eCRF. The results of clinical laboratory tests, 
excluding urine hCG tests, will be reported directly to the sponsor from the central 
laboratory via electronic file transfer; therefore, recording of the results in the eCRF is 
not needed. The results of urine hCG tests will be recorded in the eCRF.
8.8.3
Physical Examination
Physical examinations will be performed at the time points described in the schedule of 
assessments (Table 1.3-1). In the physical examination, the following organ systems will 
be assessed/observed: general appearance; head, eyes, ears, nose, and throat; chest and 
lungs; heart; abdomen; musculoskeletal; skin; lymph nodes; and neurological. Physical 
examinations of individual subjects will be performed by the same site personnel in so far 
as possible. On the eCRF, the date and results of assessments will be recorded at 
Visit 1/Screening, and only the date of assessments will be recorded at Visit 2/Baseline 


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and subsequent visits. Any clinically significant physical finding that is not observed at 
Visit 1/Screening but seen at Visit 2/Baseline or any later visit will be considered an AE, 
recorded in the source documents and eCRF, and monitored until its outcome has been 
sufficiently evaluated.
8.8.4
Vital Signs
Vital signs will be collected at the time points described in the schedule of assessments 
(Table 1.3-1). Before blood pressure and pulse rate are measured, subjects must remain at 
rest in a sitting, supine, or standing position for at least 5 minutes. Subjects should be 
monitored for potentially clinically significant vital sign values. Date of measurement, 
body position, body part, systolic and diastolic blood pressures (integer; mmHg), pulse 
rate (integer; beats/min), temperature (up to one decimal place; °C), and respiratory rate 
(integer; breaths/min) will be recorded in the eCRF. Any vital sign value, excluding 
temperature, which is measured up to one decimal place or more will be rounded to the
closest whole number, and any temperature value measured up to more than one decimal 
place will be rounded to one decimal place.
8.8.5
Electrocardiogram
Electrocardiograms will be performed at the time points described in the schedule of 
assessments (Table 1.3-1). Electrocardiograms will be performed with a 12-lead ECG
provided by the sponsor-selected central laboratory after the subject has rested in a supine 
position for at least 5 minutes. Electrocardiograms will be measured and transmitted to
the protocol-selected central laboratory in accordance with a separate operational 
procedure. Any unscheduled ECGs must also be transmitted to the designated central 
laboratory. The central laboratory will report interpretations to the investigator, who will 
then review the interpretations promptly and date and sign the ECG report as an official 
document.
The investigator will clinically assess the ECG results. Subjects should be monitored for 
potentially clinically significant ECG results. The date of ECG measurement and the 
investigator’s interpretation will be recorded in the eCRF. The central ECG results and 
interpretations will be reported directly to the sponsor from the central laboratory via 
electronic file transfer; therefore, recording of the results and interpretations in the eCRF 
is not needed.


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8.8.6
Suicidality Monitoring
8.8.6.1
Columbia-Suicide Severity Rating Scale
Suicidality monitoring will occur at the time points described in the schedule of 
assessments (Table 1.3-1). The Columbia-Suicide Severity Rating Scale (C-SSRS) will 
be used to assess the subject’s suicidal ideation/suicidal behavior, intensity, and 
frequency. This scale consists of the C-SSRS Baseline Version, which assesses a lifetime
history of suicide-related events and suicidal ideation, and the C-SSRS Since Last Visit 
Version, which focuses on suicidality since the last visit (see Section 10.6 and 
Section 10.7). The C-SSRS Baseline Version will be completed at Visit 2/Baseline and 
the C-SSRS Since Last Visit Version will be completed at all subsequent visits. The date 
and results of assessment will be recorded in the source documents and eCRF.
The subject will answer “yes” or “no” to suicidal ideation questions 1 and 2. If the 
answer to question 2 is “yes,” then the subject will also answer suicidal ideation 
questions 3 through 5. If the answer to either question 1 or 2 is “yes,” the intensity of 
suicidal ideation will also be assessed. For the intensity of suicidal ideation, frequency 
and duration will be rated on a scale of 1 to 5, and controllability, deterrents, reasons for 
ideation will be rated on a scale of 0 to 5.15
The subject will also answer “yes” or “no” to the suicidal behavior questions shown 
below. If the answer to any question is “yes,” a more detailed answer will be requested
and assessed. The total number of each actual, interrupted, or aborted attempts will be 
recorded.
If the subject actually attempted suicide, actual lethality/medical damage will be rated on 
a scale of 0 to 5. If the actual lethality/medical damage is rated 0, then potential lethality 
will be rated on a scale of 0 to 2.
Suicide ideation:
1. Wish to be dead
2. Non-specific active suicidal thoughts
3. Active suicidal ideation with any methods (not plan) without intent to act
4. Active suicidal ideation with some intent to act, without specific plan
5. Active suicidal ideation with specific plan and intent
Suicidal behavior:
Actual attempt, self-injurious behavior without suicidal intent, interrupted attempt
Aborted or self-interrupted attempt, preparatory acts or behavior, suicidal behavior, 
completed suicide (the Since Last Visit version only)


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8.8.7
Other Safety Variables
8.8.7.1
Height and Weight
Height and weight will be measured at the time points described in the schedule of 
assessments (Table 1.3-1) and BMI will be calculated. Weight will be measured while 
minimizing fluctuations associated with clothing. Date of measurement, height, and 
weight will be recorded in the eCRF. Any height/weight measured up to more than one 
decimal place will be rounded to one decimal place.
8.8.7.2
Injection Site Reaction Assessment
Injection site reaction will be assessed at the time points described in the schedule of 
assessments (Table 1.3-1). Injection site reaction assessments will occur immediately and 
1 hour after each IMP administration. When the IMP is self-administered at home, the 
subject will self-assess and record injection site reactions immediately and 1 hour after 
IMP administration. At a later visit, the investigator will assess injection site reactions
based on the record of the subject’s self-assessment and medical interview with the 
subject.
The injection site(s) will be observed for erythema, induration, ecchymosis, and pain, and 
severity will be graded according to the following criteria. If a subject has severe 
injection site erythema, induration, and/or ecchymosis, or grade 3 (severe) or grade 4 
(worst possible) injection site pain at 1 hour after completion of IMP administration, the 
subject will be monitored for hourly reassessment thereafter until the reaction/pain is of 
moderate or less severity. For self-administration at home, injection site reaction/pain 
will also be recorded hourly until reaction/pain is of moderate or less severity.

Injection-site erythema, induration, and ecchymosis will be graded as follows:
Absent, 5 to ≤50 mm (mild), > 50 to ≤100 mm (moderate), and > 100 mm (severe). 
Induration must be assessed by careful superficial palpation while avoiding placing 
pressure on or squeezing the injection site.

Injection-site pain will be evaluated according to Table 8.8.7.2-1.
The date and time and results of injection site assessment will be recorded in the eCRF, 
and an injection site reaction (mild, moderate, severe, or worst possible) will be reported 
as an AE. Needle puncture-related pain will not be assessed or considered an AE.


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Table 8.8.7.2-1
Severity Grading of Pain for Injection Site Assessment
Grade
Assessment
0
No pain
1
Mild
2
Moderate
3
Severe
4
Worst possible
8.9
Adverse Events
8.9.1
Definitions
An AE is defined as any untoward medical occurrence in a clinical trial subject 
administered an IMP and which does not necessarily have a causal relationship with this 
treatment. Adverse events would not include information recorded as medical history at 
screening for pre-planned procedures for which the underlying condition was known and 
no worsening occurred. An adverse reaction is any untoward and unintended response to 
an IMP related to any dose administered.
A suspected adverse reaction is any AE for which there is a reasonable possibility that the 
IMP caused the AE.
Treatment-emergent AEs (TEAEs) are defined as AEs with an onset date on or after the 
start of treatment. In more detail, TEAEs are all adverse events which started after the 
start of IMP treatment; or if the event was continuous from baseline and was worsening
after the start of IMP treatment.
An SAE includes any event that results in any of the following outcomes:

Death

Life-threatening; ie, the subject was, in the opinion of the investigator, at 
immediate risk of death from the event as it occurred. It does not include an event 
that, had it occurred in a more severe form, might have caused death.

Persistent or significant incapacity/disability or substantial disruption of the 
ability to conduct normal life functions.

Requires inpatient hospitalization or prolongs hospitalization.

Hospitalization itself should not be reported as an SAE; whenever possible the 
reason for the hospitalization should be reported.

Hospitalizations or prolonged hospitalizations for social admissions (ie, those 
required for reasons of convenience or other nonmedical need) are not 
considered SAEs.

Prescheduled hospitalization to address a condition that has existed prior to 
the signing of the ICF should not be considered an SAE.

Congenital anomaly/birth defect.


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
Other medically significant events that, based upon appropriate medical 
judgment, may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed above; eg, allergic 
bronchospasm requiring intensive treatment in an emergency room or home, 
blood dyscrasias or convulsions that do not result in hospitalization, or the 
development of drug dependency or drug abuse.
Nonserious AEs are all AEs that do not meet the criteria for a “serious” AE.
Immediately Reportable Event (IRE):

Any SAE.

Possibility of developing into an SAE (ie, An observed deficiency with the AI 
device, though not causing an SAE at the moment, may possibly develop into an 
SAE. Where the possibility exists that an SAE may develop, this must be 
reported, using the IRE form, to the sponsor as described in Section 6.2.5, 
Reporting of Product Quality Complaints. It will be recorded on the AE eCRF
only if an AE occurs.)

Any adverse events of special interest (AESIs) (ie, any ophthalmic AE of at least 
moderate severity and any event of suspected anaphylaxis or severe 
hypersensitivity reaction).

Any AE related to occupational exposure (any AE related to handling of the IMP 
affecting the investigator or trial personnel [eg, dacryorrhea occurring in a nurse 
who has accidentally spilt/splashed an injection drug and its droplets have entered
his/her eye(s).])

Potential serious hepatotoxicity (see Section 8.9.6).

Pregnancies are also defined as IREs. Although normal pregnancy is not an AE, it 
will mandate IMP discontinuation and must be reported on an IRE form and the 
Pregnancy Surveillance Form(s) to the sponsor. Pregnancy will only be 
documented on the AE eCRF if there is an abnormality or complication. This 
includes pregnancy of the subject or the partner of the subject.

All infections: Only cases of suspected contamination of biological IMPs with 
pathogens, including HBV, HCV, HIV, and the like. Seasonal infections such as 
the common cold are not included.
Clinical Laboratory Test Value Changes: It is the investigator’s responsibility to review 
the results of laboratory tests for each individual subject as they become available. This 
review will be documented by the investigator’s dated signature on the laboratory report. 
The investigator may repeat the laboratory test or request additional tests to verify the 
results of the original laboratory tests. If this laboratory value is considered medically 
relevant (ie, clinically significant) by the investigator (subject is symptomatic, requiring 
corrective treatment or further evaluation), or if the laboratory value leads to 
discontinuation, and/or fulfills a seriousness criterion, this is considered an AE.


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Severity: Adverse events will be graded on a 3-point scale and reported as indicated on 
the eCRF. The severity of an adverse experience is defined as follows:
1 = Mild:
Discomfort noticed, but no disruption to daily activity.
2 = Moderate:
Discomfort sufficient to reduce or affect normal daily activity.
3 = Severe:
Inability to work or perform normal daily activity.
TEV-48125 Causality: Assessment of causal relationship of an AE to the use of 
TEV-48125 is defined as follows:
Related: 
There is a reasonable possibility of a temporal and causal 
relationship between TEV-48125 and the AE.
Not Related: 
There is no temporal or causal relationship between TEV-48125
and the AE.
AI Device Causality: Assessment of causal relationship of an AE to the use of the AI 
device is defined as follows:
Related: 
There is a reasonable possibility of a temporal and causal 
relationship between the AI device and the AE.
Not Related: 
There is no temporal or causal relationship between the AI device
and the AE.
Manipulation Causality: Assessment of causal relationship of an AE to the manipulation
is defined as follows:
Related:
There is a reasonable possibility of a temporal and causal 
relationship between subject’s manipulation and the AE.
Not Related: 
There is no temporal or causal relationship between subject’s 
manipulation and the AE.
8.9.2
Eliciting and Reporting Adverse Events
The investigator will regularly assess subjects for the occurrence of AEs. To avoid bias in 
eliciting AEs, subjects should be asked the nonleading question: “How have you felt 
since your last visit?” All AEs (serious and nonserious) reported by the subject must be 
recorded on the source documents and eCRF provided by the sponsor. Adverse event 
collection will begin after a subject signs the ICF.
Medical terminology should be used for AE reporting. Adverse events should be reported 
as a single unifying diagnosis whenever possible or, in the absence of a unifying 
diagnosis, as individual signs or symptoms.
Exacerbation or disease progression should be reported as an AE only if there are 
unusual or severe clinical features that were not present, or experienced earlier, or not 
expected based on the course of the condition.


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In addition, the sponsor must be notified immediately by e-mail in principle of any IREs 
according to the procedure outlined below, in Section 8.9.3, Immediately Reportable 
Events. Special attention should be paid to recording hospitalization and concomitant 
medications.
See Section 6.2.5, Reporting of Product Quality Complaints, for the procedure for 
reporting AI device deficiencies that have not caused SAEs or are unlikely to cause
SAEs. Any AI device deficiency that has caused or may cause an SAE must be handled 
as an IRE in accordance with Section 8.9.3, Immediately Reportable Events.
Adverse event, start date, end date, seriousness, severity, relationship to TEV-48125
treatment (TEV-48125 Causality), relationship to AI device (AI Device Causality), 
relationship to the subject’s manipulation (Manipulation Causality), action taken with 
trial treatment and outcome will be recorded on the source documents and in the eCRF.
8.9.3
Immediately Reportable Events
The investigator must immediately report (within 24 hours), using an IRE form, after the 
investigator or site personnel becomes aware of any IRE (see Section 8.9.1, Definitions), 
by e-mail in principle to the sponsor or designee using the contact information on the 
cover page of this protocol (Please note that the IRE form is NOT the AE eCRF.). When 
sending an IRE form by e-mail, etc, sufficient care and attention must be taken to protect 
subject privacy.
8.9.4
Medical Device Incidents (Including Malfunctions)
In this trial, the injector prefilled with TEV-48125 (combination product of TEV-48125 
and AI) will be handled as the IMP. However, the “status of deficiencies with AI device” 
and “AI Device Causality” of AEs will also be investigated in the trial (see Section 6.1.3, 
Information Regarding Trial Treatment Administration, and Section 8.9.1, Definitions).
8.9.5
Adverse Events of Special Interest
Adverse events of special interest are defined below. These will be immediately reported 
to the sponsor as IREs according to the procedure outlined in Section 8.9.3, Immediately 
Reportable Events.

Any ophthalmic AE of at least moderate severity

Any event of suspected anaphylaxis or severe hypersensitivity reaction
In response to the finding of mild ciliary periarteritis in monkeys treated with TEV-48125 
in a 3-month multiple-dose toxicity study, ophthalmic AE was addressed as an AESI in 3 
multinational phase 3 trials (Trials TV48125-CNS-30049, TV48125-CNS-30050, and


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TV48125-CNS-30051). These trials demonstrated neither clinically significant 
differences from placebo nor TEV-48125-related abnormal patterns. Three ongoing 
Korean and Japanese trials (Trials 406-102-00001, 406-102-00002, and 406-102-00003) 
are also addressing ophthalmic AE as an AESI. In line with this approach, the present 
trial will handle ophthalmic AE in the same way.
Severe hypersensitivity reaction will be monitored using the clinical criteria for 
diagnosing anaphylaxis16 proposed in the second symposium on the definition and 
management of anaphylaxis hosted by National Institute of Allergy and Infectious 
Disease and Food Allergy and Anaphylaxis Network in 2006 (see Section 10.8). If 
anaphylaxis is suspected, vital signs (eg, oxygen saturation and respiratory rate) will be 
measured. If severe hypersensitivity reaction (eg, anaphylaxis) is suspected, ADA will be 
assessed. The investigator may perform other assessments at his/her discretion and decide 
whether or not to continue the subject’s trial participation. If it is decided to discontinue 
the trial, necessary actions will be taken in accordance with Section 7.3.2, Treatment 
Discontinuation.
8.9.6
Potential Serious Hepatotoxicity
For a subject who experiences an elevation in AST or ALT that is 3 times the ULN, a
total bilirubin level should also be evaluated. If the total bilirubin is 2 times the ULN, 
complete an IRE form with all values listed and also report as an AE on the eCRF.
8.9.7
Procedure for Breaking the Blind
This trial will not use blinding procedures.
8.9.8
Follow-up of Adverse Events
8.9.8.1
Follow-up of Nonserious Adverse Events
Nonserious AEs that are identified at any time during the trial must be recorded on the 
AE eCRF with the current status (ongoing or resolved/recovered) noted. All nonserious 
events (that are not IREs) that are ongoing at the last scheduled contact will be recorded 
as ongoing on the eCRF. For any AE having been identified throughout the trial, during 
analysis, additional relevant medical history information may be requested by the sponsor 
to further ascertain causality (including, but not limited to, information such as risk-
related behavior, family history and occupation).
8.9.8.2
Follow-up of Immediately Reportable Events
This trial requires that subjects be actively monitored for IREs up to 28 days after the last 
dose of IMP is administered.


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Immediately reportable events that are identified up to the last schedules contact or 
ongoing at the last scheduled contact must be recorded as such on the AE eCRF page and 
the IRE form. If updated information (eg, resolved status) on IRE status becomes 
available after a subject’s last scheduled contact (up to last subject last visit for the entire 
trial), this must be reported to the sponsor and recorded on the AE eCRF page and the 
IRE form, according to the appropriate reporting procedures described in Section 8.9.3, 
Immediately Reportable Events.
It is expected that the investigator will provide or arrange appropriate supportive care for 
the subject and will provide prompt updates on the subject’s status to the sponsor. The 
investigator will follow IREs until the events are:

Resolved,

Stabilized,

The subject is lost to follow-up, or

Has died.
Resolution means that the subject has returned to the baseline state of health and 
stabilized means that the investigator does not expect any further improvement or 
worsening of the subject’s condition. The investigator will continue to report any 
significant follow-up information to the sponsor up to the point the event has resolved or 
stabilized, or the subject is lost to follow-up, or has died.
Refer to Section 10.3 for additional information regarding the follow-up period for 
subjects that become pregnant or for pregnant partners of male subjects.
8.9.8.3
Follow-up and Reporting of Immediately Reportable Events 
Occurring After Last Scheduled Contact
Any new IREs which are reported to the investigator after the last scheduled contact and 
are determined by the investigator to be reasonably associated with the use of the IMP, 
should be reported to the sponsor according to the procedures outlined in Section 8.9.3, 
Immediately Reportable Events. This may include IREs that are captured on follow-up 
telephone contact or at any other time point after the defined trial period and any 
significant follow-up information should continue to be reported to the sponsor until the 
events have resolved or stabilized, or the subject is lost to follow-up or has died.
8.10
Treatment of Overdose
For treatment of overdose, please refer to IB Section 7.6, Overdosage.
There is no TEV-48125-specific antidote for overdosage. Overdosage should be treated 
with symptomatic therapies and common supportive care.


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8.11
Subject Assessment Recording
8.11.1
Electronic Headache Diary
Headache-related efficacy endpoints will be derived from headache data collected using 
an eDiary. At Visit 1/Screening, eligible subjects will receive comprehensive training 
from trial personnel on the use of the eDiary. On each day, the subject will be asked to 
enter headache data in the eDiary for the previous 24-hour period. Subjects who report 
headache on the previous day will answer questions about the headache (ie, occurrence of 
headache, duration of headache, maximum severity of headache, presence/absence of 
associated symptoms, and use of acute headache medications).
Headache data for the preceding day should be entered into the eDiary no later than the 
data entry time limit of 2 days (48 hours). If this time limit is exceeded, the subject will 
not be able to enter headache information for the applicable day, and it will be considered 
a missed day. The subject should enter headache information into the eDiary on at least 
75% of the days between the scheduled visits.
Overall headache duration will be recorded numerically, in hours, as well as number of 
hours with headache of at least moderate severity.
If headache is reported, then headache severity will be subjectively rated by the subject as 
follows:

Mild headache

Moderate headache

Severe headache
Subjects will also record the presence or absence of photophobia, phonophobia, nausea, 
or vomiting, and the status of use of any acute headache medications.
8.11.2
Recording Information on Self-administration at Home
The subject will assess and record in a check sheet the execution status of self-
administration at home, his/her compliance with the specified procedure, and presence or 
absence of deficiencies with the AI device. Any injection site reaction will also be 
recorded in the check sheet. The completed check sheet will be submitted to the 
investigator.


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8.12
Other Assessments
8.12.1
Assessment of Self-administration at Home
The following information will be collected to facilitate a comprehensive evaluation of 
the feasibility of AI-assisted self-administration of TEV-48125 at home.

Execution status of self-administration at home

Subject compliance with the self-administration procedure
Any deficiencies with the AI device will also be assessed.
9
Statistical Considerations
9.1
Sample Size
The statistically required sample size based on power was not calculated. The sample size 
for evaluating the safety of TEV-48125 when subcutaneously self-administered at the 
trial site and at home was set at 50 subjects.
9.2
Datasets for Analysis
The safety dataset includes all subjects that were administered at least one dose of IMP. 
The efficacy dataset includes all subjects who were administered at least one dose of IMP 
and have eDiary data for efficacy evaluation at baseline and for at least 10 days after 
baseline.
9.3
Handling of Missing Data for Primary Endpoint Analysis
Missing data will not be imputed.
9.4
Statistical Analyses
9.4.1
Efficacy Analyses
Efficacy analysis is described in Section 9.4.3.7, Exploratory Endpoint Analysis.
9.4.2
Safety Analysis
The safety dataset will be used in safety analysis.
9.4.2.1
Adverse Events
All AEs will be coded by system organ class and Medical Dictionary for Regulatory 
Activities (MedDRA) preferred term. The incidence of the following events will be 
summarized overall, by self-administration at the trial site, and by self-administration at
home:


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
TEAEs

TEAEs by severity

TEAEs potentially causally related to TEV-48125

TEAEs potentially causally related to AI device

TEAEs potentially causally related to subject’s manipulation

TEAEs with an outcome of death

Serious TEAEs

TEAEs leading to discontinuation of the IMP
9.4.2.2
Execution Status of Self-administration and Subject 
Compliance With Self-administration Procedure
Frequency distributions will be determined by location (trial site or home) for the 
execution status of self-administration and subject compliance with the self-
administration procedure.
9.4.2.3
Deficiencies With the Autoinjector Device
Deficiencies with the AI device will be listed.
9.4.2.4
Clinical Laboratory Data
For each laboratory parameter (excluding qualitative urinalysis), descriptive statistics will 
be calculated for measurements and changes from baseline at each time point (including 
final assessment). The central laboratory reference ranges will be used to group 
measurements into “below the reference range,” “within the reference range,” or “above 
the reference range” and a shift table from baseline will be provided.
For each qualitative laboratory parameter, a shift table from baseline will be provided.
9.4.2.5
Physical Examination and Vital Signs Data
Physical examination findings will be listed.
For each vital sign, descriptive statistics will be calculated for measurements and changes 
from baseline at each time point (including final assessment).
9.4.2.6
Electrocardiogram Data
For each ECG parameter, descriptive statistics will be calculated for measurements and 
changes from baseline at each time point (including final assessment).
For the normality/abnormality judgment, a shift table from baseline will be provided.
For QT corrected by Fridericia’s formula (QTcF), the number and proportion of subjects 
where the measured QTcF after the start of IMP administration is > 450 msec, 


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> 480 msec, and > 500 msec will be determined. The number and proportion of subjects 
with changes from baseline in the QTcF of > 30 msec and > 60 msec will also be 
determined.
9.4.2.7
Other Safety Data
9.4.2.7.1
Weight
Descriptive statistics will be calculated for measurements and changes from baseline at 
each time point (including final assessment).
9.4.2.7.2
Injection Site Reactions
Frequency distributions will be calculated for severity of injection site reactions 
(erythema, induration, ecchymosis, and pain) at each time point.
9.4.2.7.3
Columbia-Suicide Severity Rating Scale
Subjects with suicidal ideation or suicidal behavior will be listed.
9.4.3
Other Analyses
9.4.3.1
Analysis of Demographic and Baseline Characteristics
For demographic and baseline characteristics in each analysis set, frequency distributions
or descriptive statistics will be calculated depending on the nature of the data.
9.4.3.2
Pharmacokinetic Analysis
No pharmacokinetic analysis is planned.
9.4.3.3
Pharmacodynamic Analysis
No pharmacodynamic analysis is planned.
9.4.3.4
Pharmacokinetic/Pharmacodynamic Analysis
No pharmacokinetic/pharmacodynamic analysis is planned.
9.4.3.5
Immunogenicity
9.4.3.5.1
Immunogenicity Analysis
The frequency of ADA expression in the safety dataset will be calculated.
9.4.3.6
Pharmacogenomic Analysis
No pharmacogenomic analysis is planned.
9.4.3.7
Exploratory Endpoint Analysis
Descriptive statistics will be calculated for the number of migraine days per month (28 
days) in 8 weeks after the first dose of IMP and the number of migraine days per month 


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in 4 weeks after each dose as well as their respective changes from baseline in the 
efficacy dataset. The number of headache days of at least moderate severity and the 
number of headache days will also be analyzed in the same manner.
The proportion of subjects who achieved a 50% or greater reduction in the number of 
migraine days per month in 8 weeks after the first dose of IMP and the proportion of 
subjects who achieved a 50% or greater reduction in the number of migraine days per 
month in 4 weeks after each dose will be calculated. The number of headache days of at 
least moderate severity will also be analyzed in the same manner.
9.4.3.8
Plasma Drug Concentrations
Descriptive statistics will be calculated for measurements at each time point for blood 
sampling for determination of plasma drug concentrations. A box plot and a scatter plot 
will be provided for each measurement.
9.5
Interim Analysis and Adaptive Design
No interim analysis or adaptive design is applicable.
9.5.1
Data Monitoring Committee
Not applicable.


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10
Supporting Documentation and Operational Considerations
10.1
Appendix 1: Regulatory, Ethical, and Trial Oversight 
Considerations
10.1.1
Ethics and Responsibility
This trial must be conducted in compliance with the protocol, International Council for 
Harmonisation (ICH) GCP: Consolidated Guideline (E6), international ethical principles 
derived from the Declaration of Helsinki and Council for International Organizations of 
Medical Science (CIOMS) guidelines, and applicable local laws and regulations. Each 
trial site will seek approval by an IRB according to regional requirements, and the trial 
site will provide that documentation to the sponsor. The IRB will evaluate the ethical, 
scientific and medical appropriateness of the trial. Further, in preparing and handling 
eCRF, IRE form, etc, the investigator, subinvestigator and their staff will take measures 
to ensure adequate care in protecting subject privacy. To this end, a subject identifier (ID) 
will be used to identify each subject.
Financial aspects, insurance coverage for subjects, etc, and the publication policy for the 
trial will be documented in the agreement between the sponsor and the trial site.
10.1.2
Informed Consent
Informed consent will be freely obtained from all subjects (or their guardian or legally 
acceptable representative, as applicable for local laws). The ICF will be approved by the 
same IRB that approves this protocol.
Each ICF will comply with the ICH GCP: Consolidated Guideline E6 and local 
regulatory requirements. In support of the site’s standard process for administering 
informed consent, this trial will also allow for electronic informed consent (eICF) as a 
tool within applicable regions and trial sites. The eICF utilizes the IRB-approved site-
specific ICF to offer subjects an enhanced platform to review and understand their rights 
as a research subject as well as required trial procedures. When possible, trial sites will 
have subjects review and sign the eICF prior to starting any trial procedures; however, if 
local regulations do not allow for use of the electronic format, subjects may continue in 
the trial utilizing the standard paper and wet ink signature process.
Investigators may discuss trial availability and the possibility for entry with a potential 
subject without first obtaining consent. However, informed consent must be obtained and 
documented before initiation of any procedures that are performed solely for the purpose 
of determining eligibility for this trial, including withdrawal from current medication(s).


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Potential subjects are free to refuse entry into the trial, or withdraw from the trial at any 
time, without justification, and there will be no consequences to their further care.
Once appropriate essential information has been provided and fully explained in 
layman’s language to the subject by the investigator (or a qualified designee), and it has 
been documented that the subject has had the opportunity to ask questions, the 
IRB-approved written ICF will be signed and dated by both the subject and the person 
obtaining consent (investigator or designee), as well as by any other parties required by 
the IRB. The subject will receive a copy of the signed ICF; the original shall be kept on 
file by the investigator. Subjects may be asked to sign additional ICFs if the protocol is 
amended and the changes to the protocol results in additional information that needs to be 
provided to the subjects, so that they can make a knowledgeable and voluntary decision 
on continued trial participation. Female partners of male subjects who become pregnant 
during the course of the trial and up to 225 days after the final dose of IMP may be asked 
to sign additional ICFs in order to collect additional information regarding the nonsubject 
partner and fetus.
If a potential subject is a minor, voluntary, written informed consent will be obtained 
from his or her legally acceptable representative, as applicable for local laws. If the 
investigator decides that the potential subject is able to understand the explanation of the 
trial, however, the potential subject will be given an explanation appropriate to his or her 
level of understanding and then sign and date the ICF himself or herself.
10.1.3
Confidentiality
All information generated in this trial will be considered confidential and will not be 
disclosed to anyone not directly concerned with the trial without the sponsor’s prior 
written permission. Subject confidentiality requirements of the region(s) where the trial is 
conducted will be met. However, authorized regulatory officials and sponsor personnel 
(or their representatives) may be allowed full access to inspect and copy the records, 
consistent with local requirements. All IMPs, subject bodily fluids, and/or other materials 
collected shall be used solely in accordance with this protocol, unless otherwise agreed to 
in writing by the sponsor.
Subjects will be identified only by unique subject ID in eCRF. If further subject 
identification is required, subjects’ full names may be made known to a regulatory 
agency or other authorized officials if necessary, subject to local regulations.


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10.1.4
Quality Control and Quality Assurance
The sponsor will implement the trial-related quality management activities in accordance 
with ICH E6 (R2). The details of the quality management activities are separately 
described in the quality management plan.
10.1.4.1
Monitoring
The sponsor has ethical, legal, and scientific obligations to follow this trial in accordance 
with established research principles, the ICH GCP: Consolidated Guideline (E6), and 
applicable regulatory requirements and local laws. As part of a concerted effort to fulfill 
these obligations (maintain current personal knowledge of the progress of the trial), the 
sponsor's monitors will visit the site during the trial, as well as communicate frequently 
via telephone, e-mail, and written communications. In addition, all investigators and trial 
site personnel will undergo initial and ongoing training for this particular trial, and this 
training will be clearly documented.
10.1.4.2
Auditing
The sponsor's Quality Assurance Unit (or representative) may conduct trial site audits. 
Audits will include, but are not limited to, IMP supply, presence of required documents, 
the informed consent process, and a review of the eCRF with source documents, as 
applicable. The investigator agrees to participate with audits.
Regulatory authorities may inspect the investigator site during or after the trial. The 
investigator will cooperate with such inspections and will contact the sponsor 
immediately if such an inspection occurs.
10.1.5
Protocol Deviations
In the event of a significant deviation from the protocol due to an emergency, accident, or 
mistake (eg, violation of informed consent process, IMP dispensing or subject dosing 
error, subject enrolled in violation of eligibility criteria, prohibited/restricted medication 
criteria, or prohibited therapy criteria), the investigator or designee will contact the 
sponsor or designee at the earliest possible time by telephone or via e-mail. The 
investigator and sponsor (or designee) will come as quickly as possible to a joint decision 
regarding the subject’s continuation in the trial. This decision will be documented by the 
investigator and the sponsor (or designee) and reviewed by the site monitor.
Any major protocol deviation will be recorded in the eCRF along with the start date and 
details of the deviation.


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10.1.6
Records Management
10.1.6.1
Source Documents
Source documents are defined as the results of original observations and activities of a 
clinical investigation. Source documents will include but are not limited to medical 
records, electronic data, screening logs, and recorded data from automated instruments. 
All source documents pertaining to this trial will be maintained by the trial site and made 
available for direct inspection by authorized persons.
Investigator(s)/institution(s) will permit trial-related monitoring, audits, IRB review, and 
regulatory inspection(s) by providing direct access to source data/documents by 
authorized persons as defined in the ICF. Information on drug concentration 
determination and ADA analysis (eg, original reports, measurement data) will be stored 
at the bioanalytical laboratory and the ADA analytical laboratory. In all cases, subject 
confidentiality must be maintained in accordance with local regulatory requirements.
10.1.6.2
Data Collection
During each subject’s visit to the site, an investigator or their designee participating in the 
trial will record information to document all significant observations. At a minimum, 
these notes will contain:

Documentation of the informed consent process, including any revised consents;

Documentation of the investigator’s decision to enroll the subject into the trial, the 
review of all inclusion/exclusion criteria prior to IMP administration, and 
confirmation of the subject’s actual participation in the trial;

The date of the visit and the corresponding Visit or Day in the trial schedule;

General subject status remarks, including any significant medical findings. The 
severity, frequency, duration, action taken, and outcome of any AEs and the 
investigator's assessment of relationship to IMP must also be recorded;

Any changes in concomitant medications or dosages;

A general reference to the procedures completed; 

The signature (or initials) and date of the investigator (or designee) who made an 
entry in the medical record.
In addition, any contact with the subject via telephone or other means that provides 
significant clinical information will also be documented in the progress notes as 
described above.
Information from medical records and other source documents will be entered by 
investigative site personnel onto eCRFs in the sponsor’s electronic data capture (EDC) 


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system that is 21 CRF Part 11 compliant. Changes to the data will be captured by an 
automatic audit trail in the EDC system.
Data entered into the eDiary by the subject will be transferred to the EDC system and 
included in the eCRF. Data entries and transfer will also be captured by an automatic 
audit trail. Data entered in the eDiary cannot be changed.
Electronic data not included in the eCRF, such as data received from central laboratories 
and central ECG readers, will be reconciled using key data fields by the sponsor or the 
contract research organization with the eCRF data to ensure consistency.
10.1.6.3
File Management at the Trial Site
The investigator will ensure that the trial site file is maintained in accordance with 
Section 8 of the ICH GCP: Consolidated Guideline (E6) and as required by applicable 
local regulations. The investigator/institution will take measures to prevent accidental or 
premature destruction of these documents.
10.1.6.4
Records Retention at the Trial Site
The trial site will maintain all documents and records pertaining to the trial for the longer 
of the following 2 periods. If the sponsor needs a longer retention period than either of 
those specified below, the trial site will discuss with the sponsor the period and method of 
retention.

A period of at least 2 years after the date on which approval to market the drug is 
obtained. However, if the development of the drug is discontinued or if the trial site is 
notified that the results of the trial will not be included in the application dossier for 
marketing approval, a period of at least 3 years after the date on which 
discontinuation of drug development is decided or the trial site is notified that the trial 
results will not be included in the application dossier.

A period of at least 3 years after the trial is discontinued or completed.
The trial site must not dispose of any records relevant to this trial without either 
(1) written permission from the sponsor or (2) provision of an opportunity for sponsor to 
collect such records. The trial site will be responsible to maintain adequate and accurate 
electronic or hard copy source documents of all observations and data generated during 
this trial including any data clarification forms received from the sponsor. Such 
documentation is subject to inspection by the sponsor and relevant regulatory authorities.
10.1.6.5
Publication Authorship Requirements
Authorship for any Otsuka-sponsored publications resulting from the conduct of this trial 
will be based on International Committee of Medical Journal Editors (ICMJE) authorship 


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criteria (http://www.icmje.org/recommendations). According to ICMJE guidelines, one 
may be considered an author only if the following criteria are met:
1) Substantial contributions to the conception or design of the work; or the 
acquisition, analysis, or interpretation of data for the work; AND
2) Drafting the work or revising it critically for important intellectual content; AND
3) Final approval of the version to be published; AND
4) Agreement to be accountable for all aspects of the work in ensuring that questions 
related to the accuracy or integrity of any part of the work are appropriately 
investigated and resolved.
All authors must meet the above criteria, and all who qualify for authorship based on the 
above criteria should be listed as authors.
Investigators or other trial subjects who do not qualify for authorship may be 
acknowledged in publications resulting from the trial. By agreeing to participate in the 
trial, investigators or other trial subjects consent to such acknowledgement in any 
publications resulting from its conduct.


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10.2
Appendix 2: Clinical Laboratory Tests
The tests detailed in Table 10.2-1 will be performed.
Table 10.2-1
Clinical Laboratory Assessments
Hematology:
Hemoglobin (Hb)
Hematocrit (Hct)
Erythrocytes count (RBC)
Erythrocyte indices
  Mean corpuscular hemoglobin concentration
  (MCHC)
  Mean corpuscular volume (MCV)
  Red cell distribution width (RDW)
Leukocytes count (WBC) with differential count 
(absolute values and percentages)
  Neutrophils (Neu)
  Lymphocytes (Lym)
  Eosinophils (Eos)
  Monocytes (Mon)
  Basophils (Bas)
Platelet count (PLT)
Urinalysis:
Specimen appearance
Color 
Occult blood
Glucose
Microscopic analysis (high powered field)
Bacteria
Leukocytes count
Erythrocytes count
Casts
Crystals
pH
Protein
Specific gravity
Albumin (ALB)
Ketones
Leukocyte esterase
Nitrite
Direct bilirubin
Serum Chemistry:
Alkaline phosphatase (ALP)
Alanine aminotransferase (ALT)
Aspartate aminotransferase (AST)
Total bilirubin 
Direct bilirubin
Indirect bilirubin (calculated)
Urea nitrogen (BUN)
Uric acid (UA)
Calcium (Ca)
Creatinine (Cr)
Gamma glutamyl transferase (GGT)
Glucose (casual)
Lactic dehydrogenase (LDH)
Potassium (K)
Total protein 
Sodium (Na)
Phosphorus
Chloride (Cl)
Carbon dioxide
Magnesium
Albumin
Creatine phosphokinase
Coagulation
Prothrombin time (PT)
Partial thromboplastin time (PPT)
International normalization ratio (INR)
Additional Tests:
Urine (or serum) hCG test for FOCBP
(If the result of urine hCG test is positive at 
screening, serum hCG test will be performed for 
confirmation.)
RBC = red blood cell; WBC = white blood cell.


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10.3
Appendix 3: Contraceptive Guidance and Collection of Pregnancy 
Information
Females of child-bearing potential (FOCBP) are females whose menstruation has started 
and who are not documented as sterile (eg, have had a bilateral oophorectomy, or 
hysterectomy, or who have been postmenopausal for at least 12 months).
For males and FOCBP, who are sexually active, there must be a documented agreement 
that the subject and their partner will take effective measures (ie, 2 different approved 
methods of birth control or remains abstinent) to prevent pregnancy during the course of 
the trial and for 225 days after the last dose of IMP. Unless the subject is sterile (ie, 
females who have had a bilateral oophorectomy, have had a hysterectomy, or have been 
postmenopausal for at least 12 consecutive months; or males who have had a bilateral 
orchidectomy) or remains abstinent for 225 days after the last dose of IMP, 2 of the 
following approved methods of birth control must be used: vasectomy, tubal ligation, 
intrauterine device, birth control pills, or condom (all of which are approved or certified 
in Japan). Any single method of birth control, including vasectomy and tubal ligation, 
may fail, leading to pregnancy. The contraceptive method will be documented in the 
eCRF. Male subjects must also agree not to donate sperm from trial screening through 
225 days after the last dose of IMP.
Before enrolling males and females in this clinical trial, investigators must review the 
below information about trial participation as part of the ICF process. The topics should 
generally include:

General information

Informed consent form

Pregnancy prevention information

Contraceptives in current use

Follow-up of a reported pregnancy
Before trial enrollment, males and FOCBP must be advised of the importance of avoiding 
pregnancy during trial participation and the potential risk factors for an unintentional 
pregnancy. Subjects must sign the ICF confirming that the above-mentioned risk factors 
and the consequences were discussed.
A urine pregnancy test for human chorionic gonadotropin (hCG) will be performed at 
screening and at each trial site visit on all FOCBP. If a urine test is positive at screening, 
a serum hCG test will be performed using serum samples obtained for clinical chemistry 
at screening examination.


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During the trial, all FOCBP should be instructed to contact the investigator immediately 
if they suspect they might be pregnant (eg, missed or late menstrual cycle). Male subjects 
must be instructed to contact the investigator immediately, during the trial, if their partner 
suspects that she might be pregnant (eg, missed or late menstrual cycle).
If the pregnancy is confirmed, the subject must not receive the IMP and must not be 
enrolled in the trial. If pregnancy is suspected while the subject is taking IMP, the IMP 
must be withheld immediately (if reasonable, taking into consideration any potential 
withdrawal risks). If pregnancy is confirmed, the IMP will be permanently discontinued 
in an appropriate manner (eg, dose tapering if necessary for subject safety) and the 
subject will be withdrawn from the trial. Exceptions to trial discontinuation may be 
considered for life-threatening conditions only after consultations with the IRE contact 
(see the title page of this protocol for contact information).
The investigator must immediately notify the sponsor (within 24 hours) of any pregnancy 
associated with IMP exposure during the trial and for at least 225 days after the last dose 
of IMP, and record the event on the IRE form and forward it to the sponsor. The sponsor 
will forward the Pregnancy Surveillance Form(s) to the investigator for monitoring the 
outcome of the pregnancy.
Protocol required procedures for trial discontinuation and follow-up must be performed 
on the subject unless contraindicated by pregnancy (eg, x-ray studies). Other appropriate 
pregnancy follow-up procedures should be considered if indicated. In addition, the 
investigator must report to the sponsor, on the Pregnancy Surveillance Form(s), follow-
up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome. Infants will be followed for a minimum of 6 months from the date of birth.


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10.4
Appendix 4: ICHD-3 beta Diagnostic Criteria
For further details, refer to Headache Classification Committee of the International 
Headache Society (IHS) The International Classification of Headache Disorders, third 
edition ©International Headache Society 2018.
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:

unilateral location

pulsating quality

moderate or severe pain intensity

aggravation by, or causing avoidance of, routine physical activity (eg, 
walking or climbing stairs)
D.
During headache, at least 1 of the following:

nausea and/or vomiting

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:

visual

sensory

speech and/or language

motor

brainstem

retinal
C.
At least 3 of the following 6 characteristics:

at least one aura symptom spreads gradually over ≥5 minutes

two or more aura symptoms occur in succession

each individual aura symptom lasts 5 to 60 minutes

at least one aura symptom is unilateral

at least one aura symptom is positive

the aura is accompanied, or followed within 60 minutes, by headache
D.
Not better accounted for by another ICHD-3 diagnosis


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10.5
Appendix 5: Guidance on Safety Monitoring
Guidance on Monitoring Patients With Elevated Liver Function Tests
Liver enzymes (ALT, AST, GGT, and ALP) as well as total bilirubin and direct bilirubin 
will be measured (and indirect bilirubin will be calculated) at each trial visit.
In any case of elevated ALT or AST to a level exceeding ≥2 × the ULN (including 
patients whose baseline ALT or AST levels are ≥2 × and ≤3 × the ULN, who may be 
enrolled in the trial), a thorough medical history should be taken and a physical 
examination with a focus on liver disease should be performed.b In addition, the patient 
should be instructed to refrain from alcoholic beverages.
In cases where the symptoms are compatible with drug-induced liver injury during the 
trial, patients will be instructed to return to the trial site for an unscheduled visit to 
measure liver enzymes as soon as possible. Solitary elevations of total or direct bilirubin, 
not accompanied by elevations of ALT or AST, should be managed based on the 
judgement of the treating physician.
In line with Section 8.8.2, Clinical Laboratory Assessments, all blood testing will be 
performed at the central laboratory. The day on which the abnormal value is received
from the central laboratory will be considered as Day 0.
Elevation of Either ALT or AST to ≥3 × ULN
Confirmation is required prior to IMP discontinuation in cases of elevation of either ALT 
or AST ≥3 × ULN (Note: In cases of elevation of ALT or AST ≥8 × the ULN, no 
confirmation is required prior to IMP discontinuation, but the assessments below should 
be performed). The following procedures should be followed:

The investigator should repeat the test for confirmation purposes (ALT, AST, ALP,
total and direct bilirubin, complete blood count [CBC] [with differential for 
eosinophil count], and INR). The investigator should also question the patient 
regarding symptoms.
                                                
b Thorough medical history with a focus on liver disease: personal or family history of liver 
disease; personal history of a systemic disease with potential liver involvement; exposure to 
alcohol, medications (prescription or over-the-counter), herbal preparations, dietary 
supplements, recreational drugs, special diets, or environmental chemical agents; potential 
exposure to infectious agents (eg, travel to developing countries, history of potential exposure 
to blood or blood products, high-risk sexual relations); and any additional information deemed 
relevant by the principal investigator. Physical examination, including signs of chronic liver 
disease.


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The abnormality will be regarded as confirmed in each of the following scenarios:

The baseline value was within the normal range and ALT or AST is still ≥3 × the 
ULN.

The baseline value was above the ULN and ALT or AST is ≥2 × the baseline value.
Additional Tests/Evaluations:
Upon confirmation of the abnormality as noted above, the following additional 
evaluations should be performed

Serology for hepatitis A (antibody and immunoglobulin M [IgM] and IgG), B (core 
antibody total, core IgM, and surface antigen and antibody), and C (antibody) viruses 

Serology for autoimmune hepatitis: antinuclear antibodies (titer), antismooth muscle 
antibodies, and antiliver kidney microsomal antibodies

Ultrasound examination of the liver and biliary tract at the investigator’s discretion 
(date of examination and the normality/abnormality judgment will be recorded in 
CRF) 

Observation and follow-up (to be performed after the abnormality was confirmed as 
above)
ALT or AST ≥3 × (> 3.5 × the ULN if the Baseline Value Is > 2.5 × the ULN) but 
Less Than 5 × the ULN
In addition to the above procedures required for any elevation to levels > 3 × the ULN:

ALT, AST, GGT, ALP, total and direct bilirubin, CBC (including differential), and 
INR should be monitored on Days 5 (± 2 days), 8 (± 2 days), 14 (± 3 days), and 28 
(± 3 days).

Should the abnormality (≥3 × the ULN in cases where the baseline value was within 
the normal range or ≥2 × the ULN in cases where the baseline value was above ULN 
but still < 5 × the ULN) persist, the patient will be followed at the investigator’s 
discretion, but ALT, AST, GGT, ALP, and total and direct bilirubin should be 
monitored at least once monthly.
ALT or AST ≥5 × but Less Than 8 × the ULN
In addition to the above procedures required for any elevation to levels > 3 × the ULN:

ALT, AST, GGT, ALP, total and direct bilirubin, CBC (including differential), and 
INR should be monitored twice a week.


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ALT or AST ≥8 × the ULN
In addition to the above procedures required for any elevation to levels > 3 × the ULN:

The IMP should be discontinued immediately, and the early withdrawal visit should 
be performed.

For follow-up guidance, please see section below “Follow-up of Liver Enzymes After 
Stopping Rules Are Met.”
Stopping Rules
In the following circumstances, the IMP will be discontinued immediately:

Any increase in ALT or AST to ≥3 × the ULN, combined with INR > 1.5 × the ULN 
or total bilirubin ≥2 × the ULN

Any increase in ALT or AST to ≥3 × the ULN, which is accompanied by symptoms 
clearly associated with impaired liver function (eg, vomiting, nausea, fever, rash, 
eosinophilia) and not deemed related to other diseases (eg, vomiting or nausea 
triggered by migraine)

Any increase in ALT or AST to levels ≥5 but < 8 × the ULN, which is persistent for 
≥2 weeks of repeated measurements

Any increase in ALT or AST to levels ≥8 × the ULN

In any case where monitoring of liver enzymes cannot be performed according to the 
protocol guidance
Follow-up of Liver Enzymes After Stopping Rules Are Met

A patient who meets the above criteria for discontinuation of the IMP should be 
invited to the trial site to return the IMP. Withdrawal visit activities should be 
performed as soon as possible.

Liver enzymes should be monitored until normalization or stabilization of the 
abnormality, based on the judgment of the investigator.

In any case, following the withdrawal visit, the minimal follow-up period will be 30 
days and will include measurement of liver enzymes at least once weekly.

Every effort should be made to complete the additional tests/evaluations, as described 
above.


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10.6
Appendix 6: Columbia-Suicide Severity Rating Scale (Baseline)


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10.7
Appendix 7: Columbia-Suicide Severity Rating Scale (Since Last 
Visit)


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10.8
Appendix 8: Clinical Criteria for Diagnosing Anaphylaxis
Anaphylaxis is highly likely when any 1 of the following 3 criteria are fulfilled:
1) Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (eg, generalized hives, pruritus or flushing, swollen lips-
tongue-uvula) AND AT LEAST ONE OF THE FOLLOWING
a) Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, 
reduced peak expiratory flow [PEF], hypoxemia)
b) Reduced blood pressure (BP) or associated symptoms of end-organ 
dysfunction (eg, hypotonia [collapse], syncope, incontinence)
2) Two or more of the following that occur rapidly after exposure to a likely allergen 
for that subject (minutes to several hours):
a) Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, 
swollen lips-tongue-uvula)
b) Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, 
reduced PEF, hypoxemia)
c) Reduced BP or associated symptoms (eg, hypotonia [collapse], syncope, 
incontinence)
d) Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting)
3) Reduced BP after exposure to known allergen for that subject (minutes to several 
hours):
a) Infants and children: low systolic BP (age specific) or greater than 30% 
decrease in systolic BP
b) Adults: systolic BP of less than 90 mmHg or greater than 30% decrease from 
that person’s baseline
Source: Sampson HA, Muñoz-Furlong A, Campbell RL, Adkinson NF, Jr, Bock SA, 
Branum A, et al. Second symposium on the definition and management of anaphylaxis:
summary report—Second National Institute of Allergy and Infectious Disease/Food 
Allergy and Anaphylaxis Network symposium. Ann Emerg Med. 2006;47(4):373-80.


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10.9
Appendix 9: Abbreviations
Abbreviation
Definition
ADA
Antidrug antibody
AI
Autoinjector
ALB
Albumin
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase 
AST
Aspartate aminotransferase
Bas
Basophil
BMI
Body mass index
BUN
Blood urea nitrogen
Ca
Calcium
CBC
Complete blood count
CGRP
Calcitonin gene-related peptide
CIOMS
Council for International Organizations of Medical Science
Cl
Chloride
CM
Chronic migraine
Cr
Creatinine
CRF
Case report form
C-SSRS
Columbia-Suicide Severity Rating Scale
eCRF
Electronic case report form
EDC
Electronic data capture
eDiary
Electronic diary
EDTA
Ethylenediaminetetraacetic acid
EM
Episodic migraine
Eos
Eosinophil
GCP
Good Clinical Practice
γ-GTP
Gamma-glutamyl transpeptidase
Hb
Hemoglobin
HBV
Hepatitis B virus
hCG
Human chorionic gonadotropin
Hct
Hematocrit
HCV
Hepatitis C virus
HIV
Human immunodeficiency virus
ICH
The International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use
ICHD-3
The International Classification of Headache Disorders, third edition
ICMJE
International Committee of Medical Journal Editors
IgG
Immunoglobulin G
IgM
Immunoglobulin M
IHS
Headache Classification Committee of the International Headache 
Society
INR
International normalized ratio
IRB
Institutional review board


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Abbreviation
Definition
IRE
Immediately reportable event
K
Potassium
LDH
Lactate (lactic acid) dehydrogenase
Lym
Lymphocyte
MCHC
Mean corpuscular hemoglobin concentration
MCV
Mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
Mon
Monocyte
Na
Sodium
Neu
Neutrophil
OTC
Over-the-counter
PEF
Peak expiratory flow
PFS
Pre-filled syringe
PLT
Platelet
PPT
Partial thromboplastin time
PQC
Product quality complaint
PT
Prothrombin time
QTcF
QT corrected for heart rate by Fridericia’s formula
RBC
Red blood cell count
RDW
Red cell distribution width
TEAE
Treatment-emergent adverse event
UA
Uric acid
ULN
Upper limit of normal
V
Visit
WBC
White blood cell count


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10.10
Appendix 10: Protocol Amendments
The investigator will not make any changes to this protocol without the sponsor’s prior 
written consent and subsequent approval by the IRB. Any permanent change to the 
protocol, whether an overall change or a change for specific trial site(s), must be handled 
as a protocol amendment. Any amendment will be written by the sponsor. Each 
amendment will be submitted to the IRB, as required by local regulations. Except for 
“administrative” or “nonsubstantial” amendments, investigators will wait for IRB 
approval of the amended protocol before implementing the change(s). Administrative 
amendments are defined as having no effect on the safety of subjects, conduct or 
management of the trial, trial design, or the quality or safety of IMP(s) used in the trial. A 
protocol change intended to eliminate an apparent immediate hazard to subjects should be 
implemented immediately, followed by IRB notification within local applicable 
timelines. The sponsor will submit protocol amendments to the applicable regulatory 
agencies within local applicable timelines.
When the IRB, investigators, and/or the sponsor conclude that the protocol amendment 
substantially alters the trial design and/or increases the potential risk to the subject, the 
currently approved written ICF will require similar modification. In such cases, after 
approval of the new ICF by the IRB, repeat written informed consent will be obtained 
from subjects enrolled in the trial before expecting continued participation and before the 
amendment-specified changes in the trial are implemented.


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10.10.1
Protocol Amendment(s)/Administrative Change(s)
[Amendment 1] Approval Date:
16 Mar 2020 
PURPOSE:
To clarify the text and revise written errors.
BACKGROUND:
Revisions were made to clarify the text and revise written errors.
MODIFICATIONS TO PROTOCOL:
Sectional Revisions:
Protocol Section
Before Revision
After Revision
1.3
Schedule of 
Assessments
Table 1.3-1
gAssessment of injection site reaction 
will be ..., the subject will be reassessed 
hourly thereafter until the reaction and/or 
pain is of moderate or less severity. The 
investigator will perform the assessment 
using a checksheet after completion of 
self-administration at the trial site.
hWomen of childbearing potential only. 
If the result of urine hCG test at 
screening is positive, serum hCG will be 
tested to confirm that the result is 
negative by Visit 2/Baseline. ...
iInquiries about AEs will be .... At each 
subject visit, the investigator will 
perform assessment based on an 
interview and the information recorded 
by the subject.
mBlood sampling for ADA assessment at 
Visit 2/Baseline will be performed before 
administration. ...
gAssessment of injection site reaction 
will be ..., the subject will be reassessed 
hourly thereafter until the reaction and/or 
pain is of moderate or less severity. The 
investigator will perform the 
assessment after completion of self-
administration at the trial site.
hWomen of childbearing potential only. 
If the result of urine hCG test at 
screening is positive, serum hCG will be 
tested to confirm that the result is 
negative. ...
iInquiries about AEs will be .... For self-
administration at home, when the 
subject visits the trial site the 
investigator will perform assessment 
based on an interview and the 
information recorded by the subject.
mBlood sampling for serum ADA
assessment at Visit 2/Baseline will be 
performed before administration. ...
6.1
Trial Treatments 
Administered
(the first part omitted)
The IMP can be used for up to 24 hours
after it has reached room temperature.
(the rest omitted)
(the first part omitted)
The IMP can be used for up to a 
cumulative total of 8 hours after it has 
reached room temperature.
(the rest omitted)
6.5
Concomitant 
Medications or 
Therapies
The investigator will record all 
medications and therapies taken by the 
subject from 5 months before the
screening examination 
(Visit 1/Screening) through the end of 
the evaluation period (defined as the time 
period during which subjects are 
The investigator will record all 
medications and therapies taken by the 
subject from 5 months before the start of 
IMP administration (Visit 2/Baseline) 
through the end of the evaluation period 
(defined as the time period during which 
subjects are evaluated for primary and 
exploratory objectives) on the eCRF.


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Protocol Section
Before Revision
After Revision
evaluated for primary and exploratory 
objectives) on the eCRF.
8.8.2
Clinical Laboratory 
Assessments
Clinical laboratory samples will be 
collected at the time points described in 
the schedule of assessments (Table 1.3-1) 
to perform the clinical laboratory 
assessments. The total volume of blood 
to be collected for each subject is 87 mL.
(the rest omitted)
(the middle part omitted)
For WOCBP, a urine or serum pregnancy 
test (hCG test) will be performed. If a 
urine test at screening is positive, the 
investigator will perform a serum hCG 
test for confirmation.
(the rest omitted)
Clinical laboratory samples will be 
collected at the time points described in 
the schedule of assessments (Table 1.3-1) 
to perform the clinical laboratory 
assessments. The total volume of blood 
to be collected for each subject is 
87 mL, including 15 mL (5 mL × 3) for 
serum ADA assessment and 24 mL 
(6 mL × 4) for determination of 
plasma drug concentrations in 
addition to blood samples for clinical 
laboratory tests.
(the rest omitted)
(the middle part omitted)
For WOCBP, a urine or serum pregnancy 
test (hCG test) will be performed. If a 
urine test at screening is positive, an 
hCG test will be performed with a 
serum sample collected for 
biochemistry during screening.
(the rest omitted)
8.9.1
Definitions
(the first part omitted)
An adverse drug reaction is any 
untoward and unintended response to an 
IMP related to any dose administered.
(the rest omitted)
(the first part omitted)
An adverse reaction is any untoward 
and unintended response to an IMP 
related to any dose administered.
(the rest omitted)
10.1.1
Ethics and 
Responsibility
(the first part omitted)
Financial aspects, subject insurance and 
the publication policy for the trial will be 
documented in the agreement between 
the sponsor and the trial site.
(the first part omitted)
Financial aspects, insurance coverage 
for subjects, etc, and the publication 
policy for the trial will be documented in 
the agreement between the sponsor and 
the trial site.
10.3
Appendix 3: 
Contraceptive 
Guidance and 
Collection of 
Pregnancy 
Information
(the first part omitted)
A urine pregnancy test for human 
chorionic gonadotropin (hCG) will be 
performed at screening and at each trial 
site visit on all FOCBP. If a urine test is 
positive at screening, the investigator 
will follow-up with a confirmatory serum 
test.
(the rest omitted)
(the first part omitted)
A urine pregnancy test for human 
chorionic gonadotropin (hCG) will be 
performed at screening and at each trial 
site visit on all FOCBP. If a urine test is 
positive at screening, a serum hCG test 
will be performed using serum samples 
obtained for clinical chemistry at 
screening examination.
(the rest omitted)
ADDITIONAL RISK TO THE SUBJECT:
There is no additional risk to the subjects.


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11
References
1
Armour KL, Clark MR, Hadley AG, Williamson LM. Recombinant human IgG 
molecules lacking Fcgamma receptor I binding and monocyte triggering activities. 
Eur J Immunol. 1999;29(8):2613-24.
2
Zeller J, Poulsen KT, Sutton JE, Abdiche YN, Collier S, Chopra R, et al. CGRP 
function-blocking antibodies inhibit neurogenic vasodilatation without affecting heart 
rate or arterial blood pressure in the rat. Br J Pharmacol. 2008;155(7):1093-103.
3
Cowan RP, Cohen JM, Ramirez-Campos V. Simulated Use of a Fremanezumab 
Autoinjector: Use as Intended, Ease of Use, and Comfort With Using the 
Autoinjector. 2019; presented at 61st Annual Scientific Meeting of the American 
Headache Society (AHS).
4
Headache Classification Committee of the International Headache Society. The 
International Classification of Headache Disorders 3rd edition .Cephalalgia 
2018;38(1): 1-211.
5
D’Amico D, Tepper SJ. Prophylaxis of migraine: general principles and patient 
acceptance. Neuropsychiatr Dis Treat 2008;4(6): 1155-67.
6
Lipton RB, Bigal ME, Diamond M, Freitag F, Reed ML, Stewart WF. Migraine 
prevalence, disease burden, and the need for preventive therapy. Neurology. 
2007;68(5):343-9.
7
Lipton RB, Stewart WF, Diamond S, Diamond ML, Reed M. Prevalence and burden 
of migraine in the United States: data from the American Migraine Study II. 
Headache 2001;41:646-57.
8
National Institute of Neurological Disorders and Stroke (NINDS). Migraine 
Information Page. Available at: https://www.ninds.nih.gov/Disorders/All-
Disorders/Migraine-Information-Page. Last updated March 27, 2019. Accessed July 
19, 2019.
9
Sakai F, Igarashi H. Prevalence of migraine in Japan: a nationwide survey. 
Cephalalgia. 1997;17(1):15-22.
10 INTAGE Healthcare Inc. Anterio Doctor Mindscape (ADM). 2019.
11 Seng EK, Rains JA, Nicholson RA, Lipton RB. Improving medication adherence in 
migraine treatment. Curr Pain Headache Rep.2015;19(6):24.
12 Hepp Z, Dodick DW, Varon SF, Gillard P, Hansen RN, Devine EB. Adherence to 
oral migraine-preventive medications among patients with chronic migraine. 
Cephalalgia. 2015;35(6):478-88.
13 Hepp Z, Bloudek LM, Varon SF. Systematic review of migraine prophylaxis 
adherence and persistence. J Manag Care Pharm.2014 ;20(1):22-33.
14 Lipton RB, Fanning KM, Serrano D, Reed ML, Cady R, Buse DC. Ineffective acute 
treatment of episodic migraine is associated with new-onset chronic migraine. 
Neurology. 2015;84(7):688-95.
15 Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, et al. The 
Columbia-Suicide Severity Rating Scale: initial validity and internal consistency 
findings from three multisite studies with adolescents and adults. Am J Psychiatry. 
2011;168(12):1266-77.


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16 Sampson HA, Muñoz-Furlong A, Campbell RL, Adkinson NF, Jr, Bock SA, Branum 
A, et al. Second symposium on the definition and management of anaphylaxis: 
summary report--Second National Institute of Allergy and Infectious Disease/Food 
Allergy and Anaphylaxis Network symposium. Ann Emerg Med. 2006;47(4):373-80.


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Agreement
I, the undersigned principal investigator, have read and understand the protocol (including the 
Investigator’s Brochure) and agree that it contains all the ethical, legal and scientific information 
necessary to conduct this trial in accordance with the principles of Good Clinical Practices and as 
described herein and in the sponsor’s (or designee’s) Clinical Trial Agreement.
I will provide copies of the protocol to all physicians, nurses, and other professional personnel to 
whom I delegate trial responsibilities. I will discuss the protocol with them to ensure that they are 
sufficiently informed regarding the investigational new drug, combination product of TEV-48125 and 
the AI, the concurrent medications, the efficacy and safety parameters and the conduct of the trial in 
general. I am aware that this protocol must be approved by the Institutional Review Board (IRB) 
responsible for such matters in the clinical trial facility where TEV-48125 will be tested prior to 
commencement of this trial. I agree to adhere strictly to the attached protocol (unless amended in the 
manner set forth in the sponsor's Clinical Trial Agreement, at which time I agree to adhere strictly to 
the protocol as amended).
I understand that this IRB-approved protocol will be submitted to the appropriate regulatory 
authority/ies by the sponsor. I agree that clinical data entered on eCRF by me and my staff will be 
utilized by the sponsor in various ways, such as for submission to governmental regulatory authorities 
and/or in combination with clinical data gathered from other research sites, whenever applicable. I 
agree to allow sponsor and designee monitors and auditors full access to all medical records at the 
research facility for subjects screened or enrolled in the trial.
I agree to await IRB approval before implementation of any substantial amendments to this protocol. 
If, however, I have failed to be in compliance with the protocol in order to avoid an immediate 
hazards to any trial subject, I will implement the amendment immediately, and provide the 
information to the IRB within the required local applicable timelines. Administrative changes to the 
protocol will be transmitted to the IRB for informational purposes only, if required by local 
regulations.
I agree to provide all subjects with informed consent forms, as required by the applicable regulations 
and by ICH guidelines. I agree to report to the sponsor any adverse experiences in accordance with the 
terms of the sponsor's Clinical Trial Agreement and the relevant regional regulation(s) and 
guideline(s). I further agree to provide all required information regarding financial certification or 
disclosure to the sponsor for all investigators and subinvestigators in accordance with the terms of the 
relevant regional regulation(s). I understand that participation in the protocol involves a commitment 
to publish the data from this trial in a cooperative publication before publication of efficacy and safety
results on an individual basis may occur, and I consent to be acknowledged in any such cooperative 
publications that result.
_______________________________
___________________________________
Principal Investigator Print Name
Trial Site
____________________________
__________________________
Signature
Date (DD Mon YYYY)
The sponsor signed this agreement electronically. The page of electronic signature is attached to this 
agreement.

SAP_001.pdf: 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
A multicenter, open-label trial to evaluate the safety of TEV-48125 when 
subcutaneously self-administered in migraine patients at the trial site and at home 
 
 
 
 
 
NCT Number: NCT04355117 
PRT NO.: 406-102-00005 
Version Date: 15 December 2020 (Version 1.0) 


 
 
 
 
Otsuka Pharmaceutical Co., Ltd. 
 
 
Investigational Medicinal Product 
TEV-48125 
 
 
Protocol No. 406-102-00005 
 
A multicenter, open-label trial to evaluate the safety of TEV-48125 when subcutaneously 
self-administered in migraine patients at the trial site and at home 
 
Statistical Analysis Plan 
 
Version: 1.0 
Date: 15 Dec 2020 
Protocol Date: 16 Mar 2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confidential 
May not be used, divulged, published, or otherwise disclosed without the prior written 
consent of Otsuka Pharmaceutical Co., Ltd. 
 


Protocol 406-102-00005 
 
 
Statistical Analysis Plan  
2 of 35 
Version Date: 12/15/2020 
 
Table of Contents 
Table of Contents ........................................................................................... 2 
List of Appendices.......................................................................................... 4 
List of Abbreviations and Definition of Terms ........................................... 5 
1 
Introduction .......................................................................................... 6 
2 
Trial Objective ...................................................................................... 6 
3 
Trial Design ........................................................................................... 6 
3.1 
Type/Design of Trial ...........................................................................................6 
3.2 
Trial Treatments ..................................................................................................7 
3.3 
Trial Population ...................................................................................................7 
4 
Sample Size ............................................................................................ 8 
5 
Statistical Analysis Sets ........................................................................ 8 
5.1 
Safety Set .............................................................................................................8 
5.2 
Efficacy Analysis Set ..........................................................................................8 
5.3 
Handling of Missing Data ...................................................................................8 
6 
Primary and Other Outcome Variables ............................................. 8 
7 
Disposition and Demographic Analysis .............................................. 9 
7.1 
Subject Disposition..............................................................................................9 
7.2 
Judgment on Self-administration.........................................................................9 
7.3 
Demographic and Baseline Characteristics .........................................................9 
7.4 
Baseline Disease Evaluation ...............................................................................9 
7.5 
Treatment Compliance ......................................................................................10 
7.6 
Prior and Concomitant Medications ..................................................................10 
7.7 
Protocol Deviations ...........................................................................................11 
8 
Efficacy Analyses ................................................................................ 11 
9 
Safety Analyses ................................................................................... 11 
9.1 
Extent of Exposure ............................................................................................11 
9.2 
Adverse Events ..................................................................................................12 
9.3 
Execution Status of Self-administration and Subject Compliance With 
Self-administration Procedure ...........................................................................13 
9.4 
Deficiencies With the Autoinjector Device .......................................................13 


Protocol 406-102-00005 
 
 
Statistical Analysis Plan  
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Version Date: 12/15/2020 
 
9.5 
Clinical Laboratory Data ...................................................................................13 
9.6 
Vital Sign and Weight Data...............................................................................13 
9.7 
Physical Examination Data ...............................................................................14 
9.8 
Electrocardiogram Data .....................................................................................14 
9.9 
Other Safety Data ..............................................................................................15 
9.9.1 
Injection Site Reactions ..................................................................................15 
9.9.2 
Columbia-Suicide Severity Rating Scale ........................................................15 
10 
Pharmacokinetic Analyses ................................................................. 15 
11 
Pharmacodynamic Analyses .............................................................. 15 
12 
Pharmacogenomic Analyses .............................................................. 15 
13 
Exploratory Endpoints ....................................................................... 15 
13.1.1 
Technical Computational Details for Headache-Related Data .......................15 
14 
Plasma Drug Concentration .............................................................. 17 
15 
Interim Analysis .................................................................................. 17 
16 
Changes in the Planned Analyses ...................................................... 17 
17 
References ............................................................................................ 18 
 


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List of Appendices 
Appendix 1 
Criteria for Identifying Potentially Clinically Significant 
Laboratory Values ......................................................................... 19 
Appendix 2 
Criteria for Identifying Potentially Clinically Significant 
Vital Signs ..................................................................................... 20 
Appendix 3 
Logics for Migraine Day Derivation............................................. 21 
Appendix 4 
List of Summary Tables ................................................................ 23 
Appendix 5 
List of Subject Data Listings......................................................... 34 


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List of Abbreviations and Definition of Terms 
 
Abbreviation Definition 
AI 
Autoinjector 
AE 
Adverse event 
CM 
Chronic migraine 
ECG 
Electrocardiogram 
eDiary 
Electronic headache diary 
EM 
Episodic migraine 
EOT 
End of Treatment 
EAS 
Efficacy Analysis Set 
ICHD-3 
The International Classification of Headache Disorders, 3rd edition 
IMP 
Investigational medicinal product 
MedDRA 
Medical Dictionary for Regulatory Activities 
PCS 
Potentially Clinically Significant 
PK 
Pharmacokinetic 
PT 
Preferred Term 
QTcB 
QT corrected for heart rate by Bazett’s formula 
QTcF 
QT corrected for heart rate by Fridericia’s formula 
SAP 
Statistical Analysis Plan 
SD 
Standard deviation 
SMQ 
Standardized MedDRA Queries 
SOC 
System Organ Class 
SS 
Safety Set 
TEAE 
Treatment-emergent adverse event 
 
 
 


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1 
Introduction 
This statistical analysis plan (SAP) documents the statistical methodology and data 
analysis algorithms and conventions to be applied for statistical analysis and reporting of 
efficacy, safety and pharmacokinetic data of Trial 406-102-00005. Analysis of 
immunogenicity is described in the bioanalytical protocol. All amendments to the 
protocol are taken into consideration in developing the SAP. 
2 
Trial Objective 
The primary objective is to assess the safety of TEV-48125 (generic name: 
fremanezumab) when subcutaneously self-administered in Japanese migraine patients 
using an autoinjector (AI) at home. 
3 
Trial Design 
3.1 
Type/Design of Trial 
This trial is a multicenter, open-label trial in migraine patients. The schematic of the trial 
design is shown in Figure 3.1-1 and trial assessment time points are summarized in the 
protocol Table1.3-1. 
The trial will consist of a 4-week screening period and an 8-week treatment period. 
After obtaining written informed consent from each subject, the investigator will screen 
the subject for eligibility (Visit 1/Screening). On each day during the screening and the 
treatment periods, subjects are to enter headache data in the electronic headache diary 
(eDiary) provided for use in this trial. 
By Visit 2/Baseline, the investigator will provide subjects who have been diagnosed with 
migraine and who meet all the inclusion criteria and do not fall under any of the 
exclusion criteria with sufficient instruction on self-administration using the “Procedure 
for TEV-48125 AI Self-administration.” At Visit 2/Baseline subjects for whom the 
investigator judges self-administration to be possible in compliance with the procedure 
will perform self-administration using the AI at the trial site under the supervision of the 
investigator. 
The investigator will confirm whether the subject is able to perform self-administration in 
compliance with the procedure, and judge whether self-administration at home is 
possible. Subjects for whom the investigator judges self-administration at home to be 
possible will perform self-administration using the AI at home after performing protocol-
specified procedures at Visit 3. Subjects will be asked to visit the trial site for blood 
sampling for plasma drug concentration measurement at 3 to 10 days after investigational 


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medicinal product (IMP) administration at Visit 2/Baseline and Visit 3. At 4 weeks after 
final IMP administration (self-administration at home) subjects will visit the trial site for 
the final evaluation (Visit 4/End of Treatment [EOT]). For subjects who are withdrawn 
from the trial, a withdrawal examination will be performed wherever possible. 
 
 
Figure 3.1-1 
Trial Design Schematic 
 
3.2 
Trial Treatments 
In this trial, each subject will subcutaneously self-administer TEV-48125 at 
225 mg/1.5 mL (150 mg/mL) once monthly for a total of 2 doses. The first dose will be 
self-administered at the trial site under the supervision of the investigator and the second 
dose will be self-administered at home. The injection site may be the back of the upper 
arm, the abdomen, or the front of the thigh. To the extent possible, the injection site 
should be the same for both doses (but not exactly in the same location). 
3.3 
Trial Population 
Migraine patients age 18 to 70 years, inclusive, who have a history of migraine (The 
International Classification of Headache Disorders, 3rd edition [ICHD-3] criteria [see 
Section 10.4 in the protocol]) or for whom clinical judgment suggests a migraine 
diagnosis (not better accounted for by another ICHD-3 diagnosis) for ≥ 12 months prior 
to giving informed consent. 
Subjects who are using preventive migraine medications (see Table 6.5.2-1 List of 
Restricted Concomitant Medications [Preventive Migraine Medications] in the protocol) 
will be permitted to continue using no more than 2 preventive migraine medications only 


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if the dose and regimen have been stable for at least 2 months prior to screening 
examination (Visit 1/Screening). 
4 
Sample Size  
The statistically required sample size based on power was not calculated. The sample size 
for evaluating the safety of TEV-48125 when subcutaneously self-administered at the 
trial site and at home was set at 50 subjects. 
5 
Statistical Analysis Sets 
5.1 
Safety Set 
The safety set (SS) includes all subjects who received at least one dose of IMP. 
5.2 
Efficacy Analysis Set 
The efficacy analysis set (EAS) includes all subjects who received at least one dose of 
IMP and have eDiary data for efficacy evaluation at baseline and for at least 10 days after 
baseline. 
5.3 
Handling of Missing Data 
Missing data will not be imputed. 
6 
Primary and Other Outcome Variables 
The primary objective is to assess the safety of TEV-48125 when subcutaneously self-
administered in Japanese migraine patients using an AI at home. 
The primary endpoint of the trial is the occurrence of adverse events (AEs), and the 
safety of the IMP will be assessed based on the occurrence of AEs. Other endpoints will 
include evaluation of the execution status of self-administration at home and subject 
compliance with the self-administration procedure, and an overall evaluation of the 
feasibility of self-administration of TEV-48125 at home. In addition, as the IMP is a 
combination product, any deficiencies with the AI device will also be evaluated.  
As exploratory endpoints, efficacy parameters including the number of migraine days, the 
number of headache days, and the number of headache days of at least moderate severity 
will be evaluated. 


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7 
Disposition and Demographic Analysis 
7.1 
Subject Disposition 
The number of subjects from whom informed consent has been obtained and the number 
of screen failure subjects and of enrolled subjects who are judged to be eligible will be 
summarized. For the enrolled subjects, the number and percentage of subjects in whom 
IMP is administrated, in whom IMP is not administrated, who completed the trial, who 
are withdrawn from the trial will be summarized. The primary reason for discontinuation 
will also be summarized. The number and percentage of subjects who are included in the 
SS and EAS, and who are excluded from the SS and EAS will be summarized. 
7.2 
Judgment on Self-administration 
For the enrolled subjects, frequency distributions for judgment on self-administration at 
the trial site and at home will be summarized. 
7.3 
Demographic and Baseline Characteristics 
Data will be summarized for the enrolled subjects.  
The following demographic and baseline characteristics will be summarized. Continuous 
variables will be summarized using descriptive statistics (number of subjects, mean, 
standard deviation (SD), median, minimum, and maximum; hereinafter the same applies). 
Categorical variables will be summarized using the number and percentage of subjects. 
 Age (45, ≥46 to 64, ≥65), sex (male, female) 
 Country, ethnicity, detailed ethnicity, race 
 Weight at screening, height, body mass index 
 Use of preventive migraine medication at baseline (yes, no) 
 Years since onset of migraines 
 
Medical history and complications will be coded by system organ class (SOC) and 
Medical Dictionary for Regulatory Activities (MedDRA Version 23.1) preferred term 
(PT). The number and percentage of subjects with medical history and complications will 
be summarized by SOC and PT for the enrolled subjects. Subjects are counted only once 
in each SOC and only once in each PT. 
7.4 
Baseline Disease Evaluation 
Data will be summarized for the enrolled subjects. 


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The following baseline disease evaluation will be summarized. Continuous variables will 
be summarized using descriptive statistics. Categorical variables will be summarized 
using the number and percentage of subjects. 
 Migraine subtype 
 Number of headache days of any duration and any severity 
 Number of migraine days  
 Number of headache days of at least moderate severity 
 
Migraine subtype (chronic migraine [CM] or episodic migraine [EM]) will be determined 
based on the eDiary data during the 28-day screening period (from Day −28 to Day −1). 
Criteria for CM and EM are defined as follows. 
[EM] 
Headache days: ≥ 4 and ≤ 14 days 
Migraine days: ≥ 4 days 
[CM] 
Headache days: ≥ 15 days 
Migraine days: ≥ 8 days 
Subjects who do not meet the criteria for CM and EM will be classified as “Other”. 
 
The baseline value will be calculated using all data collected from the day of 
V1/Screening through the day before V2/Baseline and normalized to 28 days (ie, if the 
number of days from V1/Screening through the day before V2/Baseline is greater or less 
than 28 days, the baseline value will be normalized to 28 days, see Section 13.1.1) using 
the electronic headache diary data collected through the corresponding headache diary 
questions. 
7.5 
Treatment Compliance 
The information for self-administration of IMP is described in Section 9.3. 
7.6 
Prior and Concomitant Medications 
Data will be summarized for the enrolled subjects. 
All prior and concomitant medications collected via case report form will be coded using 
the World Health Organization dictionary of medical codes (WHO Drug Dictionary 
Global B3 March 2020). The number and percentage of subjects with prior medications 
and concomitant medications will be summarized by medication class and preferred 
name. Subjects are counted only once in each medication class category, and only once in 
each preferred name category.  Prior medications will include all medications taken prior 


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to the first dose of IMP. Concomitant medications will include all medications taken after 
the first dose of IMP. 
The subset of prior medications and concomitant medications will be summarized for the 
following categories.  
 Prohibited and restricted medications for preventive treatment of migraine 
medication  
 Triptans and ergots for treatment of acute migraine  
 Non-steroidal anti-inflammatory drugs (NSAIDs) for treatment of acute migraine 
 Opioids for treatment of acute migraine 
 
Additionally, the number and percentage of subjects with restricted concomitant 
medications (preventive treatment of migraine medications, Table 6.5.2-1 in the protocol) 
used at baseline will also be summarized. 
7.7 
Protocol Deviations 
The number and percentage of subjects with any major protocol deviations and each 
classification will be provided in each trial site and overall site for enrolled subjects. 
8 
Efficacy Analyses 
The information for efficacy analyses is described in Section 13. 
9 
Safety Analyses 
The SS will be used for all safety analyses. Descriptive statistics will include number of 
subjects, mean, SD, median, minimum, and maximum. 
9.1 
Extent of Exposure 
Duration of treatment (days treated) is the number of days on treatment based on the first 
dose of IMP day and EOT visit day/early withdrawal day (EOT visit day – first day of 
IMP + 1). For subjects who are lost to follow-up, the EOT date is defined as the last dose 
of IMP date + 27. The number of subjects receiving ≥1 dose and ≥2 doses will be 
summarized. Duration of treatment (days) will be summarized using descriptive statistics 
and frequency distribution for the cumulative categories (>0 months, ≥1 month, and ≥2 
months). One month will be defined as 28 days. The total exposure of IMP allocated at 
each administration will also be summarized. 


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9.2 
Adverse Events  
All AEs will be coded by SOC and MedDRA PT.  The incidence of the following events 
will be summarized for overall treatment period, self-administration at trial site (at the 
time of or after the self-administration at trial site to before the self-administration at 
home), and self-administration at home (at the time of or after the self-administration at 
home to the end of study): 
  Treatment-emergent AEs (TEAEs) 
  TEAEs by severity 
  TEAEs with an outcome of death 
  Serious TEAEs 
  TEAEs leading to discontinuation of the IMP 
  TEAEs reported in at least 2% of subjects 
 
The above summaries will also be prepared for TEAEs potentially causally related to 
TEV-48125, TEAEs potentially causally related to AI device, and TEAEs potentially 
causally related to the subject’s manipulation. In addition, the following TEAEs will be 
tabulated. 
 
 Injection site reaction TEAEs 
Injection site reaction AEs are determined by the investigator. 
 Ophthalmic TEAEs of at least moderate severity 
Ophthalmic AEs are defined as coded Eye disorders (10015919) by SOC. 
 Drug-related Hepatic TEAEs 
Drug-related hepatic AEs will be captured using the standardized MedDRA query 
(SMQ) Drug related hepatic disorders - comprehensive search (20000006). 
 Anaphylaxis and severe hypersensitivity reaction TEAEs 
Anaphylaxis and severe hypersensitivity reaction AEs will be captured using the 
SMQ Hypersensitivity (20000214). 
 Cardiovascular-related TEAEs 
Cardiovascular-related AEs will be captured using the SMQ Central nervous 
system vascular disorders (20000060), Cardiac arrhythmias (20000049), Cardiac 
failure (20000004), Cardiomyopathy (20000150), Ischaemic heart disease 
(20000043), Hypertension (20000147), Torsade de pointes/QT prolongation 
(20000001), and coded Vascular disorders (10047065) by SOC. 
 Non-serious TEAEs reported in at least 5% of subjects 
 


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9.3 
Execution Status of Self-administration and Subject Compliance 
With Self-administration Procedure 
Frequency distributions will be determined by location (at trial site or at home) for the 
execution status of self-administration and subject compliance with the self-
administration procedure. 
Frequency distributions for the execution status of self-administration and subject 
compliance with self-administration procedure will be summarized for self-
administration at trial site and for self-administration at home. Status of leakage of drug 
solution on the skin after subcutaneous injection will also be summarized using 
dichotomized categories (0 to 2 and 3 to 4) of the descriptions. 
9.4 
Deficiencies With the Autoinjector Device 
Deficiencies with the AI device will be listed. 
9.5 
Clinical Laboratory Data 
Descriptive statistics will be calculated for clinical laboratory data and changes from 
baseline at each time point (Baseline, V3/Month 1, V4/Month 2, and final evaluation). 
Frequency distributions with the numbers and percentages of subjects with potentially 
clinically significant (PCS) values with any post-baseline (including unscheduled 
assessments and final evaluation) will be presented. The denominator for calculating the 
percentage of subjects will be the number of subjects with at least one post-baseline result 
for each test. Listing of subjects with PCS values will be prepared. The criteria are 
presented in Appendix 1. 
For clinical laboratory items, other than qualitative urinalysis, the baseline and post-
baseline values will be assessed as normal, high, or low, based on the reference range, 
and shift tables of those values will be prepared for each time point. 
Baseline value will be the last value prior to the first dose of IMP. Each time point for 
post-baseline will be the nominal visits. Final evaluation will be based on the last 
observed post-baseline data (including scheduled, unscheduled, and withdrawal visits). 
Summaries of PCS values will include all post-baseline data. 
9.6 
Vital Sign and Weight Data 
Descriptive statistics will be calculated for vital sign and weight measurements and 
changes from baseline at each time point (Baseline, V3/Month 1, V4/Month 2, and final 
evaluation).  


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Frequency distributions with the numbers and percentages of subjects with PCS values 
with any post-baseline (including unscheduled assessments and final evaluation) will be 
presented. The denominator for calculating the percentage of subjects will be the number 
of subjects with at least one post-baseline result for each test item. Listing of subjects 
with PCS values will be prepared. The criteria are presented in Appendix 2. 
Baseline value will be the last value prior to the first dose of IMP. Each time point for 
post-baseline will be the nominal visits. Final evaluation will be based on the last 
observed post-baseline data (including scheduled, unscheduled, and withdrawal visits). 
Summaries of PCS values will include all post-baseline data. 
9.7 
Physical Examination Data 
A listing of physical examination findings will be prepared for each subject. 
9.8 
Electrocardiogram Data 
Descriptive statistics will be calculated for electrocardiogram (ECG) measurements and 
changes from baseline at each time point (Baseline, V3/Month 1, V4/Month 2, and final 
evaluation). Shift tables will be created for baseline vs post-baseline assessment results 
(normal, abnormal not clinically significant, or abnormal clinically significant) at final 
evaluation vs worst value at any time point. 
For QTcB and QTcF, frequency distributions with the numbers and percentages of 
subjects will be presented for the following criteria:  
 Subject with a value of >450 msec post-baseline*  
 Subject with a value of >480 msec post-baseline*  
 Subject with a value of >500 msec post-baseline* 
 Subject with prolongation from baseline of >30 msec at post-baseline* 
 Subject with prolongation from baseline of >60 msec at post-baseline* 
* “post-baseline” in the above criteria are at final evaluation and worst value.  
 
Baseline value will be the last value prior to the first dose of IMP. Each time point for 
post-baseline will be the nominal visits. Final evaluation will be based on the last 
observed post-baseline data (including scheduled, unscheduled and withdrawal visits). 
Worst value will be derived using all post-baseline data. 


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9.9 
Other Safety Data 
9.9.1 
Injection Site Reactions 
For severities of the injection site reactions (erythema, induration, ecchymosis, and pain), 
frequency distributions will be obtained by IMP administration visit (V2/Self-
administration at the Trial Site and V3/Self-administration at Home) and time point   
(immediately postdose and 1 hour postdose). 
9.9.2 
Columbia-Suicide Severity Rating Scale 
A listing of subjects showing suicidal ideation or behavior, evaluated based on the C-
SSRS results, will be prepared. 
10 
Pharmacokinetic Analyses 
Not applicable. 
11 
Pharmacodynamic Analyses 
Not applicable. 
12 
Pharmacogenomic Analyses 
Not applicable. 
13 
Exploratory Endpoints 
For the EAS, descriptive statistics of values and changes from baseline in the monthly 
average number of migraine days during the 8-week period after the first dose of IMP 
and during the 4-week period after each dose will be summarized. The same analysis will 
be performed for the number of headache days of at least moderate severity and the 
number of headache days of any severity. 
Proportion of subjects reaching at least 50% reduction in the monthly average number of 
migraine days during the 8-week period after the first dose of IMP and during the 4-week 
period after each dose will be summarized. The same analysis will be performed for 
number of headache days of at least moderate severity. 
13.1.1 
Technical Computational Details for Headache-Related Data 
 Definition of migraine day  
A migraine day for CM subjects is defined as when at least one of the following 
situations occurs: 


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 A calendar day (0000 to 2359) with at least 4 consecutive hours of headache 
meeting the criteria for migraine with or without aura 
 A calendar day (0000 to 2359) with at least 4 consecutive hours of headache 
meeting the criteria for probable migraine, a migraine subtype where only 
one migraine criterion is missing 
 A calendar day (0000 to 2359) with a headache of any duration that was 
treated with migraine-specific medication (triptans and ergot compounds) 
A migraine day for EM and other subjects is defined as when at least one of the 
following situations occurs: 
 A calendar day (0000 to 2359) with at least 2 consecutive hours of headache 
meeting the criteria for migraine with or without aura 
 A calendar day (0000 to 2359) with at least 2 consecutive hours of headache 
meeting the criteria for probable migraine, a migraine subtype where only 
one migraine criterion is missing 
 A calendar day (0000 to 2359) with a headache of any duration that was 
treated with migraine specific-medication (triptans and ergot compounds) 
The derivation logic is presented in Appendix 3. 
 Definition of headache day of at least moderate severity 
A headache day of at least moderate severity is defined as when at least one of the 
following situations occurs: 
 A calendar day (0000 to 2359) with headache pain that lasts ≥4 hours with a 
peak severity of at least moderate severity  
 A calendar day (0000 to 2359) when the subject used acute migraine-specific 
medication (triptans or ergots) to treat a headache of any severity or duration 
 Definition of headache day of any severity 
The headache day of any severity is defined as a calendar day (0000 to 2359) with 
headache pain that lasts ≥4 hours of any severity or a day when the subject used 
acute migraine-specific medication (triptans or ergots) to treat headache of any 
severity or duration. 
 Variable definitions 
The baseline value will be calculated using all data collected from the day of 
V1/Screening through the day before V2/Baseline and normalized to 28 days (ie, 
if the number of days from V1/Screening through the day before V2/Baseline is 
greater or less than 28 days, the baseline value will be normalized to 28 days; see 
the following formula). 
∑𝐷𝑎𝑦𝑠 𝑜𝑓 𝑒𝑓𝑓𝑖𝑐𝑎𝑐𝑦 𝑣𝑎𝑟𝑖𝑎𝑏𝑙𝑒 𝑑𝑢𝑟𝑖𝑛𝑔 𝑡ℎ𝑒 𝑠𝑐𝑟𝑒𝑒𝑛𝑖𝑛𝑔 𝑝𝑒𝑟𝑖𝑜𝑑
∑𝐷𝑎𝑦𝑠 𝑤𝑖𝑡ℎ 𝑎𝑠𝑠𝑒𝑠𝑠𝑚𝑒𝑛𝑡𝑠 𝑟𝑒𝑐𝑜𝑟𝑑𝑒𝑑 𝑖𝑛 𝑡ℎ𝑒 𝑒𝐷𝑖𝑎𝑟𝑦 𝑓𝑜𝑟 𝑡ℎ𝑒 𝑠𝑐𝑟𝑒𝑒𝑛𝑖𝑛𝑔 𝑝𝑒𝑟𝑖𝑜𝑑× 28 
The monthly average number of efficacy endpoints (eg, migraine days, headache 
days of at least moderate severity, etc.) during the 8-week period after the first 
dose of IMP will be derived and normalized to 28 days (see the following 
formula), if a subject has ≥10 days of electronic headache diary data after the first 
dose of IMP.  


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∑𝐷𝑎𝑦𝑠 𝑜𝑓 𝑒𝑓𝑓𝑖𝑐𝑎𝑐𝑦 𝑣𝑎𝑟𝑖𝑎𝑏𝑙𝑒 𝑜𝑣𝑒𝑟 𝑡ℎ𝑒 8 𝑤𝑒𝑒𝑘 𝑝𝑒𝑟𝑖𝑜𝑑
∑𝐷𝑎𝑦𝑠 𝑤𝑖𝑡ℎ 𝑎𝑠𝑠𝑒𝑠𝑠𝑚𝑒𝑛𝑡𝑠 𝑟𝑒𝑐𝑜𝑟𝑑𝑒𝑑 𝑖𝑛 𝑡ℎ𝑒 𝑒𝐷𝑖𝑎𝑟𝑦 𝑓𝑜𝑟 𝑡ℎ𝑒 8 𝑤𝑒𝑒𝑘 𝑝𝑒𝑟𝑖𝑜𝑑× 28 
The monthly number of days of efficacy endpoints (eg, migraine days, headache 
days of at least moderate severity, etc.) during a 4-week period after each dose at 
Visits 2 and Visit 3 (ie, for Months 1 and Month 2) will be derived and 
normalized to 28 days (see the following formula), respectively. If a subject is 
withdrawn early or has intermittent missing days and has <10 days of electronic 
headache diary entries for a month, that month’s value will be considered as 
missing. 
∑𝐷𝑎𝑦𝑠 𝑜𝑓 𝑒𝑓𝑓𝑖𝑐𝑎𝑐𝑦 𝑣𝑎𝑟𝑖𝑎𝑏𝑙𝑒 𝑜𝑣𝑒𝑟 𝑡ℎ𝑒 4 𝑤𝑒𝑒𝑘 𝑝𝑒𝑟𝑖𝑜𝑑
∑𝐷𝑎𝑦𝑠 𝑤𝑖𝑡ℎ 𝑎𝑠𝑠𝑒𝑠𝑠𝑚𝑒𝑛𝑡𝑠 𝑟𝑒𝑐𝑜𝑟𝑑𝑒𝑑 𝑖𝑛 𝑡ℎ𝑒 𝑒𝐷𝑖𝑎𝑟𝑦 𝑓𝑜𝑟 𝑡ℎ𝑒 4 𝑤𝑒𝑒𝑘 𝑝𝑒𝑟𝑖𝑜𝑑× 28 
 
14 
Plasma Drug Concentration 
For the SS, descriptive statistics will be calculated for measured values at each sampling 
time point for plasma drug concentration. Box-plot and scatter plot for measured values 
will be provided. 
15 
Interim Analysis 
None. 
16 Changes in the Planned Analyses 
The categorical analysis for QTcB is added in Section 9.8. 


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17 
References 
None. 
 


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Appendix 1 
Criteria for Identifying Potentially Clinically Significant 
Laboratory Values 
Laboratory Tests 
Criteria 
Serum chemistry 
 
 
Alanine aminotransferase 
 
 3 x upper limit of normal 
 
Aspartate aminotransferase 
 
 3 x upper limit of normal 
 
Alkaline phosphatase 
 
 3 x upper limit of normal 
 
Gamma glutamyl transferase 
 
 3 x upper limit of normal 
 
Lactate dehydrogenase 
 
 3 x upper limit of normal 
 
Urea Nitrogen 
 
 30 mg/dL 
 
Creatinine 
 
 2.0 mg/dL 
 
Total bilirubin 
 
 2.0 mg/dL 
Coagulation 
 
 
International normalized ratio 
 
> 1.5 
Hematology 
 
 
Hematocrit 
 
 
 
Male 
 
< 37 %  
 
 
Female 
 
< 32 % 
 
Hemoglobin 
 
 
 
Male 
 
 11.5 g/dL 
 
 
Female 
 
 9.5 g/dL 
 
Leukocytes count 
 
 3,000 uL or  20,000/ uL 
 
Eosinophils 
 
 10% 
 
Neutrophils 
 
 1,000 uL 
 
Platelet count 
 
 7.5 10^4/uL  or  70 10^4/uL  
Urinalysis 
 
 
Occult blood 
 
 2 units increase from baseline 
 
Glucose  
 
 2 units increase from baseline 
 
Ketones 
 
 2 units increase from baseline 
 
Protein  
 
 2 units increase from baseline 
 


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Appendix 2 
Criteria for Identifying Potentially Clinically Significant Vital 
Signs 
Variable 
Criterion Value 
Change Relative to Baseline 
Pulse Rate 
 
 120 beats/min 
 
 50 beats/min 
 
Increase of  15 beats/min 
 
Decrease of  15 beats/min 
Systolic Blood Pressure 
 
 180 mmHg 
 
 90 mmHg 
 
Increase of  20 mmHg 
 
Decrease of  20 mmHg 
Diastolic Blood Pressure 
 
 105 mmHg 
 
 50 mmHg 
 
Increase of  15 mmHg 
 
Decrease of  15 mmHg 
Respiratory Rate 
 
< 10 breaths/min 
 
- 
Body Temperature 
 
≥ 38.3C 
 
Change of  1.1C 
 


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Appendix 3 
Logics for Migraine Day Derivation 
Migraine Day will be 1 of the following 4 options. 
Option 1: Part 1 met and at least 2 of the Part 2 met and at least 1 of the Part 3 met 
Option 2: A1 = Yes and D3 = Yes (medication were “Ergot” or “Triptan”) 
Option 3: A1 = Yes and “B7 = Yes and/or B8 = Yes” 
Option 4 (Probable Migraine):  
-Part 1 met and at least 2 of the Part 2 met, and only one of met in “B5 = Yes or B6 = 
Yes” 
-Part 1 met and at least 1 of the Part 3 met, and only one of met in Part 2 
-At least 2 of the Part 2 met, at least 1 of the Part 3 met, and A1 = Yes 
Part  
Electronic Headache Diary Questionnaire 
Part 1  
1 
A1 = Yes 
2 for CM subjects 
A2 = Yes  
2 for EM and other 
subjects 
A2 = Yes or A3 = Yes 
Part 2 
1 
A4 = Moderate or Severe 
2 
B1 = Yes 
3 
B2 = Yes 
4 
B3 = Yes 
Part 3  
1 
B4 = Yes 
2 
B5 = Yes and B6 = Yes 
CM = Chronic migraine; EM = Episodic migraine 
 
 Electronic Headache Diary Questionnaire 
A1 
Did you experience a headache of any severity yesterday? 
A2 
Did you have at least four (4) consecutive hours of headache yesterday? 
A3 
Did you have at least two (2) consecutive hours of headache yesterday? 
A4 
What was the greatest severity that your headache reached at anytime yesterday? 
A5 
How many total hours did you have a headache of any severity yesterday? 
A6 
How many total hours of moderate or severe headache did you have yesterday? 
B1 
Was it worse on one side of the head than on the other, and/or limited to one side of the head? 
B2 
Was it pounding, pulsating, or throbbing? 
B3 
Was it made worse by routine activities such as walking or climbing stairs? 
B4 
Did you have nausea, or get sick to your stomach? 
B5 
Did light bother you more than when you didn't have a headache (did you experience 
photophobia)? 
B6 
Did sounds bother you more than when you didn't have a headache (did you experience 
phonophobia)? 
B7 
Did you experience something like seeing spots, stars, lines, flashing lights, zigzag lines, or 
"heat waves" around the time of your headache? (This is different from "light bothers you".) 
B8 
Did you have feelings such as numbness or tingling in any part of your body or face around the 
time of your headache? 


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B9 
Did you experience something like seeing spots, stars, lines, flashing lights, zigzag lines, or 
"heat waves" similar to those you may have seen when you have a headache? (This is different 
from "light bothers you") 
B10 
Did you have feelings such as numbness or tingling in any part of your body or face, similar to 
what you may have felt when you have a headache? 
C1 
What would better describe in general, how did you feel yesterday? 
D1 
Did you take any medications yesterday for your headache/migraine? 
D2 
Did you use any over the counter medications in an effort to get relief from your 
headache/migraine? 
D3 
Did you use Ergot/Triptan in an effort to get relief from your headache/migraine? 
D4 
Did you use any prescription medications other than Ergot/Triptan in an effort to get relief from 
your headache/migraine? 
 


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Appendix 4 
List of Summary Tables 
 
CT-1.1 
Subject Disposition (All Subjects) 
CT-1.2 
Judgment on Self-administration (Enrolled Subjects) 
CT-2 
Reasons for Discontinuation (Enrolled Subjects) 
CT-3.1 
Demographics and Baseline Characteristics (Enrolled Subjects) 
CT-3.2 
Medical History by MedDRA SOC and PT (Enrolled Subjects) 
CT-3.3 
Complications by MedDRA SOC and PT (Enrolled Subjects) 
CT-3.4 
Baseline Disease Evaluation - Electronic Headache Diary Data 
(Enrolled Subjects) 
CT-4.1.1 
Prior Medications by WHO Drug Medication Class and Preferred 
Name (Enrolled Subjects) 
CT-4.1.2 
Prior Medications for Migraine by WHO Drug Medication Class and 
Preferred Name, Prohibited and Restricted Medications for Preventive 
Treatment of Migraine Medication (Enrolled Subjects) 
CT-4.1.3 
Prior Medications for Migraine by WHO Drug Medication Class and 
Preferred Name, Triptans and Ergots for Treatment of Acute Migraine 
(Enrolled Subjects) 
CT-4.1.4 
Prior Medications for Migraine by WHO Drug Medication Class and 
Preferred Name, NSAIDs for Treatment of Acute Migraine (Enrolled 
Subjects) 
CT-4.1.5 
Prior Medications for Migraine by WHO Drug Medication Class and 
Preferred Name, Opioids for Treatment of Acute Migraine (Enrolled 
Subjects) 
CT-4.2.1 
Concomitant Medications by WHO Drug Medication Class and 
Preferred Name (Enrolled Subjects) 
CT-4.2.2 
Concomitant Medications for Migraine by WHO Drug Medication 
Class and Preferred Name, Prohibited and Restricted Medications for 
Preventive Treatment of Migraine (Enrolled Subjects) 


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CT-4.2.3 
Concomitant Medications for Migraine by WHO Drug Medication 
Class and Preferred Name, Triptans and Ergots for Treatment of 
Acute Migraine (Enrolled Subjects) 
CT-4.2.4 
Concomitant Medications for Migraine by WHO Drug Medication 
Class and Preferred Name, NSAIDs for Treatment of Acute Migraine 
(Enrolled Subjects) 
CT-4.2.5 
Concomitant Medications for Migraine by WHO Drug Medication 
Class and Preferred Name, Opioids for Treatment of Acute Migraine 
(Enrolled Subjects) 
CT-4.3 
Restricted Preventive Migraine Medications at Baseline by WHO 
Drug Medication Class and Preferred Name (Enrolled Subjects) 
CT-4.4 
Major Protocol Deviations (Enrolled Subjects) 
CT-5.1 
Change From Baseline in Monthly Number of Migraine Days (EAS) 
CT-5.2 
Change From Baseline in Monthly Number of Headache Days of at 
Least Moderate Severity (EAS) 
CT-5.3 
Proportion of Subjects With 50% or Greater Reduction in Monthly 
Number of Migraine Days (EAS) 
CT-5.4 
Proportion of Subjects With 50% or Greater Reduction in Monthly 
Number of Headache Days of at Least Moderate Severity (EAS) 
CT-5.5 
Change From Baseline in Monthly Number of Headache Days of Any 
Severity (EAS) 
CT-7.1 
Duration of Treatment (Days) and Extent of Exposure to Trial 
Medication (SS) 
CT-7.2 
Number of Doses of Trial Medication (SS) 
CT-7.3 
Duration of treatment, Number and Percentage of Subjects (SS) 
CT-7.4.1 
Execution Status of Self-administration - Amount of Drug Solution 
Remaining in the AI (SS) 


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CT-7.4.2 
Execution Status of Self-administration - Leakage of Drug Solution 
on the Skin After Subcutaneous Injection (SS) 
CT-7.5 
Subject Compliance with Self-administration Procedure (SS) 
CT-8.1.1 
Summary of AEs for Overall Treatment Period (SS) 
CT-8.1.2 
Summary of AEs for Self-Administration at Trial Site (SS) 
CT-8.1.3 
Summary of AEs for Self-Administration at Home (SS) 
CT-8.2.1.1 
TEAEs by MedDRA SOC and PT for Overall Treatment Period (SS) 
CT-8.2.1.2 
TEAEs by MedDRA SOC and PT for Self-Administration at Trial 
Site (SS) 
CT-8.2.1.3 
TEAEs by MedDRA SOC and PT for Self-Administration at Home 
(SS) 
CT-8.2.2.1 
Potentially Drug-related TEAEs by MedDRA SOC and PT for 
Overall Treatment Period (SS) 
CT-8.2.2.2 
Potentially Drug-related TEAEs by MedDRA SOC and PT for Self-
Administration at Trial Site (SS) 
CT-8.2.2.3 
Potentially Drug-related TEAEs by MedDRA SOC and PT for Self-
Administration at Home (SS) 
CT-8.2.3.1 
TEAEs Related to AI Device by MedDRA SOC and PT for Overall 
Treatment Period (SS) 
CT-8.2.3.2 
TEAEs Related to AI Device by MedDRA SOC and PT for Self-
Administration at Trial Site (SS) 
CT-8.2.3.3 
TEAEs Related to AI Device by MedDRA SOC and PT for Self-
Administration at Home (SS) 
CT-8.2.4.1 
TEAEs Related to Subject Manipulation by MedDRA SOC and PT 
for Overall Treatment Period (SS) 
CT-8.2.4.2 
TEAEs Related to Subject Manipulation by MedDRA SOC and PT 
for Self-Administration at Trial Site (SS) 
CT-8.2.4.3 
TEAEs Related to Subject Manipulation by MedDRA SOC and PT 
for Self-Administration at Home (SS) 


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CT-8.3.1.1 
TEAEs by Severity by MedDRA SOC and PT for Overall Treatment 
Period (SS) 
CT-8.3.1.2 
TEAEs by Severity by MedDRA SOC and PT for Self-Administration 
at Trial Site (SS) 
CT-8.3.1.3 
TEAEs by Severity by MedDRA SOC and PT for Self-Administration 
at Home (SS) 
CT-8.3.2.1 
Potentially Drug-related TEAEs by Severity by MedDRA SOC and 
PT for Overall Treatment Period (SS) 
CT-8.3.2.2 
Potentially Drug-related TEAEs by Severity by MedDRA SOC and 
PT for Self-Administration at Trial Site (SS) 
CT-8.3.2.3 
Potentially Drug-related TEAEs by Severity by MedDRA SOC and 
PT for Self-Administration at Home (SS) 
CT-8.3.3.1 
TEAEs Related to AI Device by Severity by MedDRA SOC and PT 
for Overall Treatment Period (SS) 
CT-8.3.3.2 
TEAEs Related to AI Device by Severity by MedDRA SOC and PT 
for Self-Administration at Trial Site (SS) 
CT-8.3.3.3 
TEAEs Related to AI Device by Severity by MedDRA SOC and PT 
for Self-Administration at Home (SS) 
CT-8.3.4.1 
TEAEs Related to Subject Manipulation by Severity by MedDRA 
SOC and PT for Overall Treatment Period (SS) 
CT-8.3.4.2 
TEAEs Related to Subject Manipulation by Severity by MedDRA 
SOC and PT for Self-Administration at Trial Site (SS) 
CT-8.3.4.3 
TEAEs Related to Subject Manipulation by Severity by MedDRA 
SOC and PT for Self-Administration at Home (SS) 
CT-8.4.1.1 
TEAEs With an Outcome of Death by MedDRA SOC and PT for 
Overall Treatment Period (SS) 
CT-8.4.1.2 
TEAEs With an Outcome of Death by MedDRA SOC and PT for 
Self-Administration at Trial Site (SS) 
CT-8.4.1.3 
TEAEs With an Outcome of Death by MedDRA SOC and PT for 
Self-Administration at Home (SS) 


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CT-8.4.2.1 
Potentially Drug-related TEAEs With an Outcome of Death by 
MedDRA SOC and PT for Overall Treatment Period (SS) 
CT-8.4.2.2 
Potentially Drug-related TEAEs With an Outcome of Death by 
MedDRA SOC and PT for Self-Administration at Trial Site (SS) 
CT-8.4.2.3 
Potentially Drug-related TEAEs With an Outcome of Death by 
MedDRA SOC and PT for Self-Administration at Home (SS) 
CT-8.4.3.1 
TEAEs Related to AI Device With an Outcome of Death by MedDRA 
SOC and PT for Overall Treatment Period (SS) 
CT-8.4.3.2 
TEAEs Related to AI Device With an Outcome of Death by MedDRA 
SOC and PT for Self-Administration at Trial Site (SS) 
CT-8.4.3.3 
TEAEs Related to AI Device With an Outcome of Death by MedDRA 
SOC and PT for Self-Administration at Home (SS) 
CT-8.4.4.1 
TEAEs Related to Subject Manipulation With an Outcome of Death 
by MedDRA SOC and PT for Overall Treatment Period (SS) 
CT-8.4.4.2 
TEAEs Related to Subject Manipulation With an Outcome of Death 
by MedDRA SOC and PT for Self-Administration at Trial Site (SS) 
CT-8.4.4.3 
TEAEs Related to Subject Manipulation With an Outcome of Death 
by MedDRA SOC and PT for Self-Administration at Home (SS) 
CT-8.5.1.1 
Serious TEAEs by MedDRA SOC and PT for Overall Treatment 
Period (SS) 
CT-8.5.1.2 
Serious TEAEs by MedDRA SOC and PT for Self-Administration at 
Trial Site (SS) 
CT-8.5.1.3 
Serious TEAEs by MedDRA SOC and PT for Self-Administration at 
Home (SS) 
CT-8.5.2.1 
Potentially Drug-related Serious TEAEs by MedDRA SOC and PT 
for Overall Treatment Period (SS) 


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CT-8.5.2.2 
Potentially Drug-related Serious TEAEs by MedDRA SOC and PT 
for Self-Administration at Trial Site (SS) 
CT-8.5.2.3 
Potentially Drug-related Serious TEAEs by MedDRA SOC and PT 
for Self-Administration at Home (SS) 
CT-8.5.3.1 
Serious TEAEs Related to AI Device by MedDRA SOC and PT for 
Overall Treatment Period (SS) 
CT-8.5.3.2 
Serious TEAEs Related to AI Device by MedDRA SOC and PT for 
Self-Administration at Trial Site (SS) 
CT-8.5.3.3 
Serious TEAEs Related to AI Device by MedDRA SOC and PT for 
Self-Administration at Home (SS) 
CT-8.5.4.1 
Serious TEAEs Related to Subject Manipulation by MedDRA SOC 
and PT for Overall Treatment Period (SS) 
CT-8.5.4.2 
Serious TEAEs Related to Subject Manipulation by MedDRA SOC 
and PT for Self-Administration at Trial Site (SS) 
CT-8.5.4.3 
Serious TEAEs Related to Subject Manipulation by MedDRA SOC 
and PT for Self-Administration at Home (SS) 
CT-8.6.1.1 
TEAEs Leading to Discontinuation of the IMP by MedDRA SOC and 
PT for Overall Treatment Period (SS) 
CT-8.6.1.2 
TEAEs Leading to Discontinuation of the IMP by MedDRA SOC and 
PT for Self-Administration at Trial Site (SS) 
CT-8.6.1.3 
TEAEs Leading to Discontinuation of the IMP by MedDRA SOC and 
PT for Self-Administration at Home (SS) 
CT-8.6.2.1 
Potentially Drug-related TEAEs Leading to Discontinuation of the 
IMP by MedDRA SOC and PT for Overall Treatment Period (SS) 
CT-8.6.2.2 
Potentially Drug-related TEAEs Leading to Discontinuation of the 
IMP by MedDRA SOC and PT for Self-Administration at Trial Site 
(SS) 
CT-8.6.2.3 
Potentially Drug-related TEAEs Leading to Discontinuation of the 
IMP by MedDRA SOC and PT for Self-Administration at Home (SS) 


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CT-8.6.3.1 
TEAEs Related to AI Device Leading to Discontinuation of the IMP 
by MedDRA SOC and PT for Overall Treatment Period (SS) 
CT-8.6.3.2 
TEAEs Related to AI Device Leading to Discontinuation of the IMP 
by MedDRA SOC and PT for Self-Administration at Trial Site (SS) 
CT-8.6.3.3 
TEAEs Related to AI Device Leading to Discontinuation of the IMP 
by MedDRA SOC and PT for Self-Administration at Home (SS) 
CT-8.6.4.1 
TEAEs Related to Subject Manipulation Leading to Discontinuation 
of the IMP by MedDRA SOC and PT for Overall Treatment Period 
(SS) 
CT-8.6.4.2 
TEAEs Related to Subject Manipulation Leading to Discontinuation 
of the IMP by MedDRA SOC and PT for Self-Administration at Trial 
Site (SS) 
CT-8.6.4.3 
TEAEs Related to Subject Manipulation Leading to Discontinuation 
of the IMP by MedDRA SOC and PT for Self-Administration at 
Home (SS) 
CT-8.7.1.1 
TEAEs Reported in at Least 2% of Subjects for Overall Treatment 
Period (SS) 
CT-8.7.1.2 
TEAEs Reported in at Least 2% of Subjects for Self-Administration at 
Trial Site (SS) 
CT-8.7.1.3 
TEAEs Reported in at Least 2% of Subjects for Self-Administration at 
Home (SS) 
CT-8.7.2.1 
Potentially Drug-related TEAEs Reported in at Least 2% of Subjects 
for Overall Treatment Period (SS) 
CT-8.7.2.2 
Potentially Drug-related TEAEs Reported in at Least 2% of Subjects 
for Self-Administration at Trial Site (SS) 
CT-8.7.2.3 
Potentially Drug-related TEAEs Reported in at Least 2% of Subjects 
for Self-Administration at Home (SS) 
CT-8.7.3.1 
TEAEs Related to AI Device Reported in at Least 2% of Subjects for 
Overall Treatment Period (SS) 


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CT-8.7.3.2 
TEAEs Related to AI Device Reported in at Least 2% of Subjects for 
Self-Administration at Trial Site (SS) 
CT-8.7.3.3 
TEAEs Related to AI Device Reported in at Least 2% of Subjects for 
Self-Administration at Home (SS) 
CT-8.7.4.1 
TEAEs Related to Subject Manipulation Reported in at Least 2% of 
Subjects for Overall Treatment Period (SS) 
CT-8.7.4.2 
TEAEs Related to Subject Manipulation Reported in at Least 2% of 
Subjects for Self-Administration at Trial Site (SS) 
CT-8.7.4.3 
TEAEs Related to Subject Manipulation Reported in at Least 2% of 
Subjects for Self-Administration at Home (SS) 
CT-8.8.1.1 
Injection Site Reaction TEAEs by MedDRA SOC and PT for Overall 
Treatment Period (SS) 
CT-8.8.1.2 
Injection Site Reaction TEAEs by MedDRA SOC and PT for Self-
Administration at Trial Site (SS) 
CT-8.8.1.3 
Injection Site Reaction TEAEs by MedDRA SOC and PT for Self-
Administration at Home (SS) 
CT-8.8.2.1 
Ophthalmic TEAEs of at Least Moderate Severity by MedDRA SOC 
and PT for Overall Treatment Period (SS) 
CT-8.8.2.2 
Ophthalmic TEAEs of at Least Moderate Severity by MedDRA SOC 
and PT for Self-Administration at Trial Site (SS) 
CT-8.8.2.3 
Ophthalmic TEAEs of at Least Moderate Severity by MedDRA SOC 
and PT for Self-Administration at Home (SS) 
CT-8.8.3.1 
Drug-related Hepatic TEAEs by MedDRA SOC and PT for Overall 
Treatment Period (SS) 
CT-8.8.3.2 
Drug-related Hepatic TEAEs by MedDRA SOC and PT for Self-
Administration at Trial Site (SS) 
CT-8.8.3.3 
Drug-related Hepatic TEAEs by MedDRA SOC and PT for Self-
Administration at Home (SS) 
CT-8.8.4.1 
Anaphylaxis and Severe Hypersensitivity Reaction TEAEs by 
MedDRA SOC and PT for Overall Treatment Period (SS) 


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CT-8.8.4.2 
Anaphylaxis and Severe Hypersensitivity Reaction TEAEs by 
MedDRA SOC and PT for Self-Administration at Trial Site (SS) 
CT-8.8.4.3 
Anaphylaxis and Severe Hypersensitivity Reaction TEAEs by 
MedDRA SOC and PT for Self-Administration at Home (SS) 
CT-8.8.5.1 
Cardiovascular-related TEAEs by MedDRA SOC and PT for Overall 
Treatment Period (SS) 
CT-8.8.5.2 
Cardiovascular-related TEAEs by MedDRA SOC and PT for Self-
Administration at Trial Site (SS) 
CT-8.8.5.3 
Cardiovascular-related TEAEs by MedDRA SOC and PT for Self-
Administration at Home (SS) 
CT-8.8.6.1 
Non-Serious TEAEs Greater Than or Equal to 5% by MedDRA SOC 
and PT for Overall Treatment Period (SS) 
CT-8.8.6.2 
Non-Serious TEAEs Greater Than or Equal to 5% by MedDRA SOC 
and PT for Self-Administration at Trial Site (SS) 
CT-8.8.6.3 
Non-Serious TEAEs Greater Than or Equal to 5% by MedDRA SOC 
and PT for Self-Administration at Home (SS) 
CT-9.1 
Listing of Serious Adverse Events (SS) 
CT-9.2 
Listing of Adverse Events Leading to Discontinuation of the IMP (SS) 
CT-9.3 
Listing of Deaths (SS) 
CT-9.4 
Listing of Injection Site Reaction Adverse Events (SS) 
CT-9.5 
Listing of Ophthalmic Adverse Events of at Least Moderate Severity 
(SS) 
CT-9.6 
Listing of Drug-related Hepatic Adverse Events (SS) 
CT-9.7 
Listing of Anaphylaxis and Severe Hypersensitivity Reaction Adverse 
Events (SS) 
CT-9.8 
Listing of Cardiovascular-related Adverse Events (SS) 
CT-10.1.1 
Descriptive Statistics for Laboratory Values (Serum Chemistry) (SS) 
CT-10.1.2 
Descriptive Statistics for Laboratory Values (Hematology) (SS) 


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CT-10.1.3 
Descriptive Statistics for Laboratory Values (Coagulation) (SS) 
CT-10.1.4 
Descriptive Statistics for Laboratory Values (Urinalysis) (SS) 
CT-10.2.1 
Incidences of PCS Abnormalities in Laboratory Tests (Serum 
Chemistry) (SS) 
CT-10.2.2 
Incidences of PCS Abnormalities in Laboratory Tests (Hematology 
and Coagulation) (SS) 
CT-10.2.3 
Incidences of PCS Abnormalities in Laboratory Tests (Urinalysis) 
(SS) 
CT-10.3.1 
Listing of PCS Abnormalities in Serum Chemistry Laboratory Tests 
(SS) 
CT-10.3.2 
Listing of PCS Abnormalities in Hematology and Coagulation 
Laboratory Tests (SS) 
CT-10.3.3 
Listing of PCS Abnormalities in Urinalysis Laboratory Tests (SS) 
CT-10.4.1 
Shift Table of Laboratory Values (Serum Chemistry) (SS) 
CT-10.4.2 
Shift Table of Laboratory Values (Hematology) (SS) 
CT-10.4.3 
Shift Table of Laboratory Values (Coagulation) (SS) 
CT-10.4.4.1 
Shift Table of Laboratory Values (Urinalysis1) (SS) 
CT-10.4.4.2 
Shift Table of Laboratory Values (Urinalysis2) (SS) 
CT-11.1 
Descriptive Statistics for Vital Sign and Weight Values (SS) 
CT-11.2 
Incidences of PCS Abnormalities in Vital Signs (SS) 
CT-11.3 
Listing of PCS Abnormalities in Vital Signs Values (SS) 
CT-12.1 
Descriptive Statistics for ECG Parameters (SS) 
CT-12.2 
Shift Table of ECG Findings (Investigators ECG Interpretation) (SS) 
CT-12.3 
Incidence of Categorical Changes in ECG Parameters (SS) 
CT-12.4 
Listing of Categorical Changes in Electrocardiogram Evaluations (SS) 
CT-13.1 
Injection Site Assessments - Injection-site Pain (SS) 


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CT-13.2 
Injection Site Assessments - Injection-site Erythema (SS) 
CT-13.3 
Injection Site Assessments - Injection-site Induration (SS) 
CT-13.4 
Injection Site Assessments - Injection-site Ecchymosis (SS) 
CT-13.5 
Subjects with Suicidal Ideation and Behavior for Columbia-Suicide 
Severity Rating Scale Assessment (SS) 
CT-14 
Descriptive Statistics for Plasma Drug Concentration (SS) 
CF-1 
Box-plot for Plasma Drug Concentration (SS) 
CF-2 
Scatter Plot of Plasma Drug Concentration for Home versus Trial Site 
(SS) 
CF-3 
Scatter Plot of Plasma Drug Concentration versus Time After 
Administration (SS) 
 


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Appendix 5 
List of Subject Data Listings 
 
PDATA-1 
Subject Disposition (Enrolled Subjects) 
PDATA-2 
Analysis Population Flag (Enrolled Subjects) 
PDEV-1 
Major Protocol Deviations (Enrolled Subjects) 
DEMOG-1 
Demographics (Enrolled Subjects) 
DEMOG-2 
Initial Migraine Diagnosis Date (Enrolled Subjects) 
DEMOG-3 
Childbearing Potential (Females Only) (Enrolled Subjects) 
PDATA-3 
Medical History (Enrolled Subjects) 
PDATA-4 
Complications (Enrolled Subjects) 
PDATA-5 
Prior and Concomitant Medications and Therapy (Enrolled Subjects) 
SMED-1 
Study Drug Administration (Enrolled Subjects) 
SMED-2 
Extent of Exposure (Enrolled Subjects) 
SMED-3 
Judgment on Self-administration (Enrolled Subjects) 
SMED-4 
Adherence to Self-administration Procedure (Enrolled Subjects) 
SMED-5 
Problems With AI Device (Enrolled Subjects) 
PDATA-6 
Vital Signs Values (Enrolled Subjects) 
PDATA-7.1 
Electrocardiogram Measurement (Enrolled Subjects) 
PDATA-7.2 
Electrocardiogram Interpretation (Enrolled Subjects) 
PDATA-7.3 
Electrocardiogram Findings (Enrolled Subjects) 
PDATA-7.4 
Electrocardiogram Technical (Enrolled Subjects) 
PDATA-8 
Physical Examination Findings (Enrolled Subjects) 
PDATA-9 
Columbia-Suicide Severity Rating Scale Assessment (Enrolled 
Subjects) 
PDATA-10 
Injection Site Assessment (Enrolled Subjects) 
PDATA-11 
Screen Failures (Screen Failure) 


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PDATA-12 
Subjects Who Did Not Meet Inclusion Criteria or Meet Exclusion 
Criteria (Screen Failure) 
PDATA-13 
Pharmacokinetic Blood Draw Date and Times (Enrolled Subjects) 
PDATA-14 
Anti-drug Antibodies Blood Draw Date and Times (Enrolled 
Subjects) 
PDATA-15 
Subjects Who Did Not Meet Inclusion Criteria or Meet Exclusion 
Criteria (Enrolled Subjects) 
PDATA-16 
Information on Subjects Lost to Follow-up (Enrolled Subjects) 
EFF-1 
Electronic Headache Diary Questionnaire - Questions List 
EFF-2 
Electronic Headache Diary Questionnaire - Results (Enrolled 
Subjects) 
EFF-3 
Electronic Headache Diary Questionnaire - Derived (Enrolled 
Subjects) 
AE-1 
Treatment-Emergent Adverse Events (Enrolled Subjects) 
AE-2 
Prior to Treatment Adverse Events (Enrolled Subjects) 
LAB-1 
Serum Chemistry Laboratory Tests Results (Enrolled Subjects) 
LAB-2 
Hematology Laboratory Tests Results (Enrolled Subjects) 
LAB-3 
Coagulation Laboratory Tests Results (Enrolled Subjects) 
LAB-4 
Urinalysis Laboratory Tests Results (Enrolled Subjects) 
LAB-5 
Pregnancy Test Results (Females Only) (Enrolled Subjects)