Clinical trial NCT03303079
Conditions: Migraine
Sponsor: Otsuka Pharmaceutical Co., Ltd.
Start date: 2017-12-19; Completion date: 2019-11-30
Enrollment: 571 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To evaluate the efficacy and safety of subcutaneous (SC) administration of TEV-48125 \[monthly TEV-48125 225 mg (loading dose only: 675 mg) and TEV-48125 675 mg once over a period of 3 months\] compared with placebo for preventive treatment in Chronic Migraine patients

Detailed description:

Arms: arm 1: TEV-48125 will be subcutaneously administered once monthly for 3 months (675/225/225 mg). arm 2: TEV-48125 or placebo will be subcutaneously administered once monthly for 3 months (675 mg/ placebo/placebo). arm 3: Placebo will be subcutaneously administered once monthly for 3 months (placebo/placebo/placebo).
Interventions: intervention 1: TEV-48125 intervention 2: TEV-48125 or placebo intervention 3: Placebo
Intervention descriptions: intervention 1: TEV-48125 will be subcutaneously administered once monthly for 3 months. intervention 2: TEV-48125 or placebo will be subcutaneously administered once monthly for 3 months. intervention 3: Placebo will be subcutaneously administered once monthly for 3 months.

Protocol documents:
Prot_000.pdf: 
 
 
CLINICAL STUDY PROTOCOL 
 
 
 
A Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group Trial 
Evaluating the Efficacy and Safety of Subcutaneous Administration of TEV-48125 for 
the Preventive Treatment of Chronic Migraine 
 
 
 
 
NCT Number: NCT03303079 
PRT NO.: 406-102-00001 
Version Date: 08 July 2019 (Version 5.0) 


Protocol 406-102-00001 
<English Translation of Japanese Original> 
 
Otsuka Pharmaceutical Co., Ltd. 
 
Investigational Medicinal Product 
TEV-48125 
 
 
CLINICAL PROTOCOL 
 
A Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group Trial 
Evaluating the Efficacy and Safety of Subcutaneous Administration of TEV-48125 for 
the Preventive Treatment of Chronic Migraine 
 
Protocol No. 406-102-00001 
 
CONFIDENTIAL – PROPRIETARY INFORMATION 
 
Clinical Development Phase: 
2b/3 
Sponsor: 
Otsuka Pharmaceutical Co., Ltd. 
 
Immediately Reportable Event: 
PAREXEL International Global Medical Services, 
Pharmacovigilance 
 
E-mail:  IRE_406-102-00001@otsuka.jp 
 
 
Issue Date (Original): 
10 Aug 2017 
Amendment 1: 
30 Nov 2017 
Amendment 2: 
18 Jun 2018  
Amendment 3: 
28 Feb 2019 
Amendment 4: 
08 Jul 2019 
 
Version No.: 
5.0 
(English translation, 06 Aug 2019) 


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Protocol Synopsis 
Name of Sponsor:  Otsuka Pharmaceutical 
Co., Ltd.  
Name of Investigational Medicinal Product:  
TEV-48125  
Protocol No.:  406-102-00001  
Protocol Title: 
A Multicenter, Randomized, Double-blind, Placebo-
controlled, Parallel-group Trial Evaluating the Efficacy and 
Safety of Subcutaneous Administration of TEV-48125 for 
the Preventive Treatment of Chronic Migraine 
Clinical Phase/Trial Type: 
Phase 2b/3 confirmatory trial 
Treatment Indication: 
Preventive treatment of chronic migraine (CM)  
Objectives: 
To evaluate the efficacy and safety of subcutaneous (SC) 
administration of TEV-48125  [monthly TEV-48125 225 
mg (loading dose only:  675 mg) and TEV-48125 675 mg 
once over a period of 3 months] compared with placebo for 
preventive treatment in CM patients 
Trial Design: 
Multicenter, randomized, double-blind, placebo-controlled, 
parallel group trial 
Subject Population: 
540 males or females (180 per group, a total of 3 groups) 
with CM aged 18 to 70 years, inclusive (the plan is to enroll 
at least approximately half of the subjects in Japan) 
Inclusion/Exclusion 
Criteria: 
Main inclusion criteria are as follows: 
 Patient has a history of migraine (according to The 
International Classification of Headache Disorders, third 
edition [beta version] [ICHD-3 beta] criteria 
[Classification Committee of the International Headache 
Society 2013]) or clinical judgment suggests a migraine 
diagnosis (not better accounted for by another ICHD-3 
beta diagnosis) for ≥ 12 months prior to giving informed 
consent 
 Patient fulfills all the following criteria for CM in 
baseline information collected during the 28-day 
screening period: 
 Headache occurring on ≥ 15 days 
 Fulfilling any of the following on ≥ 8 days: 
 ICHD-3 beta diagnostic criteria C and D for 1.1 
Migraine without aura 
 ICHD-3 beta 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 established headache. 


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 Not using preventive migraine medications (prohibited 
or restricted medications, see Table 4.1.1-1 and Table 
4.1.2-1) for migraine or other medical conditions (ie, at 
least 5 half-lives have passed since last use) or using no 
more than 1 preventive migraine medication (restricted 
medications, see Table 4.1.2-1) 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 giving informed consent. 
 Patient demonstrates compliance with the electronic 
headache diary 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. 
Main exclusion criteria are as follows: 
 Patients who have previously failed (lack of efficacy) 2 
or more of the clusters of the following medications for 
treatment of EM or CM after use for at least 3 months at 
accepted migraine therapeutic doses: 
 Cluster A:  topiramate, divalproex sodium and 
sodium valproate 
 Cluster B:  lomerizine, flunarizine and pizotifen 
 Cluster C:  amitriptyline, nortriptyline, venlafaxine, 
and duloxetine 
 Cluster D:  atenolol, nadolol, metoprolol, 
propranolol, and timolol 
 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. 
 Hematological, cardiac, renal, endocrine, pulmonary, 
gastrointestinal, genitourinary, neurologic, hepatic, or 
ocular disease considered clinically significant in the 
judgment of the investigator 
Trial Sites: 
Approximately 60 sites (52 sites in Japan and 8 sites in 
South Korea) (planned) 
Investigational Medicinal 
Products, Dose, Dosage 
Regimen, Treatment 
Period, Formulation, Mode 
of Administration: 
TEV-48125 or placebo will be subcutaneously administered 
once monthly for 3 months for a total of 3 doses.  Monthly 
dosing refers to dosing every 4 weeks (28 days).  The 
investigational medicinal product (IMP) will be 
administered by trial personnel responsible for 
administration of injections. 


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 TEV-48125 675/225/225 mg group: 
Subjects will receive 675 mg of TEV-48125 as 3 active 
injections (225 mg/1.5 mL) at Visit (V) 2/Baseline and 
225 mg of TEV-48125 as a single active injection 
(225 mg/1.5 mL) at V3/Month 1 and V4/Month 2. 
 TEV-48125 675 mg/placebo/placebo group: 
Subjects will receive 675 mg of TEV-48125 as 3 active 
injections (225 mg/1.5 mL) at V2/Baseline and placebo 
as a single 1.5-mL injection at V3/Month 1 and 
V4/Month 2. 
 Placebo group: 
Subjects will receive three 1.5-mL placebo injections at 
V2/Baseline and a single 1.5-mL placebo injection at 
V3/Month 1 and V4/Month 2. 
Trial Assessments: 
Efficacy:  Electronic headache diary, 6-Item Headache 
Impact Test (HIT-6), 2-Item Patient Health Questionnaire/9-
Item Patient Health Questionnaire (PHQ-2/PHQ-9), 
Migraine-Specific Quality of Life (MSQOL) questionnaire, 
EuroQol-5 Dimension, 5 response level version (EQ-5D-
5L) questionnaire, Patient Global Impression of Change 
(PGIC) scale, and Work Productivity and Activity 
Impairment (WPAI) questionnaire 
Safety:  Adverse events, clinical laboratory tests, physical 
examination, weight, vital signs, 12-lead 
electrocardiograms, electronic Columbia-Suicide Severity 
Rating Scale (eC-SSRS), injection site reaction, urine 
human chorionic gonadotropin (HCG) test (women of 
childbearing potential [WOCBP] only), and concomitant 
medications and therapies 
Pharmacokinetics:  Blood sampling for measurement of 
plasma drug concentrations 
Screening/Other:  Height, prior medications and therapies, 
serum HCG test (WOCBP only), follicle-stimulating 
hormone test (women at least 12 months postmenopausal 
only), blood sampling for serum antidrug antibody 
assessment, blood sampling for pharmacogenomic analysis, 
and blood and urine sampling for biomarker analysis 
Criteria for Evaluation: 
Primary Endpoint:  Mean change from baseline in the 
monthly (28-day) average number of headache days of at 
least moderate severity during the 12-week period after the 
first dose of IMP 
Secondary Endpoints: 
 Mean change from baseline in the monthly average 
number of migraine days during the 12-week period 
after the first dose of IMP 


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 Proportion of subjects reaching at least 50% reduction in 
the monthly average number of headache days of at least 
moderate severity during the 12-week period after the 
first dose of IMP 
 Mean change from baseline in the monthly average 
number of days with use of any acute headache 
medications during the 12-week period after the first 
dose of IMP 
 Mean change from baseline in the monthly average 
number of headache days of at least moderate severity 
during the 12-week period after the first dose of IMP in 
subjects not receiving concomitant preventive migraine 
medications 
 Mean change from baseline in disability score, as 
measured by the HIT-6, at 4 weeks after the final (third) 
dose of IMP 
Statistical Methods: 
Analysis of Primary Endpoint: 
The primary endpoint will be analyzed in the full analysis 
set (FAS) using an analysis of covariance model.  The 
model will include treatment group, sex, country, and 
baseline preventive medication use as fixed effects and the 
baseline number of headache days of at least moderate 
severity and years since onset of migraines as covariates.  
Two-sided 95% confidence intervals and p-values will be 
constructed for the least squares mean differences between 
each TEV-48125 group and the placebo group. 
Multiplicity problems will be avoided using a closed testing 
procedure.  If superiority of the TEV-48125 
675/225/225 mg group to the placebo group is confirmed at 
a two-sided significance level of 0.05, then the TEV-48125 
675 mg/placebo/placebo group vs the placebo group will be 
tested at a two-sided significance level of 0.05. 
Rationale for Target Sample Size: 
In a phase 2b trial in CM patients (Trial LBR-101-021), 
concerning the mean change from baseline in the monthly 
average number of headache days of at least moderate 
severity during the 12-week period after the first dose of 
IMP, the difference between the TEV-48125 
675/225/225 mg group and the placebo group was 1.7 days 
and the standard deviation was 4.9 days.  On the assumption 
that this trial will also yield a similar result to the phase 2b 
trial (Trial LBR-101-021), a sample size of 176 subjects per 
group gives more than 90% power for the trial to succeed at 
a significance level of 0.05 (two-sided).  Based on the above 
and taking into account a small percentage of subjects who 


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may be excluded from the FAS, the target sample size was 
determined to be 180 subjects per group and 540 subjects as 
the overall total included in the trial. 
Trial Duration: 
Overall trial period:  Aug 2017 through Mar 2020 (planned) 
Trial participation period for individual subjects:  
approximately 112 days 
(Screening period of 4 weeks [28 days] and double-blind 
treatment period of 12 weeks [84 days]) 
 


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Table of Contents 
Protocol Synopsis ........................................................................................... 2 
Table of Contents ........................................................................................... 7 
List of In-text Tables ...................................................................................13 
List of In-text Figures ..................................................................................14 
List of Appendices........................................................................................15 
List of Abbreviations and Definitions of Terms .......................................16 
1 
Introduction ........................................................................................18 
1.1 
Pathology and Treatment of Migraine.............................................................. 18 
1.2 
TEV-48125 ....................................................................................................... 19 
1.3 
Nonclinical Data ............................................................................................... 19 
1.4 
Clinical Data ..................................................................................................... 20 
1.4.1 
Clinical Pharmacology Trials ........................................................................ 20 
1.4.2 
Clinical Safety and Efficacy Trials ................................................................ 21 
1.5 
Known and Potential Risks and Benefits ......................................................... 22 
2 
Trial Rational and Objectives ...........................................................23 
2.1 
Trial Rationale .................................................................................................. 23 
2.2 
Rationale for DNA Storage .............................................................................. 24 
2.3 
Dosing Rationale .............................................................................................. 25 
2.4 
Rationale for Treatment Period ........................................................................ 26 
2.5 
Trial Objective .................................................................................................. 26 
3 
Trial Design .........................................................................................26 
3.1 
Type/Design of Trial ........................................................................................ 26 
3.2 
Trial Treatments ............................................................................................... 27 
3.3 
Trial Population ................................................................................................ 28 
3.3.1 
Number of Subjects and Description of Population ...................................... 28 
3.3.2 
Subject Selection and Numbering ................................................................. 29 
3.4 
Eligibility Criteria............................................................................................. 29 
3.4.1 
Informed Consent .......................................................................................... 29 
3.4.2 
Inclusion Criteria ........................................................................................... 30 
3.4.3 
Exclusion Criteria .......................................................................................... 31 


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3.5 
Endpoints .......................................................................................................... 33 
3.5.1 
Primary Endpoint ........................................................................................... 33 
3.5.2 
Secondary Endpoints ..................................................................................... 33 
3.5.2.1 
Efficacy Endpoints ..................................................................................... 33 
3.5.2.2 
Safety Endpoints ........................................................................................ 34 
3.5.3 
Exploratory Endpoints ................................................................................... 34 
3.5.4 
Pharmacokinetic Endpoint ............................................................................. 35 
3.5.5 
Immunogenicity Endpoints ............................................................................ 35 
3.6 
Measures to Minimize/Avoid Bias ................................................................... 35 
3.7 
Trial Procedures ............................................................................................... 35 
3.7.1 
Schedule of Assessments ............................................................................... 37 
3.7.1.1 
Screening Period ........................................................................................ 37 
3.7.1.1.1 
Visit 1/Screening (Day −28; Acceptable Window:  −3 Days) ............... 38 
3.7.1.2 
Double-blind Treatment Period.................................................................. 39 
3.7.1.2.1 
Baseline .................................................................................................. 39 
3.7.1.2.1.1 
Visit 2/Baseline (Day 1)...................................................................... 39 
3.7.1.2.1.2 
Randomization .................................................................................... 40 
3.7.1.2.2 
Visit 3/Month 1 (Day 29; Acceptable Window:   3 Days) and 
Visit 4/Month 2 (Day 57; Acceptable Window:   3 Days) ................... 41 
3.7.1.2.3 
Visit 5/End of Treatment (Day 85; Acceptable Window:   3 Days) 
and Withdrawal (Acceptable Window:  Day of Withdrawal 
Decision + 7 Days) ................................................................................. 42 
3.7.1.3 
Two Additional Visits for Pharmacokinetic Analysis (3 to 10 Days 
and 14 to 21 Days After One of the IMP Administrations at Either 
Visit 2/Baseline, Visit 3/Month 1, or Visit 4/Month 2) ............................. 43 
3.7.1.4 
Unscheduled Visits .................................................................................... 43 
3.7.2 
Efficacy Assessments .................................................................................... 43 
3.7.2.1 
Electronic Headache Diary ........................................................................ 43 
3.7.2.2 
Six-Item Headache Impact Test ................................................................. 44 
3.7.2.3 
Two-Item Patient Health Questionnaire/Nine-Item Patient Health 
Questionnaire ............................................................................................. 44 
3.7.2.4 
Migraine-Specific Quality of Life Questionnaire ...................................... 45 
3.7.2.5 
EuroQol-5 Dimension, 5 Response Level Version Questionnaire ............ 45 
3.7.2.6 
Patient Global Impression of Change Scale ............................................... 45 


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3.7.2.7 
Work Productivity and Activity Impairment Questionnaire ...................... 45 
3.7.3 
Safety Assessments ........................................................................................ 46 
3.7.3.1 
Adverse Events........................................................................................... 46 
3.7.3.2 
Clinical Laboratory Assessments ............................................................... 46 
3.7.3.3 
Physical Examination ................................................................................. 47 
3.7.3.4 
Height and Weight ..................................................................................... 48 
3.7.3.5 
Vital Signs .................................................................................................. 48 
3.7.3.6 
Twelve-lead Electrocardiography .............................................................. 48 
3.7.3.7 
Electronic Columbia-Suicide Severity Rating Scale.................................. 49 
3.7.3.8 
Injection Site Reaction Assessments .......................................................... 49 
3.7.3.9 
Prior and Concomitant Therapy or Medication ......................................... 50 
3.7.4 
Pharmacokinetic/pharmacodynamic/pharmacogenomic Assessments .......... 50 
3.7.4.1 
Pharmacokinetics ....................................................................................... 50 
3.7.4.1.1 
Pharmacokinetic Blood Samples ............................................................ 50 
3.7.4.2 
Immunogenicity ......................................................................................... 51 
3.7.4.3 
Pharmacogenomics .................................................................................... 52 
3.7.4.3.1 
DNA Storage .......................................................................................... 52 
3.7.4.4 
Biomarkers ................................................................................................. 54 
3.7.5 
End of Trial .................................................................................................... 55 
3.8 
Stopping Rules, Withdrawal Criteria, and Procedures ..................................... 56 
3.8.1 
Discontinuation of Entire Trial ...................................................................... 56 
3.8.2 
Discontinuation at Individual Sites ................................................................ 56 
3.8.3 
Individual Subject Discontinuation ............................................................... 56 
3.8.3.1 
Treatment Discontinuation ......................................................................... 56 
3.8.3.2 
Documenting Reasons for Treatment Discontinuation .............................. 57 
3.8.3.3 
Withdrawal of Consent .............................................................................. 58 
3.8.3.4 
Procedures to Encourage Continued Trial Participation ............................ 59 
3.9 
Screen Failures ................................................................................................. 59 
3.10 
Definition of Completed Subjects .................................................................... 59 
3.11 
Definition of Subjects Lost to Follow-up ......................................................... 60 
3.12 
Protocol Deviations .......................................................................................... 60 
4 
Restrictions ..........................................................................................61 


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4.1 
Prohibited/Restricted Medications ................................................................... 61 
4.1.1 
Prohibited Medications (Preventive Migraine Medications) ......................... 61 
4.1.2 
Restricted Concomitant Medications (Preventive Migraine 
Medications) .................................................................................................. 61 
4.2 
Prohibited Concomitant Therapies ................................................................... 62 
5 
Reporting of Adverse Events .............................................................62 
5.1 
Definitions ........................................................................................................ 62 
5.2 
Eliciting and Reporting Adverse Events .......................................................... 64 
5.3 
Immediately Reportable Events ....................................................................... 65 
5.4 
Potential Drug-induced Liver Injury ................................................................ 65 
5.5 
Events of Suspected Anaphylaxis or Severe Hypersensitivity Reaction ......... 65 
5.6 
Pregnancy ......................................................................................................... 66 
5.7 
Procedure for Breaking the Blind ..................................................................... 67 
5.8 
Follow-up of Adverse Events ........................................................................... 68 
5.8.1 
Follow-up of Nonserious Adverse Events ..................................................... 68 
5.8.2 
Follow-up of Serious Adverse Events ........................................................... 68 
5.8.3 
Follow-up and Reporting of Serious Adverse Events Occurring After 
End of Trial Date for Individual Subject (Last Scheduled Contact) ............. 69 
6 
Pharmacokinetic/pharmacodynamic/pharmacogenomic 
Analysis ................................................................................................69 
6.1 
Pharmacokinetics.............................................................................................. 69 
6.1.1 
Pharmacokinetic Analysis Set ....................................................................... 69 
6.1.2 
Pharmacokinetic Analysis ............................................................................. 69 
6.2 
Population Pharmacokinetic Analysis .............................................................. 70 
6.3 
Immunogenicity................................................................................................ 70 
6.3.1 
Immunogenicity Analysis Set ........................................................................ 70 
6.3.2 
Immunogenicity Analysis .............................................................................. 70 
6.4 
Pharmacogenomics ........................................................................................... 70 
6.5 
Biomarkers ....................................................................................................... 70 
7 
Statistical Analysis ..............................................................................70 
7.1 
Sample Size ...................................................................................................... 70 
7.2 
Analysis Sets .................................................................................................... 71 
7.3 
Handling of Missing Data ................................................................................ 71 


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7.4 
Primary and Secondary Endpoint Analyses ..................................................... 71 
7.4.1 
Primary Endpoint Analysis ............................................................................ 71 
7.4.2 
Secondary Endpoint Analysis ........................................................................ 71 
7.4.3 
Exploratory Efficacy Endpoint Analysis ....................................................... 72 
7.5 
Analysis of Demographic and Baseline Characteristics................................... 72 
7.6 
Safety Analysis ................................................................................................. 73 
7.6.1 
Adverse Events .............................................................................................. 73 
7.6.2 
Clinical Laboratory Data ............................................................................... 73 
7.6.3 
Vital Signs and Weight Data ......................................................................... 73 
7.6.4 
Electrocardiogram Data ................................................................................. 73 
7.6.5 
Injection Site Reactions ................................................................................. 73 
7.6.6 
Electronic Columbia-Suicide Severity Rating Scale ..................................... 74 
8 
Management of Investigational Medicinal Product ........................74 
8.1 
Packaging and Labeling ................................................................................... 74 
8.2 
Storage .............................................................................................................. 74 
8.3 
Accountability .................................................................................................. 74 
8.4 
Returns and Destruction ................................................................................... 74 
8.5 
Reporting of Product Quality Complaints ........................................................ 75 
8.5.1 
Eliciting and Reporting Product Quality Complaints .................................... 75 
8.5.2 
Information Required for Reporting Purposes .............................................. 75 
8.5.3 
Return Process ............................................................................................... 76 
8.5.4 
Assessment/Evaluation .................................................................................. 76 
9 
Records Management .........................................................................76 
9.1 
Source Documents ............................................................................................ 76 
9.2 
Data Collection ................................................................................................. 76 
9.3 
File Management at the Trial Site .................................................................... 77 
9.4 
Records Retention at the Trial Site................................................................... 77 
10 
Quality Control and Quality Assurance ...........................................78 
10.1 
Monitoring ........................................................................................................ 78 
10.2 
Auditing ............................................................................................................ 78 
11 
Ethics and Responsibility ...................................................................79 
12 
Confidentiality ....................................................................................79 


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13 
Amendment Policy ..............................................................................79 
14 
Publication Authorship Requirements .............................................80 
15 
References ............................................................................................81 
 
 


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List of In-text Tables 
Table 3.4.2-1 
Inclusion Criteria .......................................................................... 30 
Table 3.4.3-1 
Exclusion Criteria ......................................................................... 31 
Table 3.7-1 
Schedule of Assessments .............................................................. 36 
Table 3.7.3.2-1 
Clinical Laboratory Assessments .................................................. 47 
Table 3.7.3.8-1 
Severity Grading of Pain for Injection Site Assessments ............. 49 
Table 4.1.1-1 
List of Prohibited Concomitant Medications (Preventive 
Migraine Medications) .................................................................. 61 
Table 4.1.2-1 
List of Restricted Concomitant Medications (Preventive 
Migraine Medications) .................................................................. 62 
 
 
 
 


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List of In-text Figures 
Figure 3.1-1 
Trial Design Schematic ................................................................. 27 
 
 
 


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List of Appendices 
Appendix 1 
Handling and Shipment of Bioanalytical Samples ....................... 83 
Appendix 2 
Clinical Criteria for Diagnosing Anaphylaxis .............................. 86 
Appendix 3 
ICHD-3 beta Diagnostic Criteria .................................................. 87 
Appendix 4 
Guidance on Safety Monitoring .................................................... 88 
Appendix 5 
Protocol Amendments/Administrative Changes ........................... 91 
 
 


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List of Abbreviations and Definitions of Terms 
Abbreviation 
Definition 
ADA 
Antidrug antibody  
AE 
Adverse event  
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AST 
Aspartate aminotransferase 
BMI 
Body mass index 
CBC 
Complete blood count  
CDMS 
Clinical data management system 
CFR 
Code of Federal Regulations  
CGRP 
Calcitonin gene-related peptide 
CM 
Chronic migraine  
Cmax 
Maximum (peak) plasma concentration of the drug  
CRF 
Case report form  
CRO 
Clinical Research Organization  
DILI 
Drug-induced liver injury 
DNA 
Deoxyribonucleic acid 
EC 
Ethics committee 
ECG 
Electrocardiogram  
eC-SSRS 
Electronic Columbia-Suicide Severity Rating Scale 
EDC 
Electronic data capture 
eDiary 
Electronic diary 
EDTA 
Ethylenediaminetetraacetic acid 
EM 
Episodic migraine  
EOT 
End-of-treatment (visit) 
ePRO 
Electronic patient-reported outcome 
EQ-5D-5L 
EuroQol-5 Dimension, 5 response level version 
ES 
Enrolled set 
EU 
European Union 
FAS 
Full analysis set  
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GGT 
Gamma glutamyl transferase 
HBV 
Hepatitis B virus 
HCG 
Human chorionic gonadotropin 
HCV 
Hepatitis C virus 
HIT-6 
6-Item Headache Impact Test 
HIV 
Human immunodeficiency virus 
ICF 
Informed consent form 
ICH 
International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use 
ICHD-3 beta 
International Classification of Headache Disorders, third edition (beta version) 
ICMJE 
International Committee of Medical Journal Editors 
IEC 
Independent ethics committee  
IgG 
Immunoglobulin G 
IgM 
Immunoglobulin M 
IHS 
International Headache Society 
IMP 
Investigational medicinal product 
INR 
International normalization ratio 
IRB 
Institutional review board 
IRE 
Immediately reportable event 
IRT 
Interactive response technology 


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Abbreviation 
Definition 
ITT 
Intent-to-treat 
IUD 
Intrauterine device 
IV 
Intravenous  
MedDRA 
Medical Dictionary for Regulatory Activities 
MSQOL 
Migraine-Specific Quality of Life 
NOAEL 
No-observed-adverse-effect level 
PE 
Physical examination 
PEF 
Peak expiratory flow 
PGIC 
Patient Global Impression of Change 
PHQ-2 
2-Item Patient Health Questionnaire 
PHQ-9 
9-Item Patient Health Questionnaire 
PMDA 
Pharmaceuticals and Medical Devices Agency 
PQC 
Product quality complaint 
RBC 
Red blood cell 
RNA 
Ribonucleic acid 
RS 
Randomized set 
SAE 
Serious adverse event 
SC 
Subcutaneous 
SD 
Standard deviation 
SS 
Safety set 
t1/2 
Elimination half-life 
TEAE 
Treatment-emergent adverse event 
tmax 
Time to maximum (peak) plasma concentration 
ULN 
Upper limit of normal 
US or USA 
United States or United States of America 
V 
Visit  
WBC 
White blood cell 
WPAI 
Work Productivity and Activity Impairment 
WOCBP 
Women of childbearing potential 
YLD 
Year lived with disability 
 


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1 
Introduction 
1.1 
Pathology and Treatment of Migraine 
Migraine is a prevalent condition characterized by attacks of headache (of moderate to 
severe severity, unilateral, and/or pulsating) and associated symptoms (such as nausea, 
photophobia, or phonophobia).  Global Burden of Disease studies 2015 rank migraine as 
the seventh highest cause of years lived with disability (YLDs) and as the third highest 
cause of YLDs for ages 15 to 49 years, suggesting that the disease not only imposes a 
considerable disability burden on the daily and social lives of affected individuals but it 
also causes a serious social loss.1 
Episodic migraine (EM) and chronic migraine (CM) are 2 common forms of migraine.  
Individuals with EM have headaches on less than 15 days per month,2 while those with 
CM present with headaches on 15 or more days per month and have migraine on at least 
8 days per month.3  Approximately 3% of individuals with EM evolve, in any given year, 
to a significantly more disabling condition called CM.4,5 
Although the pathophysiology of migraine has yet to be fully elucidated, it is believed 
that a certain stimulus works on the perivascular trigeminal axon, leading to the release of 
vasoactive neuropeptides, which act as neurotransmitters, including substance P and 
calcitonin gene-related peptide (CGRP), from nerve terminals and that this in turn 
triggers neurogenic inflammation around dura mater, contributing to the production of 
pain.6,7,8  CGRP is thus involved in the pathophysiology of migraine.6  Inhibition of 
CGRP has demonstrated efficacy in the treatment of EM and CM.9,10 
Pharmacotherapeutic management of migraine consists of acute treatment and preventive 
treatment.  The goals of acute treatment are to rapidly and certainly relieve attacks of 
migraine and restore the patient’s ability to function.  On the other hand, the goals of 
preventive treatment are:  1) to reduce the frequency, severity, and duration of headache; 
2) to improve response to acute treatment; and 3) to improve life functions and reduce 
disabilities in daily life.11  Currently available drug therapies for preventive treatment of 
migraine include antiepileptic drugs, beta-blockers, antidepressants, angiotensin receptor 
blockers, angiotensin-converting enzyme inhibitors, and calcium channel blockers.  
Medications covered by Japanese health insurance for preventive treatment of migraine 
include lomerizine, valproic acid, propranolol, and dihydroergotamine, for which there 
are varying response rates in their ability to prevent migraine. 


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1.2 
TEV-48125 
TEV-48125 (also known as PF-04427429, RN307, or LBR-101) is a fully humanized 
immunoglobulin G (IgG) 2a/kappa monoclonal antibody derived from a murine precursor.  
TEV-48125 is a potent, selective CGRP binder and blocks both CGRP isoforms (α- and 
β-CGRP) from binding to the CGRP receptor.  TEV-48125 is specific for CGRP and 
does not bind to the closely related family members amylin, calcitonin, or 
adrenomedullin peptides.  Two mutations were introduced into the constant region of the 
TEV-48125 heavy chain to limit antibody effector functions.  This loss of function 
prevents TEV-48125 from stimulating antibody-dependent cell-mediated cytotoxicity and 
triggering complement-mediated lysis; complement-mediated lysis can lead to unwanted 
consequences such as cell lysis, opsonization, and cytokine release and inflammation.12,13  
With a different mechanism of action from existing migraine prophylactics, TEV-48125 
has acceptable tolerability, as confirmed from both nonclinical and clinical data, and a 
long plasma elimination half-life (t1/2), thus representing a promising therapeutic 
candidate for the preventive treatment of migraine, which is expected to reduce dosing 
frequency compared to existing counterparts and provide an additional treatment option. 
1.3 
Nonclinical Data 
In vivo pharmacology studies of TEV-48125 in animal models indicate that TEV-48125 
prevented an increase in blood flow in rat paw skin and the middle meningeal artery after 
electrical stimulation and produced a dose-dependent inhibition of the capsaicin-induced 
skin flare response in cynomolgus monkeys. 
Safety pharmacology parameters of TEV-48125 were assessed in the toxicology studies 
in Sprague Dawley rats and cynomolgus monkeys and a separate cardiovascular safety 
pharmacology study in male cynomolgus monkeys.  There were no treatment-related 
changes in electrocardiograms (ECGs) and heart rates in the 1- and 3-month toxicity 
studies, and a single intravenous (IV) dose of TEV-48125 at 100 mg/kg did not result in 
changes in cardiovascular parameters or body temperature in monkeys.  Additionally, no 
target organ toxicity was identified.  In these referenced studies, the no-observed-
adverse-effect level (NOAEL) ranged from 100 to 300 mg/kg dosed either intravenously 
or subcutaneously.  In a 3-month monkey study, perivascular inflammation of the ciliary 
artery was observed in a few animals at doses ≥ 100 mg/kg.  The inflammation was 
suspected to be the result of immune complex formation/deposition from the monkeys’ 
immunogenic response to the drug (TEV-48125).  In the 6-month chronic toxicity study 
in monkeys following once-weekly subcutaneous (SC) dosing at dosage levels of up to 
300 mg/kg/week, reaching high exposure throughout the study, no microscopic findings 


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were noted in any of the organs, including the ciliary vessels of the eyes, and the NOAEL 
of the chronic toxicity study was determined to be the highest dose tested, 
300 mg/kg/week.  Thus, it is believed that in view of the low frequency (ie, observed in 
very few animals) and minimal severity, the finding (perivascular inflammation) that was 
only recorded in the 3-month toxicity study, and had been resolved during the recovery 
period, is an incidental finding. 
The pharmacokinetics of TEV-48125 in animals (rats and monkeys) is the same as that of 
a typical humanized IgG2 antibody, with low mean plasma clearance, low volume of 
distribution at steady state, and a long t1/2.  The maximum observed plasma concentration 
(Cmax) and the area under the plasma concentration-time curve increased linearly across 
doses following single and repeated once-weekly dosing.  No gender differences in 
exposure were observed in rats or monkeys. 
Additionally, reproductive and developmental toxicity studies in rabbits and rats with 
TEV-48125 were conducted and completed.  Preliminary data suggest that weekly dosing 
with TEV-48125 was well tolerated and did not induce any obvious maternal toxicity at 
any dose level.  No apparent evidence of embryo-fetal toxicity was noted in any dose 
group. 
Overall, no toxicological concerns were identified following up to 6 months of dosing to 
the experimental animals. 
1.4 
Clinical Data 
To date, TEV-48125 has been studied in seven phase 1 trials in healthy adults and two 
phase 2b trials in migraine patients.  In total, 532 subjects (166 healthy adults and 366 
migraine patients) received at least 1 dose of TEV-48125 via IV or SC administration.  
Currently, 3 multinational phase 3 trials (Trials TV48125-CNS-30049, TV48125-CNS-
30050, and TV48125-CNS-30051) to further evaluate the efficacy, safety, and tolerability 
of dose regimens of TEV-48125 for the preventive treatment of CM and EM are ongoing. 
1.4.1 
Clinical Pharmacology Trials 
A total of 166 subjects received at least 1 dose of TEV-48125 across 7 completed phase 1 
trials at doses ranging from 0.2 through 2000 mg.  Trials included 2 single-dose-
escalation pharmacokinetic and pharmacodynamic trials in healthy adult men (Trials 
B0141001 and B0141002); a 2-cohort, placebo-controlled, crossover trial to examine the 
acute effects administration of TEV-48125 on capsaicin flare response in healthy adult 
men (Trial B0141006); a parallel-group, repeat-dose trial of TEV-48125 in healthy adult 
men and women (Trial B0141007); a single-dose trial evaluating the safety, tolerability, 


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and pharmacokinetics of doses up to 2000 mg administered to healthy adult women (Trial 
LBR-101-008); and a single-dose trial comparing the safety, tolerability, absolute 
bioavailability, and pharmacokinetics of SC and IV TEV-48125 in healthy adult men and 
women (Trial LBR-101-011), and a trial evaluating the pharmacokinetics, safety, and 
tolerability of a single SC administration of TEV-48125 in healthy Japanese and 
Caucasian adult men and women (Trial TV48125-PK-10078). 
Based on noncompartmental analysis, TEV-48125 exposure increases with dose in a 
more than dose-proportional manner from 225 to 900 mg following SC administration.  
The time to maximum (peak) plasma concentration (tmax) following SC administration at 
225 to 900 mg ranged from 5 to 7 days with the dose having no observed impact on tmax.  
The mean t1/2 following SC administration ranged from 32.23 to 36.15 days with no 
impact of the dose observed. 
TEV-48125 was well tolerated with favorable safety profile.  The treatment-emergent 
adverse events (TEAEs) reported in the phase 1 trials were predominantly mild or 
moderate in severity.  Neither a specific “pattern of adverse events (AEs)” that was 
thought to be associated with a dose of TEV-48125, nor a maximally tolerated dose was 
identified.  There were no deaths.  One serious adverse event (SAE) reported as “thoracic 
aortic aneurysm aggravated” in an individual receiving a single IV 300-mg TEV-48125 
dose resolved. 
TEV-48125 was not associated with any clinically relevant patterns of change in vital 
signs (systolic and diastolic blood pressure, temperature, and heart rate) or cardiac 
conduction and repolarization (P-R interval, QT interval corrected for heart rate using 
Bazett’s and Fridericia’s formulas) measured by frequent 12-lead ECGs.  No changes in 
liver function tests (aspartate aminotransferase [AST], alanine aminotransferase [ALT], 
total bilirubin, and alkaline phosphatase [ALP]) or differences between TEV-48125 and 
placebo in hematological parameters, tests assessing renal function, electrolytes, or 
urinalysis has been observed in any of the phase 1 trials. 
1.4.2 
Clinical Safety and Efficacy Trials 
The efficacy, safety, tolerability, and pharmacokinetics of TEV-48125 were evaluated in 
migraine patients in two phase 2b trials (Trial LBR-101-021 and Trial LBR-101-022).  
The first trial (Trial LBR-101-021) was a multicenter, randomized, double-blind, 
placebo-controlled, parallel-group trial using TEV-48125 (2 dose levels) in 264 patients 
with CM.  Following a 28-day run-in period, participants were randomized and treated 
SC once monthly for 3 months.  One TEV-48125 group received a first dose of 675 mg 
followed by 225 mg on the subsequent 2 months.  The other TEV-48125 group received 


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900 mg per month.  The mean change in headache hours relative to baseline for each 
TEV-48125 dose group showed a statistically significant reduction in headache hours 
compared to the placebo group at 3 months (primary endpoint) and reductions also at 1 
and 2 months.  Both doses were also superior to placebo for the secondary endpoint 
(decrease in the number of days with moderate or severe headache at 3 months).  At the 
doses tested, TEV-48125 was well tolerated, and no investigational medicinal product 
(IMP)-related SAEs were reported.  Most TEAEs were mild or moderate.  No safety 
signals were observed in the clinical laboratory tests, vital signs, physical examination, or 
ECGs. 
The other phase 2b trial (Trial LBR-101-022) was a multicenter, randomized, double-
blind, placebo-controlled, parallel-group trial using TEV-48125 (2 dose levels) in 297 
patients with EM.  Following a 28-day run-in period, subjects were randomized and 
treated subcutaneously once monthly for 3 months.  Two doses of TEV-48125 were 
tested, 225 mg given monthly for 3 months, and 675 mg given monthly for 3 months.  
The mean change in number of migraine days relative to baseline for each TEV-48125 
dose group showed a statistically significant reduction in migraine days compared to the 
placebo group at 3 months (primary endpoint), and improvement at 1 and 2 months.  
Differences in the secondary and exploratory endpoints compared to the placebo group 
were also seen throughout the trial.  Both doses were well tolerated, and no IMP-related 
SAEs were reported.  Most TEAEs were mild or moderate and the lowest dose had a 
numerically lower number of subjects with adverse events relative to placebo.  No safety 
signals were observed in the clinical laboratory tests, vital signs, physical examination, or 
ECGs. 
1.5 
Known and Potential Risks and Benefits 
Identified risks (adverse drug reactions) of TEV-48125 included injection site erythema, 
administration site pain, injection site pain, injection site pruritus, injection site dermatitis, 
infusion-related reaction, and drug hypersensitivity.  Potential risks for TEV-48125 are 
perivascular inflammation; development of antidrug antibodies (ADAs); liver enzyme 
elevations; and cardiovascular consequences of CGRP inhibition, including effects on 
blood pressure, heart rate, or other cardiovascular parameters. 
Subcutaneous TEV-48125 has generally been well tolerated over the ranges of doses 
evaluated (single doses of 0.2 to 2000 mg in healthy adults, multiple doses of 30 to 
300 mg in healthy adults, and multiple doses of 225 to 900 mg in migraine patients).  The 
most common TEAEs were mild or moderate transient general administration site 
disorders/reactions.  Other commonly reported TEAEs were headache, back pain, and 
upper respiratory tract infection. 


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Based on the results from two phase 2b trials (Trials LBR-101-021 and LBR-101-022), in 
patients with CM, the mean change in headache hours relative to baseline for each TEV-
48125 dose group showed a statistically significant reduction in headache hours 
compared to the placebo group at 3 months (primary endpoint) and reductions also at 1 
and 2 months.  In patients with EM, the mean change in migraine days relative to 
baseline for each TEV-48125 dose group showed a statistically significant reduction in 
migraine days compared to the placebo group at 3 months (primary endpoint) and 
improvement at 1 and 2 months.  Furthermore, results for several secondary/exploratory 
endpoints also showed TEV-48125 to be superior to placebo. 
Based on the above safety profile and the demonstrated efficacy of SC TEV-48125, the 
benefits of TEV-48125 are expected to outweigh the risks. 
 
Detailed information is presented in the Investigator’s Brochure. 
2 
Trial Rational and Objectives 
2.1 
Trial Rationale 
Nonclinical studies of TEV-48125 required for the conduct of this trial have been 
completed.  The pharmacokinetics and tolerability of TEV-48125 (IV doses ranging from 
0.2 to 2000 mg and SC doses of 225, 675, and 900 mg) have been well-characterized in 
the phase 1 trials.  Furthermore, the safety and effectiveness of TEV-48125 have been 
demonstrated in a randomized, double-blind, placebo-controlled phase 2b trial (Trial 
LBR-101-021) of 2 SC dosing regimens of TEV-48125 (monthly TEV-48125 at 900 mg 
or TEV-48125 at 675 mg followed by monthly TEV-48125 at 225 mg) in patients with 
CM and a randomized, double-blind, placebo-controlled phase 2b trial (Trial LBR-101-
022) of 2 SC dosing regimens of TEV-48125 (monthly TEV-48125 at 675 and 225 mg) 
in patients with EM.  Based on these results, 2 multinational phase 3 confirmatory trials 
(Trials TV48125-CNS-30049 and TV48125-CNS-30050) and a long-term trial (Trial 
TV48125-CNS-30051) are ongoing ahead of this trial. 
The results of a phase 1 single-dose trial in healthy Japanese and Caucasian subjects 
(Trial TV48125-PK-10078) have demonstrated similarities in the safety profile of TEV-
48125 between the 2 populations, and Japanese patients are enrolled in ongoing 
multinational phase 3 confirmatory trials (Trials TV48125-CNS-30049 and TV48125-
CNS-30050), which began ahead of this trial.  It is considered necessary to investigate 
recommended doses and regimens in Japanese patients by assessing the response in this 
population to 2 different doses and regimens and to demonstrate that the efficacy and 
safety of TEV-48125 in Japanese patients is similar to the efficacy and safety observed in 


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the multinational phase 3 confirmatory trials (Trials TV48125-CNS-30049 and 
TV48125-CNS-30050), which warrants the implementation of this clinical trial. 
This trial will be conducted in Japan and South Korea.  Although no TEV-48125 data 
from Koreans are available, an absence of ethnicity difference in CGRP polymorphism 
and key pharmacological properties of TEV-48125 suggest that TEV-48125 is less 
susceptible to intrinsic factors.  In addition, in the light of minimal differences between 
Japan and South Korea in diagnostic criteria, epidemiology, and therapeutic approach, 
TEV-48125 is unlikely to be affected by extrinsic factors.  Based on the above, the 
pharmacokinetics, safety, and efficacy of TEV-48125 is expected to be virtually the same 
between Japanese and Korean populations, and the conduct of this trial in both Japanese 
and Korean patients to assess the efficacy and safety of TEV-48125 should be 
appropriate. 
Prior to the implementation of this trial, the sponsor held Additional Consultation (Other 
Than Orphan Drugs) and Consultation After Face-to-face Meeting with the 
Pharmaceuticals and Medical Devices Agency (PMDA) on 01 Nov 2016 and 16 Mar 
2017, respectively, and received the PMDA’s advice on the appropriateness of 
conducting a Japanese and Korean collaborative clinical trial, efficacy endpoints, dose 
selection, sample size, and other issues. 
2.2 
Rationale for DNA Storage 
In this trial, deoxyribonucleic acid (DNA) samples will be stored on a voluntary basis.  
Only trial sites that have agreed in advance to collect samples for DNA storage will 
collect the samples from subjects who have provided written informed consent to the 
storage of their DNA samples.  Concerning collecting DNA samples and storing them 
during the trial period, the Ministry of Health, Labour and Welfare states in Q&A14 in 
“Clinical trials based on pharmacogenomics” (Notification No. 0930007 of the 
Evaluation and Licensing Division, Pharmaceutical and Food Safety Bureau issued on 30 
Sep 2008) that samples for genomic/genetic analysis related to the evaluation of an 
investigational product (eg, pharmacokinetic, efficacy, and safety evaluation) may be 
collected from subjects during a clinical trial 1) if the target and time of genomic/genetic 
analysis have been determined when a clinical trial is conducted, or 2) if the target and 
time of genomic/genetic analysis have not yet been determined when a clinical trial is 
conducted but there is a plan to perform such analysis in the future to further characterize 
the investigational product. 


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In view of the above, it is considered acceptable to store DNA samples for future 
exploration of possible relationships between treatment response to TEV-48125 and 
variations of DNA characteristics (eg, genetic polymorphism). 
2.3 
Dosing Rationale 
TEV-48125 is a preparation for SC injection.  Given that a preventive drug needs to be 
administered for at least 3 to 6 months to prevent migraine attacks, SC administration, an 
easier dosing modality compared with IV administration, was selected for the 
convenience of use. 
The doses and dosing regimens of SC TEV-48125 in this trial are mainly based on 
relevant data including the results from phase 2b trials (Trials LBR-1012-021 and LBR-
101-022) that assessed efficacy, safety, and regimens in patients with migraine.  The 
doses and dosing regimens used in phase 2b trials (Trials LBR-101-021 and LBR-101-
022) were selected based on the result that the 225-mg dose of TEV-48125 was 
considered the lowest effective dose as demonstrated in nonclinical studies and that the 
safety of TEV-48125 was confirmed at doses ranging from approximately 225 to 900 mg 
in phase 1 trials. 
In a phase 2b trial in CM patients (Trial LBR-101-021), 2 regimens of 225 mg once 
monthly (except for a loading dose of 675 mg) and 900 mg once monthly were found to 
be effective and well tolerated.  Both TEV-48125 dose groups showed improvement 
compared to the placebo group from Month 1, and the difference from placebo group for 
each TEV-48125 dose group was similar.  Based on these findings, the lower dose of 
TEV-48125 used in the phase 2b trial (Trial LBR-101-021) was considered appropriate 
for this trial.  In the lower dose group in the phase 2b trial (Trial LBR-101-021), a 
loading dose of 675 mg was used despite the lowest effective dose of 225 mg.  Since 
early appropriate preventive treatment for CM is recommended,11 this trial will also use a 
loading dose of 675 mg as in the phase 2b trial (Trial LBR-101-021) to facilitate a rapid 
onset of effect.  Therefore, in this phase 2b/3 trial in CM patients (Trial 406-102-00001), 
225 mg of TEV-48125 will be administered once monthly (except for a loading dose of 
675 mg) in one of 2 TEV-48125 dose groups to evaluate the efficacy and safety in 
Japanese subjects.  In the other TEV-48125 dose group, 675 mg of TEV-48125 will be 
administered once in 3 months to determine how different doses and dosing regimens 
may affect the efficacy of TEV-48125 in Japanese subjects. 
This trial is designed to be placebo-controlled in consideration of the objective of the trial 
and the trial design recommended by the Classification Committee of the International 
Headache Society (IHS) guidelines for controlled trials of prophylactic treatment of CM 


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in adults15 and the Classification Committee of IHS recommendations for controlled 
trials of migraine prophylactic drugs.16 
2.4 
Rationale for Treatment Period 
The treatment period was determined in consideration of the treatment period 
recommended by the Classification Committee of IHS recommendations for controlled 
trials of migraine prophylactic drugs.16 
2.5 
Trial Objective 
To evaluate the efficacy and safety of SC administration of TEV-48125 (monthly TEV-
48125 225 mg [loading dose only:  675 mg] and TEV-48125 675 mg once over a period 
of 3 months) compared with placebo for preventive treatment in CM patients. 
3 
Trial Design 
3.1 
Type/Design of Trial 
This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial 
in CM patients.  The schematic of the trial design is shown in Figure 3.1-1. 
The trial consists of a 4-week screening period and a 12-week double-blind treatment 
period. 
After obtaining written informed consent from patients, the investigator will screen them 
for eligibility (Visit [V] 1/Screening).  Subjects who have been diagnosed with CM, and 
who meet all the inclusion criteria and do not fall under any of the exclusion criteria will 
be randomized in a 1:1:1 ratio to one of the following 3 treatment groups (V2/Baseline).  
The IMP will be administered at V2/Baseline, V3/Month 1, and V4/Month 2 as specified 
in Section 3.2, Trial Treatments.  Subjects will also visit the trial site at 3 to 10 days and 
at 14 to 21 days (twice) after one of IMP administrations at either V2/Baseline, 
V3/Month 1, or V4/Month 2 for pharmacokinetic assessment.  Subjects will also return to 
the trial site (V5/End of treatment) for the final assessment at 12 weeks after the first IMP 
administration.  Subjects who are withdrawn from the trial will undergo a withdrawal 
assessment. 
The trial includes the following treatment groups. 
 TEV-48125 675/225/225 mg group 
 TEV-48125 675 mg/placebo/placebo group 
 Placebo group 
 


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The period of trial participation for each subject is defined as the period from the day that 
informed consent is obtained from the patient until the day of trial completion. 
Definition of the end of trial date for individual subject: 
The end of trial date for individual subject is defined as the date of V5/End of treatment 
for the final assessment/observation or the date of trial withdrawal.  The date of trial 
withdrawal is defined as the date of withdrawal assessment, the date of the final 
assessment/observation in the double-blind treatment period, or the date of withdrawal 
decision, whichever comes later.  For subjects who are lost to follow up, the end of trial 
date for individual subject is defined as the date of their last visit/contact or the date of 
the last attempt to contact them. 
Following the end of treatment visit (V5/End of treatment), subjects will be offered the 
opportunity to enter a long-term trial for the purpose of evaluating ADA at 225 days 
(approximate equivalent of 5 half-lives) after the final dose of IMP (V4/Month 2) in this 
trial. 
 
Figure 3.1-1 
Trial Design Schematic 
PBO = placebo; R = randomization. 
 
3.2 
Trial Treatments 
In the trial, TEV-48125 or placebo will be subcutaneously administered once monthly for 
3 months for a total of 3 doses.  Monthly dosing refers to dosing every 4 weeks 
(acceptable window:  ± 3 days).  Subjects who visit the trial site earlier than the 
acceptable window will not receive the IMP and will be requested to return to the trial 
site within the acceptable window.  The IMP will be administered by trial personnel 
responsible for administration of injections. 
The dosing regimens for treatment groups are shown below. 
 V1
V2/Baseline
 V3
 V4
 V5
675 mg
225 mg
225 mg
Informed consent
675 mg
PBO
PBO
PBO
PBO
PBO
Screening period
(4 weeks)
Subjects will also visit the trial site at 3 to 10 days and 14 to 21 days (twice) after one of IMP administrations
at either V2/Baseline, V3, or V4 for pharmacokinetic assessment.
Double-blind treatment period
(12 weeks)
R


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 TEV-48125 675/225/225 mg group: 
Subjects will receive 675 mg of TEV-48125 as 3 active injections (225 mg/1.5 mL) at 
V2/Baseline and 225 mg of TEV-48125 as a single active injection (225 mg/1.5 mL) 
at V3/Month 1 and V4/Month 2. 
 TEV-48125 675 mg/placebo/placebo group: 
Subjects will receive 675 mg of TEV-48125 as 3 active injections (225 mg/1.5 mL) at 
V2/Baseline and placebo as a single 1.5-mL injection at V3/Month 1 and V4/Month 2. 
 Placebo group: 
Subjects will receive three 1.5-mg placebo injections at V2/Baseline and a single 1.5-
mL placebo injection at V3/Month 1 and V4/Month 2. 
At the time of each visit, the interactive response technology (IRT) will be queried and 
trial personnel will retrieve and administer a 1.5-mL volume from each syringe contained 
in the appropriately numbered kit(s). 
Recommended SC injection sites follow the National Institutes of Health clinical center 
patient education materials:  Giving a subcutaneous injection.17  The suggested sites of 
injection are the outside of upper arms, back of upper arms, abdomen, or front of thighs.  
At each visit and when 3 injections are administered at a visit, each of the injections 
should be given in a different location (eg, not in precisely the same place).  Trial 
personnel responsible for administration of injections should inspect previous injection 
sites to ensure that they are free from bruising and tenderness and that proper rotation of 
sites is performed. 
IMP should be removed from the refrigerator and allowed to equilibrate at room 
temperature for 45 to 60 minutes before IMP administration. 
The date and time of SC injections and their locations will be recorded for each dosing 
visit (V2/Baseline, V3/Month 1, and V4/Month 2). 
3.3 
Trial Population 
3.3.1 
Number of Subjects and Description of Population 
A total of 540 male or female (180 per group, a total of 3 groups) with CM aged 18 to 70 
years, inclusive, will be enrolled in the trial.  The plan is to enroll at least approximately 
half of the subjects in Japan.  The enrollment procedure will be continued until the 
number of enrolled subjects reaches 540. 
Continued concomitant use of some preventive migraine medications (see Table 4.1.2-1) 
may be permitted, so long as a stable dose and regimen have been maintained for at least 
2 consecutive months prior to informed consent, in which case the subject will be 
allowed to continue using no more than 1 preventive medication.  However, the total 


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number of subjects receiving concomitant preventive medication during the trial will not 
exceed 30% of the total sample size of the trial. 
3.3.2 
Subject Selection and Numbering 
After informed consent is obtained, 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-site serial number) will be given at each trial site across this trial (CM 
patients; hereinafter the same applies) and Trial 406-102-00002 (EM patients; hereinafter 
the same applies) in the chronological order informed consent is obtained in, starting at 
10001.  Following screening, subjects who meet the eligibility criteria for either this trial 
or Trial 406-102-00002 will be randomized into the trial for which they are eligible.  
Subjects who fail to meet the eligibility criteria for both this trial and Trial 
406-102-00002 after providing their consent to participate in both this trial and Trial 
406-102-00002 or only in this trial will be handled as screen failures for this trial.  Trial 
sites will prepare and retain a list of all consented subjects and their subject identification 
numbers. 
3.4 
Eligibility Criteria 
3.4.1 
Informed Consent 
Written informed consent will be freely obtained from all subjects (or legally acceptable 
representative, etc, if the subject is a minor).  Consent will be documented on a written 
informed consent form (ICF).  The written information for subjects and ICF will be 
approved by the same institutional review board or independent ethics committee/ethics 
committee (IRB/IEC/EC) that approves this protocol. 
Each written information for subjects and ICF will comply with the ICH (International 
Conference on Harmonisation) Good Clinical Practice (GCP) Guideline18 and local 
regulatory requirements.  The principal investigator will ensure that the sponsor reviews 
and authorizes any written site-specific ICF used in the trial before submission to the 
IRB/IEC/EC. 
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). 
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. 


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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- or 
IEC/EC-approved written ICF will be signed and dated by both the subject and the person 
obtaining consent (investigator or a qualified designee who gave the explanation), as well 
as by any other parties required by the IRB/IEC/EC.  The subject (or legally acceptable 
representative, etc, if the subject is a minor) will receive the written information for 
subjects and 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 to significantly 
add or change procedures. 
For DNA storage, written informed consent will be freely obtained from subjects (or 
legally acceptable representative, etc, if the subject is a minor) using separate written 
information for subjects, by following the above-mentioned procedure.  DNA samples 
will be stored on a voluntary basis, and subject’s refusal to participate in DNA storage 
will not affect their participation in the main trial. 
If a potential subject is a minor, written informed consent will be freely 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 
ability to understand and then sign and date the ICF by himself or herself. 
3.4.2 
Inclusion Criteria 
Subjects are required to meet the inclusion criteria presented in Table 3.4.2-1. 
Table 3.4.2-1 
Inclusion Criteria 
1 
Males or females age 18 to 70 years, inclusive, at 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 International Classification of The Headache 
Disorders, third edition [beta version] [ICHD-3 beta] criteria [Classification Committee of the 
International Headache Society 2013]) or clinical judgment suggests a migraine diagnosis (not 
better accounted for by another ICHD-3 beta diagnosis) for ≥ 12 months prior to giving 
informed consent 


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Table 3.4.2-1 
Inclusion Criteria 
5 
Patient fulfills all the following criteria for CM in baseline information collected during the 28-
day screening period: 
 
Headache occurring on ≥ 15 days 
 
Fulfilling any of the following on ≥ 8 days: 
 
ICHD-3 beta diagnostic criteria C and D for 1.1 Migraine without aura (see Appendix 
3) 
 
ICHD-3 beta diagnostic criteria B and C for 1.2 Migraine with aura (see Appendix 3) 
 
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 
4.1.1-1 and Table 4.1.2-1) for migraine or other medical conditions (ie, at least 5 half-lives have 
passed since last use) or using no more than 1 preventive migraine medication (restricted 
medications, see Table 4.1.2-1) 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 giving 
informed consent. 
7 
Body mass index (BMI) of 17.5 to 37.5 and total weight between 35.0 and 120.0 kg, inclusive 
8 
Patient demonstrates compliance with the electronic headache diary 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. 
9 
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, 2, and 9:  These criteria are set to appropriately evaluate efficacy and safety. 
3:  This criterion is set to ensure the conduct of the trial is ethically appropriate. 
4 and 5:  These criteria are set to identify patients with CM. 
6:  This criterion is set to appropriately evaluate efficacy.  Since the guidelines developed by the Headache 
Consortium4,19 recommend preventive therapies for all CM patients having frequent headache and severe 
impairment, the use of 1 preventive medication is permitted during the trial. 
7:  This criterion is set to ensure appropriate administration of the IMP and appropriate evaluation of 
efficacy and safety. 
8:  This criterion is set to appropriately evaluate efficacy. 
 
3.4.3 
Exclusion Criteria 
Subjects will be excluded if they fall under any of the exclusion criteria in Table 3.4.3-1. 
Table 3.4.3-1 
Exclusion Criteria 
1 
Patient has received onabotulinumtoxin A for migraine or for any medical or cosmetic reason 
requiring injection in the head, face, or neck during the 4 months prior to giving informed 
consent. 
2 
Patient is using medications containing opioids (including codeine) or barbiturates (including 
butalbital/aspirin/caffeine, butalbital/paracetamol/caffeine, or any other combination containing 
butalbital) on more than 4 days per month for the treatment of migraine or for any other reason. 


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Table 3.4.3-1 
Exclusion Criteria 
3 
Patients who have previously failed (lack of efficacy) 2 or more of the clusters of the following 
medications for treatment of EM or CM after use for at least 3 months at accepted migraine 
therapeutic doses: 
 
Cluster A:  topiramate, divalproex sodium and sodium valproate 
 
Cluster B:  lomerizine, flunarizine and pizotifen 
 
Cluster C:  amitriptyline, nortriptyline, venlafaxine, and duloxetine 
 
Cluster D:  atenolol, nadolol, metoprolol, propranolol, and timolol 
4 
Patient has used an intervention/device (eg, scheduled nerve blocks or transcranial magnetic 
stimulation) for migraine during the 2 months prior to giving informed consent. 
5 
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. 
6 
Hematological, cardiac, renal, endocrine, pulmonary, gastrointestinal, genitourinary, 
neurologic, hepatic, or ocular disease considered clinically significant in the judgment of the 
investigator 
7 
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 
8 
History of clinically significant 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 embolic events), 
such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis, 
or pulmonary embolism 
9 
Known infection or history of human immunodeficiency virus (HIV), tuberculosis, or hepatitis 
B virus (HBV) or hepatitis C virus (HCV) infection 
10 
Past or current history of cancer in the past 5 years, except for appropriately treated skin 
carcinoma other than malignant melanoma 
11 
History of hypersensitivity reactions to injected proteins, including monoclonal antibodies 
12 
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 
13 
Any prior exposure to a monoclonal antibody targeting the CGRP pathway (such as AMG334, 
ALD304, LY2951742, or TEV-48125) 
14 
Any finding in the screening or baseline 12-lead ECG considered clinically significant in the 
judgment of the investigator 
15 
Any finding that, in the judgment of the investigator, is a clinically significant abnormality, 
including in chemistry, hematology, coagulation, and urinalysis test values 
16 
ALT, AST, and 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 
17 
Serum creatinine more than 1.5 × ULN, clinically significant proteinuria, or evidence of renal 
disease at screening 
18 
History of alcohol or drug abuse during the past 2 years, or alcohol or drug dependence during 
the past 5 years 
19 
Female patient who is nursing at the time informed consent is obtained or who tests positive in 
pregnancy test at screening or baseline 


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Table 3.4.3-1 
Exclusion Criteria 
20 
Sexually active males or women of childbearing potential (WOCBP) who do not agree to 
practice 2 different methods of birth control together with their partner throughout the trial 
period 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, vaginal diaphragm, intrauterine 
device, birth control pill, birth control implant, birth control depot injection, condom with 
spermicide, or sponge with spermicide. 
Note) Nonchildbearing potential is defined as male and female subjects who are surgically 
sterile (ie, male subjects who have undergone bilateral orchidectomy and female subjects who 
have undergone bilateral oophorectomy and/or hysterectomy) and female subjects who have 
been postmenopausal (at least 12 months since last menses and follicle-stimulating hormone 
[FSH] level above 35 U/L). 
21 
The patient cannot participate or successfully complete the trial for other reasons in the opinion 
of the investigator. 
 
[Rationales for exclusion criteria] 
1 through 5:  These criteria are set to appropriately evaluate efficacy. 
6 through 10, 12, 18, and 21:  These criteria are set to appropriately evaluate efficacy and safety. 
11 and 14 to 17:  These criteria are set to appropriately evaluate the safety. 
13:  This criterion is set to avoid potential influence on the blindness and safety. 
19 and 20:  These criteria are set because the safety of the IMP in pregnant or nursing females has not been 
established. 
 
Screen failure subjects may be rescreened if prior agreement is obtained from the sponsor.  
If a subject is to be rescreened, informed consent must be newly obtained, and a new 
subject identification number must be assigned to the subject prior to the rescreening 
examination. 
3.5 
Endpoints 
3.5.1 
Primary Endpoint 
The primary endpoint is the mean change from baseline in the monthly (28-day) average 
number of headache days of at least moderate severity during the 12-week period after 
the first dose of IMP. 
This is consistent with the primary endpoint recommended by the Classification 
Committee of IHS guidelines for controlled trials of prophylactic treatment of CM in 
adults.15 
3.5.2 
Secondary Endpoints 
3.5.2.1 
Efficacy Endpoints 
The efficacy endpoints for this trial are as follows: 
 Mean change from baseline in the monthly average number of migraine days during 
the 12-week period after the first dose of IMP 


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 Proportion of subjects reaching at least 50% reduction in the monthly average number 
of headache days of at least moderate severity during the 12-week period after the 
first dose of IMP 
 Mean change from baseline in the monthly average number of days with use of any 
acute headache medications during the 12-week period after the first dose of IMP 
 Mean change from baseline in the monthly average number of headache days of at 
least moderate severity during the 12-week period after the first dose of IMP in 
subjects not receiving concomitant preventive migraine medications 
 Mean change from baseline in disability score, as measured by the 6-Item Headache 
Impact Test (HIT-6), at 4 weeks after the final (third) dose of IMP 
 
3.5.2.2 
Safety Endpoints 
The safety endpoints for this trial are as follows: 
 AEs 
 Clinical laboratory tests (chemistry, hematology, coagulation, and urinalysis) 
 12-Lead ECGs 
 Physical examination 
 Vital signs (systolic and diastolic blood pressure, pulse rate, temperature, and 
respiratory rate) 
 Weight 
 Injection site reaction (ie, erythema, induration, ecchymosis, and pain) assessments, 
including severity 
 Electronic Columbia-Suicide Severity Rating Scale (eC-SSRS) 
 
3.5.3 
Exploratory Endpoints 
The exploratory endpoints for this trial are as follows: 
 Number of migraine days 
 Number of headache days of at least moderate severity 
 Number of headache days of any severity 
 Number of headache hours 
 Number of days with use of any acute headache medications 
 Number of days with nausea or vomiting 
 Number of days with photophobia or phonophobia 
 Migraine-Specific Quality of Life (MSQOL) 
 EuroQol-5 Dimension, 5 response level version (EQ-5D-5L) 
 2-Item Patient Health Questionnaire (PHQ-2) and 9-Item Patient Health 
Questionnaire (PHQ-9) 


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 Work Productivity and Activity Impairment (WPAI) 
 Patient Global Impression of Change (PGIC) 
 
3.5.4 
Pharmacokinetic Endpoint 
The pharmacokinetic endpoint for this trial is as follows: 
 Plasma TEV-48125 concentrations 
 
3.5.5 
Immunogenicity Endpoint 
The immunogenicity endpoint for this trial is as follows: 
 Incidence of serum anti-TEV-48125 antibodies 
 
3.6 
Measures to Minimize/Avoid Bias 
In this randomized, double-blind trial, subjects will be randomly assigned with 
stratification based on sex, country, and use of preventive migraine medication at 
V2/Baseline to 3 groups in a 1:1:1 ratio.  Further details of randomization will be 
presented in the Subject Randomization Code Manual. 
In this double-blind trial, all subjects and investigators will remain blinded to the subject 
randomization code.  Any party on the sponsor’s side involved in the trial, including 
contract research organizations (CROs) but excluding drug concentration measurement 
facilities and ADA measurement facilities, will also remain blinded to the subject 
randomization code during the trial period.  Prior to trial commencement, the 
indistinguishability of IMP will be confirmed by the sponsor.  The emergency code will 
be controlled by the IRT until the end of the trial.  In the event that a subject experiences 
a medical emergency or the safety of a subject needs to be confirmed immediately and 
knowledge of the IMP assignment code is considered essential to adequately treat the 
subject, the emergency code for the subject may be broken (see Section 5.7, Procedure 
for Breaking the Blind).  However, the results of ADA and pharmacokinetic assessments 
should not be disclosed until code breaking at the end of the trial.  ADA and 
pharmacokinetics will be assessed by specified facilities, not by laboratories at trial sites. 
3.7 
Trial Procedures 
Trial assessment time points are summarized in Table 3.7-1. 
 


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Table 3.7-1 
Schedule of Assessments 
 
Visit V1/Screening
V2/Baseline
V3/Month 1
V4/Month 2
Additional
visits for PKb
V5/End of
treatment
(Month 3)
Withdrawal
Study Day
Day -28
Day 1
Day 29
Day 57
Day 85
Acceptable window
-3
±3
±3
±3
Day of
withdrawal
decision + 7
Xa
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
WPAI questionnaire
X
X
X
X
X
X
X
X
X
X
Review electronic headache diary
Return electronic headache diary device
X
X
X
X
X
X
X
Procedures and
Assessments
Period
Screening
Period
Double-blind Treatment Period
Clinical laboratory tests (chemistry,
hematology, coagulation, and urinalysis)
Informed consent
Demographics
Eligibility assessment
Randomization
IMP administration
Injection site response assessmentc
Physical examination
Height
Weight
12-Lead ECGd,e
Vital signsd (systolic and diastolic pressure,
pulse rate, temperature, respiratory rate)
X
Serum HCG testf
Urine HCG testf
FSH testg
Adverse eventsh
Medication and therapy inquiry
Preventive migraine medication inquiry
eC-SSRSi
Informed consent to DNA storage
(voluntary)
Blood and urine samples for biomarker
analysis
HIT-6
PHQ-2/PHQ-9o
MSQOL questionnaire
EQ-5D-5L questionnaire
PGIC scale
Provide electronic headache diary devicej
Complete electronic headache diary entriesk
Blood samples for plasma drug
concentrationl
Blood samples for serum ADA assessmentm
Blood samples for pharmacogenomic
analysisn


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HCG = serum human chorionic gonadotropin. 
aInformed consent can be obtained prior to the day of V1/Screening. 
bA total of 2 visits will be performed at 3 to 10 days and at 14 to 21 days postdose at V2/Baseline, 
V3/Month 1, or V4/Month 2. 
cInjection site reaction will be assessed immediately and 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/pain is of moderate or less severity. 
dProcedure will be performed before other assessments (blood draws and administration of 
questionnaires). 
e12-Lead ECGs will be performed in triplicate. 
fWomen of childbearing potential only. 
gWomen at least 12 months postmenopausal only. 
hInquiries about AEs will be made before and after IMP administration.  Postdose inquiries will be made 
before the subject leaves the trial site. 
iThe eC-SSRS Baseline/Screening version will be completed at V2/Baseline, and the eC-SSRS Since 
Last Visit version will be completed at all other visits. 
jEligible subjects will be given an electronic headache diary device (eDiary) and will be trained in its 
use and compliance requirements at V1/Screening. 
kSubjects will complete electronic headache diary entries about the previous day daily beginning at 
V1/Screening through V5/End of treatment or the day before withdrawal. 
lBlood samples for plasma drug concentration determination will be collected prior to dosing at 
V2/Baseline, V3/Month 1, and V4/Month 2. 
mBlood samples for ADA assessment will also be collected upon observation of any severe 
hypersensitivity reaction (eg, anaphylaxis). 
nA single blood sample for pharmacogenomic analysis will be collected at V2/Baseline or any visit 
thereafter from subjects who consent to DNA storage.  A separate informed consent form for DNA 
storage must be signed by the subject. 
oSubjects will respond first to the PHQ-2.  They will respond to questions 3 through 9 (unique 
questions) of the PHQ-9 only if PHQ-2 is positive. 
 
3.7.1 
Schedule of Assessments 
3.7.1.1 
Screening Period 
The screening period begins on the day of informed consent and ends on the day before 
V2/Baseline. 
An appropriately signed and dated ICF will be obtained before screening procedures 
commence.  After informed consent is obtained, the investigator (or designee) will 
promptly enter the subject’s information in the IRT and obtain a subject identification 
number as described in Section 3.3.2, Subject Selection and Numbering. 


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The following information will be recorded on the case report form (CRF) 
 Informed consent 
 Date of informed consent 
 Subject identification number 
For headache information on each day from V1/Screening through the day before 
V2/Baseline, subjects will enter headache information about the previous day into the 
electronic headache diary.  The data used for inclusion criterion 5 will be those from the 
electronic headache diary within the last 28 days prior to V2/Baseline. 
12-Lead ECGs and clinical laboratory values measured by the central laboratory, which 
cannot be assessed at V1/Screening, should be checked against inclusion/exclusion 
criteria soon after they become available to determine the subject’s eligibility. 
3.7.1.1.1 
Visit 1/Screening (Day −28; Acceptable Window:  −3 Days) 
V1/Screening will take place 28 days before V2/Baseline.  In order to determine the 
subject’s eligibility, the following assessments/tests/observations will be performed and 
recorded on the CRF. 
 Visit date 
 Result of eligibility assessment 
 Demographics 
 Date of investigation 
 Birth date, age, and sex (at the time of informed consent) 
 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 preventive migraine medications (including topiramate and 
onabotulinumtoxin A) (within 2 years before the start of IMP administration [if 
discontinued before consent, its reason]) 
 History of medications or therapies other than preventive migraine medications 
(within 5 months before the start of IMP administration) 
 Vital signs (systolic and diastolic blood pressure, pulse rate, temperature, and 
respiratory rate) (should precede blood sampling) 
 Triplicate 12-lead ECGs (should precede blood sampling) 
 Physical examination 
 Height and weight (BMI will be calculated using height and weight at V1/Screening) 
 Clinical laboratory tests 


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 Chemistry, hematology, coagulation, and urinalysis 
 Serum human chorionic gonadotropin (HCG) test (women of childbearing 
potential [WOCBP] only) 
 Follicle-stimulating hormone (FSH) test (women at least 12 months 
postmenopausal only) 
 Electronic headache diary (subjects will be given an electronic headache diary device 
[eDiary], trained in its use, and given an explanation on the compliance requirements) 
 AEs 
 
3.7.1.2 
Double-blind Treatment Period 
The double-blind treatment period begins at V2/Baseline and ends at V5/End of treatment 
or the time of withdrawal. 
Each day during the double-blind treatment period, subjects will enter headache 
information about the previous day into the electronic headache diary. 
3.7.1.2.1 
Baseline 
3.7.1.2.1.1 
Visit 2/Baseline (Day 1) 
Prior to IMP administration, the following assessments/tests/observations will be 
performed and recorded on the CRF.  The investigator will confirm that the subject meets 
all the inclusion criteria and does not fall under any of the exclusion criteria. 
Trial personnel responsible for administration of injections will subcutaneously 
administer the IMP assigned by the procedure presented in Section 3.7.1.2.1.2, 
Randomization, to the subject. 
 Visit date 
 Result of eligibility assessment 
 Use of preventive migraine medications 
 Randomization 
 Date of randomization 
 Randomization number 
 Electronic headache diary 
 Vital signs (systolic and diastolic blood pressure, pulse rate, temperature, and 
respiratory rate) (should precede blood sampling and questionnaires) 
 Triplicate 12-lead ECGs (should precede blood sampling and questionnaires) 
 Physical examination 
 Weight 
 Clinical laboratory tests 
 Chemistry, hematology, coagulation, and urinalysis 


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 Urine HCG test (WOCBP only) 
 Blood sampling for serum ADA assessment 
 Blood and urine sampling for biomarker assessment 
 Blood sampling for plasma drug concentration determination 
 Blood sampling for pharmacogenomic assessment (only subjects who consent to 
DNA storage) (will be performed at V2/Baseline or any visit thereafter) 
 HIT-6 
 PHQ-2/PHQ-9 (Subjects will respond first to the PHQ-2.  They will respond to 
questions 3 through 9 [unique questions] of the PHQ-9 only if PHQ-2 is positive.) 
 MSQOL questionnaire 
 EQ-5D-5L questionnaire 
 WPAI questionnaire 
 eC-SSRS (Baseline/Screening version) 
 History of medications and therapies (within 5 months before the start of IMP 
administration) 
 AEs 
After the above predose assessments/tests/observations are completed, subjects will 
subcutaneously receive the IMP (see Section 3.2, Trial Treatments).  After IMP 
administration, the following assessments/observations will be performed and recorded 
on the CRF.  Additional assessments may be performed based on the severity of 
abnormal injection site reaction (ie, erythema, induration, ecchymosis, and pain). 
 Conditions of IMP administration 
 Date, time, and injection site of IMP administration 
 If IMP was not administered, its reason 
 Injection site reaction (ie, erythema, induration, ecchymosis, and pain) assessments, 
including severity (immediately and 1 hour postdose) 
 Postdose adverse events (occurring before the subject leaves the trial site) 
 
3.7.1.2.1.2 
Randomization 
Prior to IMP administration, the investigator will confirm that the subject meets all the 
inclusion criteria and does not fall under any of the exclusion criteria.  Trial personnel 
will enter subject information in the IRT.  Eligible subjects will be randomly assigned 
with stratification based on sex, country, and use of preventive migraine medication at 
V2/Baseline (yes, no) to one of the following 3 groups: 
 TEV-48125 675/225/225 mg group 
 TEV-48125 675 mg/placebo/placebo group 
 Placebo group 


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3.7.1.2.2 
Visit 3/Month 1 (Day 29; Acceptable Window:   3 Days) and 
Visit 4/Month 2 (Day 57; Acceptable Window:   3 Days) 
Prior to IMP administration, the following assessments/tests/observations will be 
performed and recorded on the CRF. 
 Visit date 
 Electronic headache diary 
 Vital signs (systolic and diastolic blood pressure, pulse rate, temperature, and 
respiratory rate) (should precede blood sampling and questionnaires) 
 Physical examination 
 Clinical laboratory tests 
 Chemistry, hematology, coagulation, and urinalysis 
 Urine HCG test (WOCBP only) 
 Blood sampling for serum ADA assessment (V3/Month 1 only) 
 Blood and urine sampling for biomarker assessment (V4/Month 2 only) 
 Blood sampling for plasma drug concentration determination 
 Blood sampling for pharmacogenomic assessment (only subjects who consent to 
DNA storage) (will be performed at V2/Baseline or any visit thereafter) 
 MSQOL questionnaire 
 PGIC scale 
 eC-SSRS (Since Last Visit version) 
 Concomitant medications and therapies 
 AEs 
After the above predose assessments/tests/observations are completed, subjects will 
subcutaneously receive IMP (see Section 3.2, Trial Treatments).  After IMP 
administration, the following assessments/observations will be performed and recorded 
on the CRF.  Additional assessments may be performed based on the severity of 
abnormal injection site reaction (ie, erythema, induration, ecchymosis, and pain). 
 Conditions of IMP administration 
 Date, time, and injection site of IMP administration 
 If IMP was not administered, its reason 
 Injection site reaction (ie, erythema, induration, ecchymosis, and pain) assessments, 
including severity (immediately and 1 hour postdose) 
 Postdose AEs (occurring before the subject leaves the trial site) 
 


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3.7.1.2.3 
Visit 5/End of Treatment (Day 85; Acceptable Window:  
 3 Days) and Withdrawal (Acceptable Window:  Day of 
Withdrawal Decision + 7 Days) 
As the final evaluation (V5/End of treatment), the following 
assessments/tests/observations will be performed.  For withdrawals, the following 
assessments/tests/observations will be performed wherever possible within the acceptable 
window.  The results of assessments/tests/observations will be recorded on the CRF.  The 
day of withdrawal decision is defined as the date when the subject (or legally acceptable 
representative, etc, if the subject is a minor) submits a request for withdrawal or when the 
subject’s withdrawal is considered necessary by the investigator.  Procedures for 
withdrawal from the trial are described in Section 3.8.3, Individual Subject 
Discontinuation. 
Subjects will be offered the opportunity to enter the long-term trial for the purpose of 
evaluating ADA at 225 days (approximate equivalent of 5 half-lives) after the final dose 
of IMP (V4/Month 2) in this trial. 
 Visit date 
 Completion of trial 
 Trial completion date/discontinuation date 
 In the case of withdrawal, reason for discontinuation 
 Electronic headache diary (Subjects will return the eDiary) 
 Vital signs (systolic and diastolic blood pressure, pulse rate, temperature, and 
respiratory rate) (should precede blood sampling and questionnaires) 
 Triplicate 12-lead ECGs (should precede blood sampling and questionnaires) 
 Physical examination 
 Weight 
 Clinical laboratory tests 
 Chemistry, hematology, coagulation, and urinalysis 
 Urine HCG test (WOCBP only) 
 Blood sampling for serum ADA assessment 
 Blood and urine sampling for biomarker assessment 
 Blood sampling for plasma drug concentration determination 
 Blood sampling for pharmacogenomic assessment (only subjects who consent to 
DNA storage) (will be performed at V2/Baseline or any visit thereafter) 
 HIT-6 
 PHQ-2/PHQ-9 (Subjects will respond first to the PHQ-2.  They will respond to 
questions 3 through 9 [unique questions] of the PHQ-9 only if the PHQ-2 is positive.) 
 MSQOL questionnaire 


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 EQ-5D-5L questionnaire 
 WPAI questionnaire 
 PGIC scale 
 eC-SSRS (Since Last Visit version) 
 Concomitant medications and therapies 
 AEs 
 Participation in the long-term trial (yes, no) 
 
3.7.1.3 
Two Additional Visits for Pharmacokinetic Analysis (3 to 
10 Days and 14 to 21 Days After One of the IMP Administrations 
at Either Visit 2/Baseline, Visit 3/Month 1, or Visit 4/Month 2) 
At 2 additional visits at 3 to 10 days and at 14 to 21 days after one of the IMP 
administrations at either V2/Baseline, V3/Month 1, or V4/Month 2, the following 
assessments/tests/observations will be performed and recorded on the CRF. 
 Blood sampling for plasma drug concentration determination 
 Triplicate 12-lead ECGs (should precede blood sampling) 
 Concomitant medications and therapies 
 AEs 
 
3.7.1.4 
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/observations 
will be performed.  The date of the unscheduled visit and the results of the 
assessments/tests/observations, only those performed according to the procedures 
specified in the protocol, will be recorded on the CRF.  Other procedures may be 
performed at the discretion of the investigator. 
3.7.2 
Efficacy Assessments 
Any efficacy endpoint data will be electronically collected.  Data on headache-related 
efficacy endpoints will be collected using eDiary, and data on overall functional 
assessments, physical assessments, and other relevant assessments (Section 3.7.2.2 
through Section 3.7.2.7) will be collected using Electronic Patient-Reported Outcomes 
(ePRO). 
3.7.2.1 
Electronic Headache Diary 
Headache-related efficacy endpoints will be derived from headache variables collected 
using an eDiary.  Eligible subjects will receive comprehensive training from trial 


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personnel on the use of the eDiary at V1/Screening.  On each day, the subject will be 
asked to enter headache data in the electronic headache diary 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 electronic headache diary 
by 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.  If a subject has not entered the headache data by 8 PM of the 
next day, the subject will be reminded to enter the data. 
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. 
3.7.2.2 
Six-Item Headache Impact Test 
Subjects will assess the impact of headache on social functioning, role functioning, 
vitality, cognitive functioning, and psychological distress, using the HIT-6. 
3.7.2.3 
Two-Item Patient Health Questionnaire/Nine-Item Patient Health 
Questionnaire 
The PHQ-2 and PHQ-9 will be completed by subjects for the detection and monitoring of 
depression, anxiety, and somatization during the last 2 weeks.  The PHQ is a 9-item 
questionnaire with each item corresponding to 1 criterion of the Diagnostic and Statistical 
Manual for Mental Disorders fourth edition diagnostic criteria for major depressive 
disorder.  Each of the items is scored on a scale of 0 (not at all), 1 (several days), 2 (more 
than half the days), and 3 (nearly every day) based on the frequency of symptoms during 
the past 2 weeks.  The PHQ-2 was developed from the PHQ-9 to rapidly screen for 
depression and consists of the first 2 questions from the PHQ-9. 


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All subjects will complete the PHQ-2.  If the PHQ-2 is positive (ie, a score of ≥ 3), 
subjects will complete questions 3 through 9 (unique questions) of the PHQ-9. 
3.7.2.4 
Migraine-Specific Quality of Life Questionnaire 
Using the MSQOL questionnaire, subjects will assess the impact of migraine and 
migraine treatment on their quality of life during the past 4 weeks.  The MSQOL 
measures the degree to which performance of normal activities is limited by migraine 
(Role Function-Restrictive domain comprising 7 items), the degree to which performance 
of normal activities is prevented by migraine (Role Function-Preventive domain 
comprising 4 items), and the emotional effects of migraine (Emotional Function domain 
comprising 3 items).  Scores range from 0 to 100, with higher scores indicating better 
health-related quality of life. 
3.7.2.5 
EuroQol-5 Dimension, 5 Response Level Version Questionnaire 
Using the EQ-5D-5L questionnaire, subjects will assess their overall state of health on the 
day of assessment.  The EQ-5D-5L questionnaire consists of 2 parts.  In Part 1, subjects 
rate their health state in 5 domains:  mobility, self-care, usual activities, pain/discomfort, 
and anxiety/depression, using a scale of 1 to 5 where 1 = no problems, 2 = slight 
problems, 3 = moderate problems, 4 = severe problems, and 5 = extreme problems.  In 
Part 2, subjects rate their health state on a 100-mm visual analog scale; a rating of 0 
represents the worst imaginable health state, and a rating of 100 represents the best 
imaginable health state. 
3.7.2.6 
Patient Global Impression of Change Scale 
Using the PGIC scale, subjects will assess overall change in the severity of illness 
following treatment.  Subjects will rate how they describe the change (if any) that their 
migraine/headaches have had in their general quality of life and health status since 
beginning the treatment in this trial on a 7-point scale where 1 = no change (or it got 
worse); 2 = almost the same, hardly any change at all; 3 = a little better, but no noticeable 
change; 4 = somewhat better, but the change has not made any real difference; 
5 = moderately better, and a slight but noticeable change; 6 = better, and a definite 
improvement that has made a real and worthwhile difference; and 7 = a great deal better, 
and a considerable improvement that has made all the difference. 
3.7.2.7 
Work Productivity and Activity Impairment Questionnaire 
Subjects will assess the overall effect of health on productivity at work and daily 
activities during the past 7 days prior to the assessment day using a generic version of the 
WPAI questionnaire, and the specific health problems version of the WPAI questionnaire 
allows investigators to attribute productivity and activity impairment issues to specific 


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health conditions.  After the employment status of a respondent is identified, 3 open-
ended questions are asked concerning 1) hours absent from work due to health problems 
(or specific condition), 2) hours absent from work due to other reasons, and 3) hours 
actually worked.  Two additional questions are included that ask about the impact of 
health on productivity, one concerning productivity at work and the other concerning 
daily activities outside of work. 
The response format of each item of the WPAI questionnaire consists of an 11-point scale 
ranging from 0 (no impairment) to 10 (complete impairment). 
3.7.3 
Safety Assessments 
3.7.3.1 
Adverse Events 
Refer to Section 5, Reporting of Adverse Events. 
3.7.3.2 
Clinical Laboratory Assessments 
Clinical laboratory assessments will be performed for the parameters listed in Table 
3.7.3.2-1.  The total volume of blood to be collected for each subject in this trial is 
approximately 62 mL (approximately 86 mL for Korean subjects). 
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 confirm the 
eligibility of each subject based on clinical laboratory values measured by the central 
laboratory.  Any additional clinical laboratory tests, if required besides those performed 
at scheduled time points for blood/urine collection for reasons such as AEs, will also be 
performed by the protocol-specified central laboratory.  The collection, treatment, storage, 
and shipment of samples will be performed as described in a separate operational 
procedure. 
For WOCBP, a serum HCG test will be performed at V1/Screening and a urine HCG test 
will be performed at V2/Baseline and all subsequent visits.  If a urine HCG test 
performed at V3/Month 1 or any later visit is positive, the investigator will follow up 
with a confirmatory serum HCG test.  For women who have been postmenopausal for at 
least 12 months since last menses, an FSH test will be performed at V1/Screening. 
The central laboratory will report clinical laboratory test results to the investigator.  The 
investigator will confirm the results promptly, and date and sign the clinical laboratory 
test results report as an official document.  The date and time of blood/urine collection 
and whether during menses or not will be recorded on the CRF.  The results of clinical 
laboratory tests, excluding urine HCG tests, will be directly reported from the central 


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laboratory to the sponsor via electronic file transfer; therefore, recording of the results on 
the CRF is not needed.  The results of urine HCG tests will be recorded on the CRF. 
Table 3.7.3.2-1 
Clinical Laboratory Assessments 
Hematology 
Hemoglobin 
Hematocrit 
Erythrocytes count 
Erythrocyte indices 
 
Mean corpuscular hemoglobin concentration 
 
 Mean corpuscular volume 
 
Erythrocytes distribution width 
Leukocytes count and differential count (absolute 
values and percentages) 
 
Neutrophils 
 
Lymphocytes 
 
Eosinophils 
 
Monocytes 
 
Basophils 
Platelet count 
 
Urinalysis 
Appearance 
Color 
Occult blood 
Glucose 
Microscopic tests (high-power field) 
 
Bacteria 
 
Leukocytes count 
 
Erythrocytes count 
 
Casts 
 
Crystals 
pH 
Protein 
Specific gravity 
Albumin 
Ketones 
Leukocyte esterase 
Nitrite 
Direct bilirubin 
Chemistry 
ALP 
ALT 
AST 
Total bilirubin 
Direct bilirubin 
Indirect bilirubin (calculated) 
Urea nitrogen 
Calcium 
Creatinine 
Gamma glutamyl transferase (GGT) 
Glucose 
Lactate dehydrogenase 
Potassium 
Total protein 
Sodium 
Phosphorus 
Chloride 
Carbon dioxide 
Magnesium 
Albumin 
Creatine phosphokinase 
 
Coagulation 
Prothrombin time 
Partial thromboplastin time 
International normalized ratio (INR) 
 
Additional tests 
Serum/urine HCG test for WOCBP 
FSH test for women who have been 
postmenopausal for at least 12 months since last 
menses 
 
 
 
3.7.3.3 
Physical Examination 
For 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 to the extent possible.  
On the CRF, the date and results of assessments will be recorded at V1/Screening, and 


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only the date of assessments will be recorded at V2/Baseline and subsequent visits.  Any 
clinically significant physical finding that is not observed at V1/Screening but at 
V2/Baseline or any later visit will be considered an AE, recorded on the source 
documents and CRFs, and monitored until its outcome has been sufficiently evaluated. 
3.7.3.4 
Height and Weight 
Weight will be measured while minimizing fluctuations associated with clothing.  Date of 
measurement, height (up to one decimal place; cm), and weight (up to one decimal place; 
kg) will be recorded on the CRF.  Any height/weight measured up to more than one 
decimal place will be rounded up to one decimal place. 
3.7.3.5 
Vital Signs 
As vital signs, systolic and diastolic blood pressure, pulse rate, temperature, and 
respiratory rate will be measured before other assessments (blood draws and 
questionnaires).  Before blood pressure and pulse rate are measured, the subject must be 
in a supine or semi-standing/sitting position and resting for at least 5 minutes.  The same 
position and arm should be used each time vital signs are measured for a given subject 
(however, if it is difficult to use the same position and arm due to occurrence of an AE, 
use of a different position or arm is acceptable).  Date of measurement, position, location, 
systolic and diastolic blood pressures (integer; mmHg), pulse rate (integer; beats/min), 
temperature (up to one decimal place; ºC), and respiratory rate (integer; breaths/min) will 
be recorded on the CRF.  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. 
3.7.3.6 
Twelve-lead Electrocardiography 
Using 12-lead ECG equipment provided by the central laboratory selected by the sponsor, 
ECGs will be conducted before other assessments (blood draws and questionnaires).  The 
ECGs should be performed after the subject has been supine for at least 5 minutes.  The 
ECGs will be performed in triplicate within several minutes. 
Clinical evaluation of ECG results will be performed by the investigator.  A qualified 
physician at the central laboratory selected by the sponsor will interpret ECG results.  
ECGs will be measured and transmitted in accordance with a separate operational 
procedure.  If clinically significant ECG findings are detected by the investigator, a 
medical advisor should be consulted for a definitive interpretation.  Any unscheduled 
ECGs must also be transmitted to the designated central laboratory.  The central 
laboratory will report the results of ECGs to the investigator.  The investigator will 


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confirm the results promptly, and date and sign the electrocardiogram report as an official 
document.  Date of ECG and the interpretation of the investigator will be recorded on the 
CRF.  The central ECG interpretations and findings will be directly reported from the 
central laboratory to the sponsor via electronic file transfer; therefore, recording of the 
results on the CRF is not needed. 
3.7.3.7 
Electronic Columbia-Suicide Severity Rating Scale 
The eC-SSRS will be used to assess the subject’s suicidal ideation (severity and intensity) 
and suicidal behavior.20  The investigator will ask the subject to complete the eC-SSRS 
Baseline/Screening version at V2/Baseline and the eC-SSRS Since Last Visit version at 
all other time points.  Any positive findings on the eC-SSRS Baseline/Screening version 
or the eC-SSRS Since Last Visit version require evaluation by the investigator. 
3.7.3.8 
Injection Site Reaction Assessments 
Injection site reaction assessments will be performed immediately and 1 hour after each 
IMP administration.  The injection site(s) will be assessed 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 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/pain is of 
moderate or less severity. 
 Injection-site erythema, induration, and ecchymosis will be graded according to 
measurements: 
absent, 5 to ≤ 50 mm (mild), > 50 to ≤ 100 mm (moderate), and > 100 mm (severe).  
Induration must be assessed by careful superficial palpation avoiding pressuring or 
squeezing the injection site. 
 Injection-site pain will be evaluated according to Table 3.7.3.8-1. 
For injection site assessments, the date and time and results of evaluation will be 
recorded on the CRF, and an injection site reaction (mild, moderate, or severe) is to be 
reported as an AE.  Pain caused by the puncture of the injection needle will be excluded 
from the assessment, and is not considered to be an AE. 
Table 3.7.3.8-1 
Severity Grading of Pain for Injection Site 
Assessments 
Grade 
Assessments 
0 
No pain 
1 
Mild 
2 
Moderate 
3 
Severe 
4 
Worst possible 
 


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3.7.3.9 
Prior and Concomitant Therapy or Medication 
Monitoring will be performed on any prior or concomitant preventive migraine 
medication (including topiramate and onabotulinumtoxin A) that a subject takes during 
the period from 2 years before the start of IMP administration to the end of trial date for 
individual subject (including reasons for discontinuation if any of such medications has 
been discontinued before informed consent) and any other prior or concomitant 
medication or therapy that a subject takes during the period from 5 months before the 
start of IMP administration and up to the end of trial date for individual subject.  For each 
medication or therapy, the following information will be recorded on the CRF:  name, 
indication, dose, frequency, route of administration, start date, and end date. 
3.7.4 
Pharmacokinetic/pharmacodynamic/pharmacogenomic 
Assessments 
3.7.4.1 
Pharmacokinetics 
3.7.4.1.1 
Pharmacokinetic Blood Samples 
(1) 
Timing of Blood Sampling 
 V2/Baseline (Day 1):  Predose 
 V3/Month 1 (Day 29; acceptable window:  ± 3 days):  Predose 
 V4/Month 2 (Day 57; acceptable window:  ± 3 days):  Predose 
 V5/End of treatment (Day 85; acceptable window:  ± 3 days) 
 V2/Baseline, V3/Month 1, or V4/Month 2:  3 to 10 days and 14 to 21 days postdose 
at V2/Baseline, V3/Month 1, or V4/Month 2 
 Withdrawal (acceptable window:  day of withdrawal decision + 7 days) 
As immunogenicity will be assessed at 225 days (acceptable window:  ± 15 days, the 
approximate equivalent of 5 half-lives) after the final dose of IMP in this trial, 
pharmacokinetics will also be assessed at the same time.  Blood collection for this time 
point will be performed in the long-term trial. 
(2) 
Blood Sampling and Measurement Methods 
Blood will be collected at the scheduled time points to obtain pharmacokinetic plasma 
samples.  The central laboratory will collect samples and transport them to the drug 
concentration measurement facility.  Detailed sample handling and shipping instructions 
are provided in Appendix 1. 
The drug concentration measurement facility will measure plasma concentrations of 
TEV-48125 in the TEV-48125 group using a validated measurement method.  The drug 
concentration measurement facility will submit the electronic file of the results of drug 
concentration measurements to the sponsor after unblinding. 


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Blood sampling status (performed or not) and date and time of blood sampling will be 
recorded on the CRF.  The results of measurements will be directly reported from the 
drug concentration measurement facility to the sponsor; therefore, recording of the results 
on the CRF is not needed. 
(3) 
Rationale for Timing of Blood Sampling 
It was determined to collect blood at 1 time point before the first dose and a total of 3 
time points 28 days after each of 3 doses to collect trough values at 28 days after each 
dose so that plasma concentrations of TEV-48125 following repeated administration of 
TEV-48125 can be evaluated.  In order to obtain information on the absorption phase and 
early elimination phase in patient groups in addition to the trough values stated above, it 
was also determined to collect blood at 3 to 10 days and 14 to 21 days after any of the 3 
doses of the IMP.  Consequently, blood will be collected from each subject at a total of 6 
time points. 
Because ADA will be assessed during the long-term trial at 225 days after the final dose 
of IMP in this trial (when plasma TEV-48125 concentrations are considered to be 
sufficiently decreased), one blood sampling time point is set in the long-term trial so that 
pharmacokinetics can also be assessed at the same time. 
3.7.4.2 
Immunogenicity 
(1) 
Timing of Blood Sampling 
 V2/Baseline (Day 1):  Predose 
 V3/Month 1 (Day 29; acceptable window:  ± 3 days):  Predose 
 V5/End of treatment (Day 85; acceptable window:  ± 3 days) 
 Withdrawal (acceptable window:  day of withdrawal decision + 7 days) 
 Upon observation of any severe hypersensitivity reaction (eg, anaphylaxis). 
Immunogenicity will also be assessed at 225 days (acceptable window:  ± 15 days, the 
approximate equivalent of 5 half-lives) after the final dose of the IMP in this trial.  Blood 
collection for this time point will be performed in the long-term trial. 
See Appendix 2 for the clinical criteria for diagnosing anaphylaxis. 
(2) 
Blood Sampling and Measurement Methods 
Blood will be collected at the scheduled time points to obtain serum samples for ADA 
assessments.  The central laboratory will collect samples and transport them to the ADA 
measurement facility.  Detailed sample handling and shipping instructions are provided in 
Appendix 1. 
The ADA measurement facility will measure anti-TEV-48125 antibodies in serum in the 
TEV-48125 group using a validated measurement method.  The ADA measurement 


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facility will submit the electronic file of the results of ADA measurements to the sponsor 
after unblinding. 
Blood sampling status (performed or not) and date and time of blood sampling will be 
recorded on the CRF.  The results of measurements will be directly reported from the 
ADA measurement facility to the sponsor; therefore, recording of the results on the CRF 
is not needed. 
(3) 
Rationale for Timing of Blood Sampling 
It was determined to collect blood at 1 time point before the first dose as baseline, 1 time 
point 28 days after the first dose when an increase in IgG is expected to occur, and 1 time 
point 28 days after the final dose of monthly IMP administration (equivalent to 28 days 
after the final dose of IMP administered once monthly and 12 weeks after the final dose 
of IMP administered once over a period of 3 months) in consideration of assessment time 
points recommended in the Food and Drug Administration Guidance21 (approximately 30 
days after the final dose) and the European Medicines Agency Guidelines22 (at least 4 
weeks after the final dose).  Consequently, blood will be collected from each subject at a 
total of 3 time points.  In consideration of the potential effect of residual drug in the blood 
on ADA assessment, blood will also be sampled during the long-term trial at 225 days 
after the final dose of IMP in this trial when plasma TEV-48125 concentrations are 
considered to be sufficiently decreased. 
3.7.4.3 
Pharmacogenomics 
3.7.4.3.1 
DNA Storage 
(1) 
Objectives 
DNA will be stored to analyze CGRP and migraine-associated genes and to thereby 
examine their association with clinical treatment responses to TEV-48125 and their 
potential to be markers predictive of migraine severity and progression (eg, efficacy, 
pharmacokinetics, tolerability, and safety features or disease susceptibility and severity 
features). 
(2) 
Target Patients 
Only trial sites that have agreed in advance to collect samples for DNA storage will 
collect the samples from subjects who have provided written informed consent to the 
storage of their DNA samples.  DNA storage is voluntary.  Even if a subject withdraws 
his/her consent to trial participation, the subject is not regarded as withdrawing his/her 
consent to DNA storage.  DNA samples will be stored only if approval for DNA storage 
is obtained from the IRB/IEC/EC of a trial site.  Consent to DNA storage will be obtained 
from subjects before blood is collected for DNA storage. 


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(3) 
Timing of Blood Sampling 
 V2/Baseline (Day 1) or subsequent visits:  Predose 
 
(4) 
Blood Sampling and Storage Methods 
Blood will be collected at the scheduled time points to obtain blood samples for DNA 
storage.  The central laboratory will collect samples and assign a new personal code to 
each sample to make it double-coded.  Then, DNA will be extracted from these samples.  
The central laboratory will transport DNA samples to the sample storage facility to store 
DNA.  DNA samples will be stored until either when 1) genomic/genetic analysis is 
judged to be no longer necessary, 2) 15 years have passed since informed consent was 
obtained from the last subject, or 3) a subject withdraws consent for DNA storage, 
whichever is earlier.  Upon request for destruction from the sponsor, the sample storage 
facility will destroy DNA samples in accordance with the relevant procedure specified by 
the facility. 
Detailed procedures related to DNA samples are provided in Appendix 1.  Blood 
sampling status (performed or not) and the date and time of blood sampling will be 
recorded on the CRF. 
(5) 
Genomic/Genetic Analysis 
Genomic/genetic analysis is performed only if it is considered useful to analyze CGRP 
and migraine-associated genes and to thereby examine their association with clinical 
treatment responses to TEV-48125 and their potential to be markers predictive of 
migraine severity and progression (eg, efficacy, pharmacokinetics, tolerability, and safety 
features or disease susceptibility and severity features).  If it is decided that 
genomic/genetic analysis is to be carried out, it will be performed in accordance with 
GCP after preparation of a separate protocol for pharmacogenomic research.  The results 
of the analysis will not be included in the clinical study report but in the 
pharmacogenomic research report that is separately prepared. 
Although target genes for genomic/genetic analysis may be genes having a potential 
association with CGRP and migraine, they are difficult to identify at this stage.  
Genomic/genetic analysis may include genome-wide association analysis performed 
using devices such as DNA chips, microarrays, and next-generation sequencers.  Also in 
this case, the results will not be used for any purposes other than those presented in 
Section 3.7.4.3.1 (1), Objectives.  The genomic/genetic analysis facility will report the 
results of genomic/genetic analysis of double-coded samples to the sponsor. 
Even if a subject withdraws from participation in the trial at his/her own request, the 
results of genomic/genetic analysis which have already been obtained before withdrawal 
will not be destroyed. 


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(6) 
Disclosure of the Results of Genomic/Genetic Analysis 
As a result of genomic/genetic analysis, some genetic association may be found.  
However, the resulting findings would be exploratory in nature or at an early stage of 
research without sufficient scientific reliability in terms of accuracy, certainty, and other 
relevant elements.  Given that the disclosure of scientifically ambiguous information 
would provide no benefits to subjects, the sponsor will not disclose the results of 
genomic/genetic analysis to subjects. 
(7) 
Obtainment and Withdrawal of Consent to DNA Storage 
Subjects will be asked to sign the ICF for DNA storage and genomic/genetic analysis 
using stored DNA samples.  This consent form is prepared separately from the ICF for 
the trial.  If a subject withdraws his/her consent to DNA storage during the DNA storage 
period, the sponsor will ask the sample storage facility to destroy the DNA sample from 
the subject.  A subject’s withdrawal from trial participation is not to be regarded as 
withdrawal of his/her consent to DNA storage.  Upon request for destruction from the 
sponsor, the sample storage facility will destroy relevant DNA samples while maintaining 
their anonymity.  Even if a subject withdraws from participation in the trial at his/her own 
request, the results of genomic/genetic analysis which have already been obtained before 
withdrawal will not be destroyed. 
3.7.4.4 
Biomarkers 
(1) 
Objectives 
Exploratory analysis may be conducted on inflammatory endpoints in blood to examine 
effects of TEV-48125 in patients with migraine.  In addition, exploratory analysis of 
TEV-48125-related biomarkers may be conducted in terms of blood and urine biomarkers 
for extracellular matrix turnover, bone formation, bone resorption, and angiogenesis, in 
which involvement of CGRP is suspected.  Biomarker samples will be stored for these 
exploratory analyses. 
(2) 
Timing of Sampling 
 V2/Baseline (Day 1):  Predose 
 V4/Month 2 (Day 57; acceptable window:  ± 3 days):  Predose 
 V5/End of treatment (Day 85; acceptable window:  ± 3 days) 
 Withdrawal (acceptable window:  day of withdrawal decision + 7 days) 
 
(3) 
Sampling and Storage Methods 
Blood and urine will be collected at the scheduled time points to obtain biomarker 
samples (serum, plasma, RNA, urine).  The central laboratory will collect samples and 
transport them to a sample storage facility.  Biomarker samples will be stored until either 
when 1) exploratory biomarker analysis is judged to be no longer necessary or 2) 15 


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years have passed since informed consent was obtained from the last subject, whichever 
is earlier.  Upon request for destruction from the sponsor, the sample storage facility will 
destroy relevant biomarker samples. 
Detailed procedures related to biomarker samples are provided in Appendix 1.  
Blood/urine sampling status (performed or not) and the date and time of blood/urine 
sampling will be recorded on the CRF. 
(4) 
Exploratory Biomarker Analysis 
Exploratory biomarker analysis is performed only if it is considered useful to analyze the 
relationship between effects of TEV-48125 in patients with migraine and inflammatory 
endpoints in blood and between TEV-48125 and blood and urine biomarkers for 
extracellular matrix turnover, bone formation, bone resorption, and angiogenesis, in 
which involvement of CGRP is suspected.  If it is decided to carry out exploratory 
biomarker analysis, it will be performed in accordance with GCP after preparation of a 
separate protocol for exploratory biomarker analysis.  The results of the analysis will not 
be included in the clinical study report but in the exploratory biomarker analysis report 
that is separately prepared. 
While target biomarkers for exploratory biomarker analysis may be biomarkers for 
inflammation in blood, blood and urine biomarkers for extracellular matrix turnover, 
bone formation, or bone resorption, or blood biomarkers for endothelial generation or 
angiogenesis, they are difficult to identify at this stage.  Extensive analysis may also be 
performed using a simultaneous multiple measurement panel.  Also in this case, the 
results will not be used for any purposes other than those presented in Section 3.7.4.4 (1), 
Objectives. 
Even if a subject withdraws from participation in the trial at his/her own request, the 
results of exploratory biomarker analysis which have already been obtained before 
withdrawal will not be destroyed. 
3.7.5 
End of Trial 
The end of trial date for this trial is defined as the trial completion date or discontinuation 
date that will be recorded on the completion of trial page of the CRF prepared for the last 
subject who completes or is withdrawn from the trial (for the subject who is lost to follow 
up, the date of his/her last visit/contact or the date of the last attempt to contact him/her 
recorded on the follow-up page) (the end of trial date for individual subject is defined in 
Section 3.1, Type/Design of Trial). 


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3.8 
Stopping Rules, Withdrawal Criteria, and Procedures 
3.8.1 
Discontinuation of Entire Trial 
If the sponsor terminates or suspends the trial for any reason, prompt notification will be 
given to principal investigators, IRBs/IECs/ECs, and regulatory authorities in accordance 
with regulatory requirements. 
3.8.2 
Discontinuation at Individual Sites 
Individual trial site participation may be discontinued by the sponsor, the principal 
investigator, or the IRB/IEC/EC if judged to be necessary for medical, safety, regulatory, 
ethical or other reasons consistent with applicable laws, regulations, and GCP.  The 
principal investigator will notify the sponsor promptly if the trial is terminated by the 
principal investigator or the IRB/IEC/EC at the trial site. 
3.8.3 
Individual Subject Discontinuation 
3.8.3.1 
Treatment Discontinuation 
After randomization, 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 continued treatment to the degree possible as described in 
Section 3.8.3.4, Procedures to Encourage Continued Trial Participation. 
If any of the following discontinuation criteria is met and it is decided to discontinue 
treatment for a subject, examinations at the time of discontinuation specified in 
Section 3.7.1.2.3, Visit 5/End of Treatment (Day 85; Acceptable Window:   3 Days) and 
Withdrawal (Acceptable Window:  Day of Withdrawal Decision + 7 Days), will be 
performed, and the date and reasons for discontinuation (see Section 3.8.3.2, 
Documenting Reasons for Treatment Discontinuation) will be recorded in the source 
documents and the CRF. 
1) The subject’s (or subject’s legally acceptable representative if the subject is a 
minor) requests for 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 Appendix 4). 
4) The subject uses or it is considered that the subject needs to use any prohibited 
concomitant medication or therapy. 


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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) The subject has failed to enter headache-related information at least 75% of the 
days in the electronic headache diary between the scheduled visits. 
7) A marked deviation related to IMP administration is detected. 
8) A female subject becomes pregnant, or is suspected of being pregnant, or desires 
to become pregnant (see Section 5.6, Pregnancy). 
9) Other cases where it is considered by the investigator that the subject should 
discontinue treatment for reasons such as a difficulty in complying with the 
protocol  
3.8.3.2 
Documenting Reasons for Treatment Discontinuation 
Concerning each subject undergoing treatment discontinuation, the investigator will 
choose one of the following main reasons for treatment discontinuation and record it on 
the CRF.  If a subject discontinues trial treatment due to an AE, the investigator or other 
trial personnel will make every effort to follow the event until it has resolved or stabilized. 
 Withdrawal by subject 
 Withdrawal by parent/guardian 
 Adverse event 
 Continuing IMP places the subject at undue risk as determined by the investigator 
because of the onset of an AE. 
 The subject meets any of the discontinuation criteria specified in the Guidance for 
Safety Monitoring (see Appendix 4) 
 Protocol deviation 
 The subject uses or it is considered that the subject needs to use any prohibited 
concomitant medication or therapy  
 The subject is found not to have met one or more inclusion criteria or to have 
fallen under any of the exclusion criteria. 
 The subject has failed to enter headache-related information at least 75% of the 
days in the electronic headache diary between the scheduled visits. 
 A marked deviation related to IMP administration is detected. 
 Pregnancy 
 Lost to follow-up 
 Lack of efficacy 
 Site terminated by sponsor 
 Study terminated by sponsor 
 Other 
 


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3.8.3.3 
Withdrawal of Consent 
All subjects have the right to withdraw their consent from further participation in the trial 
at any time without any disadvantage.  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 (these methods of follow up will also be noted in the trial ICF): 
 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 documents 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). 
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 his/her desire to discontinue IMP administration, which is 
not equivalent to a complete withdrawal of consent for further participation (see 
Section 3.8.3.1, Treatment Discontinuation).  A subject may, however, indicate that 
further trial participation is creating a burden on their work or social schedule.  Therefore, 
the investigator should follow the procedures outlined in Section 3.8.3.2, Documenting 
Reasons for Treatment 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 


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of the above degrees of follow-up are considered to have completely withdrawn their 
consent to participate in the trial. 
3.8.3.4 
Procedures to Encourage Continued Trial Participation 
In all cases of impending IMP discontinuation or consent withdrawal, investigators will 
be given instructions to meet and discuss with the subject their options of continuing in 
the trial, preferably on therapy.  The investigator should ensure understanding and 
documentation of the reasons for the subject’s desire to withdraw consent. 
3.9 
Screen Failures 
A screen failure subject in this trial is one from whom written informed consent is 
obtained for only this trial in patients with CM or for both this trial and Trial 406-102-
00002 in patients with EM, but who is not randomized in either of the studies. 
If the subject meets the definition of a screen failure in this trial, the following 
information will be recorded on the CRF:  
 Visit date 
 Date of informed consent 
 Date of investigation 
 Birth date 
 Sex 
 Race 
 Ethnicity 
 Country 
 Results of assessment for eligibility criteria (if the subject is found to be ineligible, 
the number of the criterion that renders the subject ineligible will be recorded.) 
 Date of assessment as a screen failure 
 Reason for screen failure 
 
3.10 
Definition of Completed Subjects 
The treatment period is defined as the time period during which subjects are evaluated for 
primary and/or secondary endpoints of the trial irrespective of whether or not the subject 
was administered all SC 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 assessments at V5/End of treatment will be 
defined as trial completers. 


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3.11 
Definition of Subjects Lost to Follow-up 
Subjects who cannot be contacted on or before V5/End of treatment during the treatment 
period, who do not have a known reason for discontinuation (eg, withdrew consent or 
AE), and for whom a survival status at the end of the trial cannot be determined will be 
classified as “lost to follow-up” as the reason for discontinuation.  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. 
3.12 
Protocol Deviations 
In the event of a deviation from the protocol due to an emergency, accident, or mistake 
(eg, noncompliance with GCP guidelines, violation of IMP assignment or treatment 
compliance, violation of inclusion/exclusion criteria or discontinuation criteria, or 
violation of concomitant medication criteria), the investigator or designee will contact the 
sponsor at the earliest possible time.  The investigator and sponsor will come as quickly 
as possible to a joint decision regarding the subject’s continuation in the trial.  The 
investigator will record any protocol deviation on the source documents.  Any major 
protocol deviation will be recorded on the CRF along with the date and details of the 
deviation. 
                                              
Start date of IMP
administration
            
Follow-up after end of trial
Until the event is 
resolved or the subject is 
lost to follow-up
Trial completion date/End of trial date for individual subject 
(final observation day)
V5/End of treatment
Treatment period
Trial period
Start date of trial
(day of informed 
consent)


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4 
Restrictions 
Use of the following medications and concomitant therapies will be prohibited or 
restricted from after informed consent (or after V1/Screening if the date of informed 
consent and V1/Screening fall on a different day) to V5/End of treatment or the time of 
withdrawal.  Restrictions in regard to pregnancy and sexual activity are detailed in 
Section 3.4.3, Exclusion Criteria.  Male patients may not donate sperm during the trial 
and for 225 days after the final dose of IMP. 
4.1 
Prohibited/Restricted Medications 
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 4.1.1-1 or Table 4.1.2-1 are allowed. 
4.1.1 
Prohibited Medications (Preventive Migraine Medications) 
Use of any preventive migraine medications other than the IMP (see Table 4.1.1-1) will 
be prohibited. 
Table 4.1.1-1 
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 irrespective of restriction conditions if 
given as a topical preparation or eye drops. 
4.1.2 
Restricted Concomitant Medications (Preventive Migraine 
Medications) 
A small subgroup of subjects (up to 30%) will be allowed to use no more than 1 
concomitant preventive migraine medication (see Table 4.1.2-1) at a stable dose and 
regimen during the trial if the medication was previously prescribed for migraine or for 


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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 informed consent. 
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 informed consent.  Subjects on such medicines or supplements should be on 
a stable dose and regimen in so far as possible. 
Table 4.1.2-1 
List of Restricted Concomitant Medications (Preventive 
Migraine Medications) 
Drug Class 
Drug Namea 
Beta-blockers 
Atenolol, propranolol, metoprolol, nadolol, and timolol 
Calcium channel 
blocker/benzocycloheptene 
Lomerizine, (flunarizine), and (pizotifen) 
Antidepressants 
Amitriptyline, venlafaxine, nortriptyline, and duloxetine 
Antiepileptic medications 
Topiramate, valproate, and (divalproate) 
aDrugs that have not been approved in Japan are shown in parentheses. 
 
Any of the medications listed above are allowed irrespective of restriction conditions if 
given as a topical preparation or as eye drops. 
4.2 
Prohibited Concomitant Therapies 
Use of an intervention/device (eg, scheduled nerve blocks and transcranial magnetic 
stimulation) for treating migraine will be prohibited. 
5 
Reporting of Adverse Events 
5.1 
Definitions 
An AE is defined as any untoward medical occurrence in a patient or clinical trial subject 
administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment.  AEs would not include information recorded as medical 
history at screening for preplanned 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. 
An SAE includes any event that results in any of the following outcomes. 
 Death 


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 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 in-patient 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 non-medical need) are not 
considered SAEs. 
 Congenital anomaly/birth defect. 
 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.  Any potential drug-induced liver injury (DILI) case (AST or ALT ≥ 3 × upper 
limit of normal [ULN], and total bilirubin ≥ 2 × ULN or INR > 1.5) is considered an 
SAE even if it does not require hospitalization. 
 
Nonserious AEs are all AEs that do not meet the criteria for a “serious” AE. 
 
An immediately reportable event (IRE) is any of the following: 
 Any SAE. 
 Any AE experienced by investigators or other trial personnel during handling of the 
IMP 
(example:  A nurse has accidental eye contact with an injection solution, which 
causes dacryorrhea.) 
 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 to the 
sponsor.  Pregnancy will only be documented on the AE CRF if there is an 
abnormality or complication. 
 
Any ophthalmic AE of at least moderate severity 
 Any event of suspected anaphylaxis or severe hypersensitivity reaction 
 Any infection caused by a biological pharmaceutical/IMP that is contaminated or 
suspected of being contaminated with viruses such as HBV, HCV, and HIV.  
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 all laboratory tests as they become available.  This review will be 


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documented by the investigator’s dated signature on the laboratory report.  For each 
abnormal laboratory test result, the investigator needs to ascertain if this is an abnormal 
(ie, clinically significant) change from baseline for that individual subject.  This 
determination, however, does not necessarily need to be made the first time an abnormal 
value is observed.  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 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. 
 
Severity:  Adverse events will be graded on a 3-point scale and reported as indicated on 
the CRF.  The intensity 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. 
 
IMP Causality:  Assessment of causal relationship of an AE to the use of the IMP is 
defined as follows: 
Related:  
There is a reasonable possibility of a temporal and causal relationship 
between the IMP and the AE. 
Not Related:  
There is no temporal or causal relationship between the IMP and the 
AE. 
5.2 
Eliciting and Reporting Adverse Events 
The investigator will periodically assess subjects for the occurrence of AEs.  To avoid 
bias in eliciting AEs, subjects should be asked the non-leading 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 CRFs provided by the sponsor.  Adverse events 
and SAEs are to be collected during the period from the time when a subject signs the 
ICF to the end of trial date for individual subject. 
Use medical terminology in 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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Any reported AE for which the severity or seriousness has changed after reporting should 
be reported as a new AE on the CRF. 
In addition, the sponsor must be notified immediately by telephone, fax, or e-mail of any 
IREs according to the procedure outlined in Section 5.3, Immediately Reportable Events.  
Special attention should be paid to recording hospitalization or concomitant medications. 
5.3 
Immediately Reportable Events 
The investigator must report within 24 hours after either the investigator or designee 
becomes aware of any IRE (see Section 5.1, Definitions) by telephone, fax, or e-mail to 
the sponsor (for contact information, see the cover page of this protocol).  An IRE form 
must be completed and sent by e-mail, fax, or overnight courier to the sponsor.  (Please 
note that the IRE form is not the AE page of the CRF.)  When sending an IRE form by e-
mail, etc, sufficient care and attention must be taken to protect subject privacy. 
Subjects experiencing SAEs should be followed clinically until the events are resolved, 
stabilized, or the subject is lost to follow-up.  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.  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. 
5.4 
Potential Drug-induced Liver Injury 
See Appendix 4 for guidance on how to monitor subjects with increased liver function 
test values.  Any potential DILI case (AST or ALT ≥ 3 × ULN and total 
bilirubin ≥ 2 × ULN or INR > 1.5) requires immediate withdrawal from the trial.  All 
values measured in accordance with the guidance on monitoring will be recorded on an 
IRE form, and the case will be recorded on the CRF as an AE. 
5.5 
Events of Suspected Anaphylaxis or Severe Hypersensitivity 
Reaction 
Severe hypersensitivity reactions will be monitored using the diagnostic clinical criteria 
for anaphylaxis as outlined by the 2006 Joint National Institute of Allergy and Infectious 
Disease/Food Allergy and Anaphylaxis Network Second Symposium on Anaphylaxis23 
(see Appendix 2).  In the event of suspected anaphylaxis, vital signs, including oxygen 
saturation and respiration rate, will be measured.  Other assessments will be performed at 
the discretion of the investigator. 


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5.6 
Pregnancy 
Women of child-bearing potential (WOCBP) are defined as female subjects for whom 
menstruation has started and who are not documented as sterile (ie, have had a bilateral 
oophorectomy and/or hysterectomy or who have been postmenopausal for at least 
12 months since last menses and whose FSH level is higher than 35 U/L). 
For WOCBP and for men who are sexually active, there must be a documented 
agreement that the subject and/or their partner will take effective measures 
(ie, double-barrier method) to prevent pregnancy during the course of the trial and for 
225 days after the final dose of IMP.  Unless the subject or their partner is sterile (ie, 
women who have had a bilateral oophorectomy and/or hysterectomy or who have been 
postmenopausal for at least 12 consecutive months since last menses and whose FSH 
level is higher than 35 U/L; or men who have had a bilateral orchidectomy) or remains 
abstinent, 2 of the following precautions must be used:  vasectomy, tubal ligation, vaginal 
diaphragm, intrauterine device, birth control pills, birth control depot injection, birth 
control implant, condom with spermicide, or sponge with spermicide.  Any single method 
of birth control, including vasectomy and tubal ligation, may fail, leading to pregnancy.  
The contraceptive method will be documented at each trial visit. 
 
Before enrolling WOCBP in this clinical trial, investigators must review the below 
guidelines about trial participation with all WOCBP.  The topics should generally 
include: 
 General information 
 ICF 
 Pregnancy prevention information 
 Drug interactions with hormonal contraceptives 
 Contraceptives in current use 
 Guidelines for the follow-up of a reported pregnancy 
 
Before trial enrollment, WOCBP must be advised of the importance of avoiding 
pregnancy during trial participation and the potential risk factors for an unintentional 
pregnancy.  The subject must sign an ICF stating that the above-mentioned risk factors 
and the consequences were discussed with her. 
A serum HCG test will be performed at V1/Screening on all WOCBP. 
During the trial, all WOCBP should be instructed to contact the investigator immediately 
if they suspect they might be pregnant (eg, missed or late menstrual cycle). 


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If a subject is suspected to be pregnant before she receives IMP, the IMP administration 
must be withheld until the results of serum HCG tests are available.  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) until 
the result of the pregnancy test is known.  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. 
The investigator must immediately notify the sponsor of any pregnancy associated with 
IMP exposure during the trial and for 225 days after the final dose of IMP, and record the 
event on the IRE form and forward it to the sponsor.  The sponsor will forward Clinical 
Trial Pregnancy and Breastfeeding Exposure Form for monitoring the outcome of the 
pregnancy (including spontaneous or elective abortion). 
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 appropriate Clinical Trial Pregnancy and 
Breastfeeding Exposure Form, 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 birth date. 
5.7 
Procedure for Breaking the Blind 
The investigator is encouraged to contact the sponsor to discuss their rationale for 
unblinding.  However, to prevent delays to the investigator or medical personnel 
responding to a potentially emergent situation, unblinding of IMP will not be dependent 
upon the investigator receiving approval from the sponsor (ie, the investigator will be 
able to obtain the code break information independent of the sponsor).  The investigator 
must contact the sponsor by telephone or e-mail with an explanation of the need for 
opening the treatment assignment code within 24 hours of opening the code.  If the blind 
is broken, the Clinical Safety and Pharmacovigilance department must be notified 
immediately (see the cover page of this protocol for contact information).  
Documentation of breaking the blind should be recorded in the subject’s medical record 
with the date and time the blind was broken and the names of the personnel involved.  
Once the blind is broken for a subject, that subject may not reinitiate treatment with the 
IMP. 


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5.8 
Follow-up of Adverse Events 
For this trial, information on AEs will be collected for the period from the time the 
subject signs the ICF until the end of trial date for individual subject (the last scheduled 
contact).  Even after the end of trial date for individual subject, AEs that meet any of the 
cases described in Section 5.8.1, Follow-up of Nonserious Adverse Events, through 
Section 5.8.3, Follow-up and Reporting of Serious Adverse Events Occurring After End 
of Trial Date for Individual Subject (Last Scheduled Contact), will be followed as 
specified in the relevant section. 
5.8.1 
Follow-up of Nonserious Adverse Events 
Nonserious AEs that are identified at any time during the trial must be recorded on the 
AE CRF with the current status noted.  If a subject has an AE or has not recovered from 
an AE at the end of trial date for individual subject (the last scheduled contact), follow-up 
contacts will be scheduled until the event is resolved, stabilized, or the subject is lost to 
follow-up.  All nonserious events that are ongoing at the end of trial date for individual 
subject (the last scheduled contact) will be recorded as ongoing on the CRF.  For any AE 
having been identified throughout the trial, during analysis, additional relevant medical 
history information may be requested to further ascertain causality (including, but not 
limited to, information such as risk-related behavior, family history and occupation).  
Follow-up information obtained after the end of trial date for individual subject (the last 
scheduled contact) will be recorded in the subject’s medical record. 
5.8.2 
Follow-up of Serious Adverse Events 
This trial requires that subjects be actively monitored for SAEs for the period from the 
time of the subject’s signing the ICF until the end of trial date for individual subject (the 
last scheduled contact) or the time of withdrawal. 
Serious AEs that are identified or ongoing at the end of trial date for individual subject 
(the last scheduled contact) must be recorded on the AE CRF page and reported to the 
sponsor according to the reporting procedures outlined in Section 5.3, Immediately 
Reportable Events.  This may include unresolved previously reported SAEs, or new 
SAEs.  Any SAE that is ongoing at the end of trial date for individual subject (the last 
scheduled contact) is recorded as ongoing on the CRF.  The investigator will follow 
SAEs until the events are resolved, stabilized, or the subject is lost to follow-up.  The 
investigator will continue to report any significant follow-up information to the sponsor 
up to the point the event is resolved, stabilized, or the subject is lost to follow-up using an 
IRE form. 


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5.8.3 
Follow-up and Reporting of Serious Adverse Events Occurring 
After End of Trial Date for Individual Subject (Last Scheduled 
Contact) 
Any new SAEs reported by the subject to the investigator that occur after the end of trial 
date for individual subject (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.  This may include SAEs that are captured on follow-up telephone contact or at 
any other time point after the defined trial period (ie, up to end date of the period of trial 
participation [the end of trial date for individual subject]).  The investigator should follow 
SAEs identified after the end of trial date for individual subject (the last scheduled 
contact) until the events are resolved, stabilized, or the subject is lost to follow-up.  The 
investigator should continue to report any significant follow-up information to the 
sponsor up to the point the event has been resolved or stabilized, or the subject is lost to 
follow-up using an IRE form. 
6 
Pharmacokinetic/pharmacodynamic/pharmacogenomic 
Analysis 
6.1 
Pharmacokinetics 
6.1.1 
Pharmacokinetic Analysis Set 
The pharmacokinetic analysis set will include all subjects in whom at least 1 dose of IMP 
is administered, and effective plasma drug concentration is measured for at least 1 time 
point after IMP dosing.  
6.1.2 
Pharmacokinetic Analysis 
(1) 
Endpoint 
Plasma TEV-48125 concentration 
(2) Dataset for Analysis 
Pharmacokinetic analysis set 
(3) 
Analysis Method 
1) Acceptance or nonacceptance of data will be determined in accordance with 
Section3.4, Exclusion from Pharmacokinetic Analysis, of the Manual Standard 
Practice for Noncompartmental Pharmacokinetic Analysis (Version 1.0).24 
2) Concerning Section 6.1.2 (1), Endpoint, descriptive statistics will be calculated by 
treatment group for each blood sampling time point.  Descriptive statistics to be 
calculated for plasma drug concentrations include the number of subjects, 
arithmetic mean, standard deviation, coefficient of variation, minimum, median, 
and maximum. 


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6.2 
Population Pharmacokinetic Analysis 
Using plasma concentration data, population pharmacokinetic analysis will be performed.  
A report will be separately prepared on the results of this analysis. 
6.3 
Immunogenicity 
6.3.1 
Immunogenicity Analysis Set 
The immunogenicity analysis set will include all subjects in whom at least 1 dose of IMP 
is administered, and serum ADA is measured for at least 1 time point after IMP dosing. 
6.3.2 
Immunogenicity Analysis 
Summary of immunogenicity results in the immunogenicity analysis set will be provided, 
and the incidence of immunogenicity expression will be calculated.   
6.4 
Pharmacogenomics 
For analyses related to pharmacogenomics, see Section 3.7.4.3.1 (5), Genomic/genetic 
Analysis. 
6.5 
Biomarkers 
For analyses related to biomarkers, see Section 3.7.4.4 (4), Exploratory Biomarker 
Analysis. 
7 
Statistical Analysis 
This section describes the statistical analysis scheduled to be performed as part of this 
trial.  Further details of statistical analysis will be presented in the Statistical Analysis 
Plan that is separately prepared and will be finalized before unblinding. 
7.1 
Sample Size 
In a phase 2b trial in CM patients (Trial LBR-101-021), concerning the mean change 
from baseline in the monthly average number of headache days of at least moderate 
severity during the 12-week period after the first dose of IMP, the difference between the 
TEV-48125 675/225/225 mg group and the placebo group was 1.7 days and the standard 
deviation was 4.9 days.  On the assumption that this trial will also yield a similar result to 
the phase 2b trial (Trial LBR-101-021), a sample size of 176 subjects per group gives 
more than 90% power for the trial to succeed at a significance level of 0.05 (two-sided).  
Based on the above and taking into account a small percentage of subjects who may be 
excluded from the FAS, the target sample size was determined to be 180 subjects per 
group and 540 subjects as the overall total included in the trial. 


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7.2 
Analysis Sets 
 Enrolled set (ES): 
Subjects from whom informed consent has been obtained 
 Randomized set (RS): 
Randomized subjects in the ES 
 Safety set (SS): 
Subjects in the RS who receive the IMP at least once 
 Full Analysis set (FAS): 
Subjects in the SS who have baseline and Week 12 data on monthly average number 
of headache days of at least moderate severity 
 
7.3 
Handling of Missing Data 
The primary analysis of the primary endpoint will be performed using electronic 
headache diary data entered by subjects.  No imputation will be performed for missing 
diary data. 
7.4 
Primary and Secondary Endpoint Analyses 
7.4.1 
Primary Endpoint Analysis 
The primary endpoint is the mean change from baseline in the monthly (28 days) average 
number of headache days of at least moderate severity during the 12-week period after 
the first dose of IMP. 
The primary endpoint will be analyzed in the FAS using an analysis of covariance 
(ANCOVA) model.  The model will include treatment, sex, country, and baseline 
preventive medication use as fixed effects and baseline number of headache days of at 
least moderate severity and years since onset of migraines as covariates.  Two-sided 95% 
confidence intervals and p-values will be constructed for the least squares mean 
differences between each TEV-48125 group and the placebo group. 
Multiplicity problems will be avoided using a closed testing procedure.  If superiority of 
the TEV-48125 675/225/225 mg group to the placebo group is confirmed at a two-sided 
significance level of 0.05, then the TEV-48125 675 mg/placebo/placebo group vs the 
placebo group will be tested at a two-sided significance level of 0.05. 
7.4.2 
Secondary Endpoint Analysis 
The secondary efficacy endpoints in this trial are as follows: 
1) Mean change from baseline in the monthly average number of migraine days 
during the 12-week period after the first dose of IMP 


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2) Proportion of subjects reaching at least 50% reduction in the monthly average 
number of headache days of at least moderate severity during the 12-week period 
after the first dose of IMP 
3) Mean change from baseline in the monthly average number of days with use of 
any acute headache medications during the 12-week period after the first dose of 
IMP 
4) Mean change from baseline in the monthly average number of headache days of 
at least moderate severity during the 12-week period after the first dose of IMP in 
subjects not receiving concomitant preventive migraine medications 
5) Mean change from baseline in disability score, as measured by the HIT-6, at 
4 weeks after the final (third) dose of IMP 
The secondary endpoints will be analyzed in the FAS.  The same analysis used for the 
primary efficacy endpoint will be performed for the above endpoints, 1), 3), 4), and 5), 
using an ANCOVA model.  For the endpoint 2), each TEV-48125 group and the placebo 
group will be compared using the Cochran-Mantel-Haenszel test stratified by baseline 
preventive medication use. 
7.4.3 
Exploratory Efficacy Endpoint Analysis 
The exploratory efficacy endpoints in this trial are as follows: 
 Number of migraine days 
 Number of headache days of at least moderate severity 
 Number of headache days of any severity 
 Number of headache hours 
 Number of days with use of any acute headache medications 
 Number of days with nausea or vomiting 
 Number of days with photophobia or phonophobia 
 MSQOL 
 EQ 5D-5L 
 PHQ-2 and PHQ-9 
 WPAI 
 PGIC 
The same analysis used for the primary or secondary endpoints will be performed as 
needed for the exploratory endpoints, using the FAS as the analysis set. 
7.5 
Analysis of Demographic and Baseline Characteristics 
For demographic and baseline characteristics in each treatment group, either descriptive 
statistics will be calculated or frequency distribution will be plotted according to the 
nature of characteristics, using the RS as the analysis set. 


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7.6 
Safety Analysis 
Safety analysis will be performed using the SS as the analysis set unless otherwise stated. 
7.6.1 
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 by treatment group: 
 Treatment-emergent AEs (TEAEs) 
 TEAEs by severity 
 TEAEs with an outcome of death 
 Serious TEAEs 
 TEAEs leading to discontinuation of the IMP 
The above summaries will also be prepared for TEAEs potentially causally related to the 
IMP. 
7.6.2 
Clinical Laboratory Data 
For each treatment group, descriptive statistics will be calculated for clinical laboratory 
data and changes from baseline at each time point (including the final evaluation). 
For the numbers of subjects with clinical laboratory data meeting the criteria for 
potentially clinically significant values in each treatment group, frequency distributions 
will be obtained. 
7.6.3 
Vital Signs and Weight Data 
For each treatment group, descriptive statistics will be calculated for vital sign and weight 
measurements and changes from baseline at each time point (including the final 
evaluation).  In addition, for the numbers of subjects with data meeting the criteria for 
potentially clinically significant values in each treatment group, frequency distributions 
will be obtained. 
7.6.4 
Electrocardiogram Data 
For each treatment group, descriptive statistics will be calculated for ECG measurements 
and changes from baseline at each time point (including the final evaluation).  For the 
results of assessments, a shift table from baseline will be displayed. 
7.6.5 
Injection Site Reactions 
For severities of the injection site reactions (erythema, induration, ecchymosis, and pain), 
frequency distributions will be obtained by treatment group and by time point. 


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7.6.6 
Electronic Columbia-Suicide Severity Rating Scale 
A list will be prepared for subjects with suicidal ideation and behavior. 
8 
Management of Investigational Medicinal Product 
For full details on IMP management, see the TEV-48125 Investigator’s Brochure. 
Each 2.25 mL prefilled syringe (with a staked 27 G ½” needle) for single-use 
administration contains TEV-48125 225 mg/1.5 mL (150 mg/mL) or placebo. 
8.1 
Packaging and Labeling 
Trial medication will be supplied to the principal investigators or the persons designated 
by the principal investigators or trial sites by the sponsor or a designated agent.  The IMP 
will be supplied as packages containing a prefilled syringe.  Each package to be used in 
the dosing period will be labeled to clearly disclose compound code, trial number, 
sponsor’s name and address, instructions for use, route of administration, and appropriate 
precautionary statements, etc. 
8.2 
Storage 
The IMP will be stored in a place where security is assured (eg, locked refrigerator).  
Access will be limited to principal investigators and their designees.  Neither principal 
investigators nor any designees may provide IMP to any subject not participating in this 
protocol. 
The IMP will be stored at 2°C to 8°C, protected from light 
The trial site staff will maintain a temperature log in the IMP storage area recording the 
temperature at least once each working day. 
8.3 
Accountability 
The principal investigator or designee must maintain an inventory record of IMP 
(including investigational product or placebo) received, dispensed, administered, and 
returned. 
8.4 
Returns and Destruction 
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 appropriate documentation and 
be identified by protocol number with trial site number on the outermost shipping 


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container.  Returned supplies should be in the original containers.  The assigned trial 
monitor will facilitate the return of unused IMP. 
8.5 
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: 
 Failure/malfunction 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 
 
8.5.1 
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) by e-mail (email address:  
PQC_406-102-00001_00002@otsuka.jp) immediately after becoming aware of the PQC 
according to the procedure outlined in Section 8.5.2 (Information Required for Reporting 
Purposes). 
Identification of a PQC by the subject should be reported to the investigator, who should 
then follow one of the reporting mechanisms above. 
8.5.2 
Information Required for Reporting Purposes 
 Description of compliant 
 Reporter identification (eg, subject, investigator, site, etc.) 
 Reporter contact information (eg, address, phone number, e-mail address) 
 ID of material (product/compound name, Kit number) 
 Clinical protocol reference (number and/or trial name) 
 Dosage form/strength (if known) 


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 Pictures (if available) 
 Complaint sample availability for return 
 
8.5.3 
Return Process 
Indicate during the report of the PQC if the complaint sample is available for return.  If a 
complaint sample is available for return, the sponsor will provide instructions for sample 
return, when applicable. 
It must be documented in the trial site accountability record that a complaint sample for a 
dispensed kit has been forwarded to the sponsor for complaint investigation. 
8.5.4 
Assessment/Evaluation 
Assessment and evaluation of PQCs will be handled by the sponsor. 
9 
Records Management 
9.1 
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, recorded data from automated instruments, 
electronic headache diary, and ePRO.  All source documents pertaining to this trial will 
be maintained by the principal investigators and made available for direct inspection by 
authorized persons.  Principal investigators/trial sites will permit trial-related monitoring, 
audits, IRB/IEC/EC review, and regulatory inspection(s) by providing direct access to 
source data/documents by authorized persons as defined in the ICF.  In all cases, subject 
confidentiality must be maintained in accordance with local regulatory requirements. 
9.2 
Data Collection 
During each subject’s visit to the trial site, the investigator will record all significant 
observations and findings in the subject’s medical records.  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; 


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 Any changes in concomitant medications or dosages; 
 A general reference to the procedures completed; 
 The signature (or initials) and date of each investigator (or designee) who made an 
entry in the medical records. 
In addition, any contact with the subject via telephone or other means that provides 
significant clinical information will also be documented in the medical records as 
described above.  Any changes to information in the medical records and other source 
documents will be initialed and dated on the day the change is made by a trial site staff 
member authorized to make the change.  Changes will be made by striking a single line 
through erroneous data (so as not to obliterate the original data), and clearly entering the 
correct data (eg, wrong data  right data).  If the reason for the change is not apparent, a 
brief explanation for the change will be written in the source documents by the 
investigator.  If electronic data systems are being utilized, a full audit trail of changes 
must be maintained. 
Information from the medical records and other source documents will be entered by trial 
site staff directly onto electronic CRFs in the sponsor’s electronic data capture (EDC) 
system.  Changes to the data will be captured by an automatic audit trail.  If data are 
processed from other sources (eg, central laboratory, bioanalytical laboratory, electronic 
headache diary, and ePRO), the results will be sent to the trial site where they will be 
retained, but not entered into the EDC unless otherwise specified in the protocol.  These 
data will also be sent electronically to the sponsor from each source.  Changes to the data 
will be captured by an automatic audit trail in the source system. 
9.3 
File Management at the Trial Site 
The principal investigator will ensure that the trial site file is maintained in accordance 
with Section 8 of the ICH GCP Guideline E6 and as required by applicable local 
regulations.  The principal investigator/trial site will take measures to prevent accidental 
or premature destruction of these documents. 
9.4 
Records Retention at the Trial Site 
Regulatory requirements for the archival of records for this trial necessitate that 
participating principal investigators maintain detailed clinical data for the longest of the 
following 4 periods: 
 A period of at least 2 years after the date on which approval to market the drug is 
obtained (or if IMP development is discontinued, the date regulatory authorities were 
notified of discontinuation); OR 
 A period of at least 3 years after the sponsor notifies the principal investigator that the 
final report has been filed with regulatory authorities. 


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 Longer, region-specific storage requirements, if applicable. 
If regional requirements are longer, the specific information for the region should be 
stated in the trial’s Operations Manual or the principal investigator’s contract. 
 Determination of the period until the termination of DNA storage or biomarker 
sample storage. 
The principal investigator 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 principal investigator 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.  If the principal investigator withdraws from the trial (eg, due to 
relocation or retirement), all trial-related records should be transferred to a mutually 
agreed-upon designee within a sponsor-specified timeframe.  Notice of such transfer will 
be given to the sponsor in writing. 
10 
Quality Control and Quality Assurance 
10.1 
Monitoring 
The sponsor has ethical, legal, and scientific obligations to follow this trial in accordance 
with established research principles, the ICH E6 GCP:  Consolidated Guidance, 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 trial site during the trial, as well as communicate 
frequently via telephone, e-mail, and written communications.  In addition, all 
investigators and trial site staff will undergo initial and ongoing training for this 
particular trial, and this training will be clearly documented. 
10.2 
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 comparison of CRFs with source documents.  The 
principal investigator agrees to cooperate with audits. 
Regulatory authorities may inspect the trial site during or after the trial.  The principal 
investigator will cooperate with such inspections and will contact the sponsor 
immediately if such an inspection occurs. 


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11 
Ethics and Responsibility 
This trial must be conducted in compliance with the protocol, ICH GCP 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/favorable opinion by an 
IRB/IEC/EC according to regional requirements, and the principal investigator will 
provide that documentation to the sponsor.  The IRB/IEC/EC will evaluate the ethical, 
scientific, and medical appropriateness of the trial.  Further, in preparing and handling 
CRFs, IRE forms, etc, the investigator and their staff will take measures to ensure 
adequate care in protecting subject privacy.  To this end, a subject number and subject 
identification code will be used to identify each subject. 
Financial aspects, subject insurance and the publication policy for the trial will be 
documented in the agreement between the sponsor and the principal investigator. 
12 
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 numbers in CRFs.  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. 
13 
Amendment Policy 
The principal investigator will not make any changes to this protocol without the 
sponsor’s prior written consent and subsequent approval/favorable opinion by the 
IRB/IEC/EC.  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/IEC/EC, as required by local regulations.  Except for “administrative” or “non-
substantial” amendments, investigators will wait for IRB/IEC/EC approval/favorable 
opinion of the amended protocol before implementing the change(s).  Administrative 


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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 after agreement by the sponsor and principal investigator, 
followed by IRB/IEC/EC notification within local applicable timelines.  The sponsor will 
submit protocol amendments to the applicable regulatory agencies within local applicable 
timelines. 
When the IRB/IEC/EC, principal 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/favorable opinion of the new ICF by the IRB/IEC/EC, 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. 
14 
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 
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. 
Principal investigators or other trial participants who do not qualify for authorship may 
be acknowledged in publications resulting from the trial.  By agreeing to participate in 
the trial, principal investigators or other trial participants consent to such 
acknowledgement in any publications resulting from its conduct. 


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15 
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Bigal ME, Lipton RB. Clinical course in migraine: conceptualizing migraine 
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Headache Classification Committee of the International Headache Society (IHC). The 
International Classification of Headache Disorders, 3rd edition (beta version). 
Cephalalgia. 2013;33(9):629-808. 
4 
Lipton RB, Bigal ME, Diamond M, Freitag F, Reed ML, Stewart WF. Migraine 
prevalence, disease burden, and the need for preventive therapy. Neurology. 
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Scher AI, Stewart WF, Ricci JA, Lipton RB. Factors associated with the onset and 
remission of chronic daily headache in a population-based study. Pain. 2003;106(1-
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Ho TW, Edvinsson L, Goadsby PJ. CGRP and its receptors provide new insights into 
migraine pathophysiology. Nat Rev Neurol. 2010;6(10):573-82. 
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Shimizu T, Shibata M, Suzuki N. Migraine: Advances in the pathophysiology and 
treatment. Clinical Neurology. 2011;51(2):103-9. 
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Moskowitz MA. The neurobiology of vascular head pain. Ann Neurol. 
1984;16(2):157-68. 
9 
Bigal ME, Edvinsson L, Rapoport AM, Lipton RB, Spierings ELH, Diener HC, et al. 
Safety, tolerability, and efficacy of TEV-48125 for preventive treatment of chronic 
migraine: a multicentre, randomised, double-blind, placebo-controlled, phase 2b 
study. Lancet Neurol. 2015;14(11):1091-100. 
10 Bigal ME, Dodick DW, Rapoport AM, Silberstein SD, Ma Y, Yang R, et al. Safety, 
tolerability, and efficacy of TEV-48125 for preventive treatment of high-frequency 
episodic migraine: a multicentre, randomised, double-blind, placebo-controlled, phase 
2b study. Lancet Neurol. 2015;14(11):1081-90. 
11 Supervised by the Japanese Society of Neurology and the Japanese Headache Society, 
compiled by the editorial committee for guidelines on the management of chronic 
headaches. Clinical Practice Guideline for Chronic Headache 2013. 1st ed. Tokyo: 
Igaku-Shoin; 2013. 
12 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. 
13 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. 
14 Clinical trials based on genome pharmacology. Notification No. 0930007 of the 
Evaluation and Licensing Division, Pharmaceutical and Food Safety Bureau, Ministry 
of Health, Labour and Welfare. 2008. 


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15 Silberstein S, Tfelt-Hansen P, Dodick DQ, Limmroth V, Lipton RB, Pascual J, et al. 
Guidelines for controlled trials of prophylactic treatment of chronic migraine in adults. 
Cephalalgia. 2008;28:484-95. 
16 Tfelt-Hansen P, Pascual J, Ramadan N, Dahlöf C, D’Amico D, Diener H, et al. 
Guidelines for controlled trials of drugs in migraine: third edition. A guide for 
investigators. Cephalalgia. 2012;32(1):6-38. 
17 NIH clinical center patient education materials. Giving a subcutaneous injection. 
[Internet]. [cited 2017 Jul 3]. Available from: 
http://www.cc.nih.gov/ccc/patient_education/pepubs/subq.pdf. 
18 International conference on harmonisation of technical requirements for registration 
of pharmaceuticals for human use. Guideline For Good Clinical Practice: E6(R1). 
Geneva, Switzerland: International Conference on Harmonisation; 1996. 
19 Silberstein SD. Practice parameter: evidence-based guidelines for migraine headache 
(an evidence-based review). Report of the quality standards subcommittee of 
American Academy of Neurology. Neurology. 2000;55:754-62. 
20 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. 
21 Food and Drug Administration. Draft guidance: Assay development and validation 
for immunogenicity testing of therapeutic protein products, April 2016. 
22 European Medicines Agency. Guideline on immunogenicity assessment of 
biotechnology-derived therapeutic proteins draft, 2015. 
23 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. [reprint in Ann Emerg Med. 
2006;47(4):373-80]. J Allergy Clin Immunol. 2006;117(2):391-7. 
24 Otsuka Pharmaceutical Co., Ltd. Manual standard practice for noncompartmental 
pharmacokinetic analysis. Version 1.0, issued 24 Dec 2015. 
 
 
 


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Appendix 1 
Handling and Shipment of Bioanalytical Samples 
 
(1) 
Handling of Samples 
A label will be firmly attached to each sample storage tube.  The label contains the 
following information:  protocol number, subject identification number, visit number (eg, 
V2/Baseline, V3/Month 1), sampling date, sampling timing (eg, before administration), 
sample type (eg, pharmacokinetics, ADA, DNA, or serum for biomarkers), and aliquot 
number (eg, Aliquot 1, Aliquot 2).  Instead of the planned sampling time point, the time 
at which specimens were actually sampled should be accurately entered on the CRF. 
(2) 
Handling and Shipment of Pharmacokinetic Samples 
Six milliliters of blood will be collected via venipuncture or indwelling catheter into a 
dipotassium ethylenediaminetetraacetic acid (EDTA) collection tube.  Then, the 
collection tube will be inverted slowly 8 to 10 times to mix the content and will be placed 
in ice water.  This sample will be centrifuged (approximately 1300 × G) at approximately 
4ºC for approximately 10 minutes between 5 minutes and 1 hour after blood collection.  
If a refrigerated centrifuge is not available, samples should be chilled before 
centrifugation.  Plasma will be aliquoted by a standard experimental procedure into 2 
appropriately labeled tubes for storage (Aliquot 1 and 2).  The 2 aliquots of the same 
plasma sample will be stored in a freezer at a temperature of below −20ºC or −70ºC 
within 60 minutes of the end of centrifugation.  Within 3 days after sampling, the central 
laboratory will collect plasma sample Aliquots 1 and 2 and store them in a freezer at a 
temperature of below −70ºC.  During transfer, all samples will be placed in a well-
insulated container filled with a sufficient amount of dry ice.  The central laboratory will 
transport Aliquot 1 plasma samples to the drug concentration measurement facility in 
accordance with instructions of the sponsor.  The central laboratory will store Aliquot 2 
plasma samples until the clinical study report is issued unless otherwise instructed by the 
sponsor. 
(3) 
Handling and Shipment of ADA Samples 
Blood will be collected via venipuncture or indwelling catheter into a collection tube 
containing no anticoagulant (containing a coagulation accelerator, 5 mL).  Blood 
collected will be left to stand at room temperature for approximately 30 minutes to allow 
for coagulation and serum separation to occur.  The sample will then be centrifuged 
(approximately 1300 × G) at approximately 4ºC for approximately 10 minutes within 
1.5 hours of sampling.  If a refrigerated centrifuge is not available, samples should be 
chilled before centrifugation.  Serum will be aliquoted by a standard experimental 
procedure into 2 appropriately labeled tubes for storage (Aliquot 1 and 2).  The 2 aliquots 
of the same serum sample will be stored in a freezer at a temperature of below −20ºC or 


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−70ºC within 60 minutes of the end of centrifugation.  Within 3 days after sampling, the 
central laboratory will collect serum sample Aliquots 1 and 2 and store them in a freezer 
at a temperature of below −70ºC.  During transfer, all samples will be placed in a well-
insulated container filled with a sufficient amount of dry ice.  The central laboratory will 
transport Aliquot 1 serum samples to the ADA measurement facility in accordance with 
instructions of the sponsor.  The central laboratory will store Aliquot 2 serum samples 
until the clinical study report is issued unless otherwise instructed by the sponsor. 
(4) 
Handling and Shipment of DNA Samples 
Six milliliters of blood will be collected via venipuncture or indwelling catheter into a 
dipotassium EDTA collection tube.  Then, the collection tube will be inverted slowly 8 to 
10 times to mix the contents.  The blood sample will be transferred into an appropriately 
labeled tube for storage.  The blood sample will be stored in a freezer at a temperature of 
below −20ºC or −70ºC within 60 minutes of sampling.  Within 3 days after sampling, the 
central laboratory will collect blood samples and store them in a freezer at a temperature 
of below −70ºC.  During transfer, all samples will be placed in a well-insulated container 
filled with a sufficient amount of dry ice.  The central laboratory will assign a new 
personal code to each sample to make it double-coded.  Then, DNA will be extracted 
from these samples.  DNA samples will be stored in a freezer at a temperature of below 
−70ºC. 
(5) 
Handling and Shipment of Serum Samples for Biomarkers 
Blood will be collected via venipuncture or indwelling catheter into a collection tube 
containing no anticoagulant (containing a coagulation accelerator, 6 mL).  Blood 
collected will be left to stand at room temperature for approximately 30 minutes to allow 
for coagulation and serum separation to occur.  The sample will then be centrifuged 
(approximately 1300 × G) at approximately 4ºC for approximately 10 minutes within 1.5 
hours of sampling.  If a refrigerated centrifuge is not available, samples should be chilled 
before centrifugation.  Serum will be transferred by a standard experimental procedure 
into an appropriately labeled tube for storage.  The serum sample will be stored in a 
freezer at a temperature of below −20ºC or −70ºC within 60 minutes of the end of 
centrifugation.  Within 3 days after sampling, the central laboratory will collect serum 
samples and store them in a freezer at a temperature of below −70ºC.  During transfer, all 
samples will be placed in a well-insulated container filled with a sufficient amount of dry 
ice. 
(6) 
Handling and Shipment of Plasma Samples for Biomarkers 
Six milliliters of blood will be collected via venipuncture or indwelling catheter into a 
dipotassium EDTA collection tube.  Then, the collection tube will be inverted slowly 8 to 
10 times to mix the content and will be placed in ice water.  The sample will then be 


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centrifuged (approximately 1300 × G) at approximately 4ºC for approximately 10 
minutes between 5 minutes and 1 hour after blood collection.  If a refrigerated centrifuge 
is not available, samples should be chilled before centrifugation.  Plasma will be 
transferred by a standard experimental procedure into an appropriately labeled tube for 
storage.  The plasma sample will be stored in a freezer at a temperature of below −20ºC 
or −70ºC within 60 minutes of the end of centrifugation.  Within 3 days after sampling, 
the central laboratory will collect plasma samples and store them in a freezer at a 
temperature of below −70ºC.  During transfer, all samples will be placed in a well-
insulated container filled with a sufficient amount of dry ice. 
(7) 
Handling and Shipment of RNA Samples for Biomarkers 
Blood (7.5 mL) will be collected via venipuncture or indwelling catheter into a 
PAXgene® Blood RNA Tube (2.5 mL) for collection.  Then, the collection tube will be 
inverted slowly 8 to 10 times to mix the content and will be left to stand in an upright 
position at room temperature for approximately 2 hours.  The blood sample will then be 
transferred into an appropriately labeled tube for storage, and stored at a temperature of 
below −20ºC or −70ºC.  Within 3 days after sampling, the central laboratory will collect 
the blood sample and store it in a freezer at a temperature of below −70ºC.  During 
transfer, the sample will be placed in a well-insulated container filled with a sufficient 
amount of dry ice. 
(8) 
Handling and Shipment of Urine Samples for Biomarkers 
Urine will be collected in a urine sampling cup after the first brief miction (a few 
milliliters) is discarded.  Approximately 10 mL of urine will be collected in a 
polypropylene container.  Within 60 minutes of sampling, the urine sample will be stored 
in a freezer at a temperature of below −20ºC or −70ºC.  Within 3 days after sampling, the 
central laboratory will collect urine samples and store them in a freezer at a temperature 
of below −70ºC.  During transfer, all samples will be placed in a well-insulated container 
filled with a sufficient amount of dry ice. 
 
 


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Appendix 2 
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 mm Hg 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. [reprint in Ann Emerg Med 
2006;47(4):373-80]. J Allergy Clin Immunol. 2006;117(2):391-7. 
 
 


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Appendix 3 
ICHD-3 beta Diagnostic Criteria 
 
For further details, refer to Classification Committee of the IHS, 20131. 
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 2 of the following 4 characteristics: 
 
 
at least 1 aura symptom spreads gradually over ≥ 5 minutes, and/or 2 or 
more symptoms occur in succession 
 
each individual aura symptom lasts 5 to 60 minutes 
 
at least 1 aura symptom is unilateral 
 
the aura is accompanied, or followed within 60 minutes, by headache 
 
D. 
Not better accounted for by another ICHD-3 diagnosis, and transient ischemic 
attack has been excluded 
 
 
 
                                                 
1 Classification Committee of the International Headache Society. The International 
Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia 2013;33(9):629-
808. 


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Appendix 4 
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.1
  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 3.7.3.2, 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 investigational medicinal product (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 
                                                 
1 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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eosinophil count), and INR].  The investigator should also question the patient 
regarding symptoms. 
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 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. 
 
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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Appendix 5 
Protocol Amendments/Administrative Changes 
 
Amendment Number: 1 
Issue Date: 
30 Nov 2017 
 
PURPOSE: 
To clarify the text and revise written errors and the like 
BACKGROUND: 
Revisions were made because unclear text, written errors and the like were found. 
MODIFICATIONS TO PROTOCOL: 
Sectional Revisions: 
 
Protocol Section 
Before Revision 
After Revision 
3.1 
Type/Design of 
Trial 
After obtaining written informed consent 
from patients (Visit [V] 1/Screening), the 
investigator will screen them for 
eligibility. 
After obtaining written informed consent 
from patients, the investigator will screen 
them for eligibility (Visit [V] 
1/Screening). 
3.2 
Trial Treatments 
IMP should be removed from the 
refrigerator and allowed to equilibrate at 
room temperature for 15 to 30 minutes 
before IMP administration. 
IMP should be removed from the 
refrigerator and allowed to equilibrate at 
room temperature for 45 to 60 minutes 
before IMP administration. 
Protocol Synopsis 
Inclusion/Exclusion 
Criteria: 
 
3.4.2; 
Table 3.4.2-1 
Inclusion Criteria,  
No. 6 
Not using preventive medications (ie, at 
least 5 half-lives have passed since last 
use) or using no more than 1 preventive 
migraine medication 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 giving informed consent. 
Not using preventive migraine 
medications (prohibited or restricted 
medications, see Table 4.1.1-1 and Table 
4.1.2-1) for migraine or other medical 
conditions (ie, at least 5 half-lives have 
passed since last use) or using no more 
than 1 preventive migraine medication 
(restricted medications, see Table 4.1.2-
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 giving informed consent. 
Protocol Synopsis 
Inclusion/Exclusion 
Criteria: 
 
3.4.3; 
Table 3.4.3-1 
Exclusion Criteria,  
No. 3 
Patients who have previously failed (lack 
of efficacy) 2 or more of the clusters of 
the following medications for treatment 
of EM or CM after use for at least 
3 months at accepted migraine 
therapeutic doses: 
 
Cluster A:  divalproex sodium and 
sodium valproate 
 
Cluster B:  flunarizine and pizotifen 
Patients who have previously failed (lack 
of efficacy) 2 or more of the clusters of 
the following medications for treatment 
of EM or CM after use for at least 
3 months at accepted migraine 
therapeutic doses: 
 
Cluster A:  topiramate, divalproex 
sodium and sodium valproate 
 
Cluster B:  lomerizine, flunarizine 


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Protocol Section 
Before Revision 
After Revision 
 
Cluster C:  amitriptyline, 
nortriptyline, venlafaxine, and 
duloxetine 
 
Cluster D:  atenolol, nadolol, 
metoprolol, propranolol, and timolol 
and pizotifen 
 
Cluster C:  amitriptyline, 
nortriptyline, venlafaxine, and 
duloxetine 
 
Cluster D:  atenolol, nadolol, 
metoprolol, propranolol, and timolol 
3.7; Table 3.7-1 
Schedule of 
Assessments  
(No footnote marker) 
A footnote marker, “a”, has been added 
to “X” in the “Informed consent” column 
for “Screening Period”.   
Accordingly, all other footnote markers 
have been updated. 
3.7; Table 3.7-1 
Schedule of 
Assessments 
(footnote) 
(No footnote) 
The following footnote has been added: 
 
aInformed consent can be obtained prior 
to the day of V1/Screening. 
 
Accordingly, all other footnote markers 
have been updated. 
3.7.1.1 
Screening Period 
The screening period begins at 
V1/Screening and ends on the day before 
V2/Baseline. 
The screening period begins on the day 
of informed consent and ends on the day 
before V2/Baseline.  An appropriately 
signed and dated ICF will be obtained 
before screening procedures commence.  
After informed consent is obtained, the 
investigator (or designee) will promptly 
enter the subject’s information in the IRT 
and obtain a subject identification 
number as described in Section 3.3.2, 
Subject Selection and Numbering. 
The following information will be 
recorded on the case report form (CRF): 
 
Informed consent 
 
Date of informed consent 
 
Subject identification number  
3.7.1.1.1 
Visit 1/Screening 
(Day −28; 
Acceptable 
Window:  −3 Days) 
An appropriately signed and dated ICF 
will be obtained before screening 
procedures commence.  After informed 
consent is obtained, the investigator (or 
designee) will promptly enter the 
subject’s information in the IRT and 
obtain a subject identification number as 
described in Section 3.3.2, Subject 
Selection and Numbering. 
V1/Screening will take place 28 days 
before V2/Baseline.  In order to 
determine the subject’s eligibility, the 
following assessments/tests/observations 
will be performed and recorded on the 
V1/Screening will take place 28 days 
before V2/Baseline.  In order to 
determine the subject’s eligibility, the 
following assessments/tests/observations 
will be performed and recorded on the 
CRF. 
 
Visit date 
 
Result of eligibility assessment 
 
Demographics 
 
Date of investigation 
 
Birth date, age, and sex (at the 
time of informed consent) 
 
Childbearing potential (Reason 
for nonchildbearing potential, or 


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Protocol Section 
Before Revision 
After Revision 
case report form (CRF). 
 
Visit date 
 
Informed consent 
 
Date of informed consent 
 
Subject identification number 
 
Result of eligibility assessment 
 
Demographics 
 
Date of investigation 
 
Birth date, age, and sex 
 
Childbearing potential (Reason 
for nonchildbearing potential, or 
contraceptive methods) 
 
Race, ethnicity, and country 
 
Medical history and 
complications 
contraceptive methods) 
 
Race, ethnicity, and country  
 
Medical history and 
complications (at the time of 
informed consent) 
4  Restrictions 
Use of the following medications and 
concomitant therapies will be prohibited 
or restricted from after informed consent 
to V5/End of treatment or the time of 
withdrawal. 
Use of the following medications and 
concomitant therapies will be prohibited 
or restricted from after informed consent 
(or after V1/Screening if the date of 
informed consent and V1/Screening fall 
on a different day) to V5/End of 
treatment or the time of withdrawal. 
4.1.2 
Restricted 
Concomitant 
Medications 
(Preventive 
Migraine 
Medications) 
A small subgroup of subjects (up to 30%) 
will be allowed to use no more than 1 
concomitant preventive migraine 
medication (see Table 4.1.2-1) during the 
trial if the medication was 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 
informed consent.  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 such a case, 
reasons for discontinuation should be 
recorded. 
A small subgroup of subjects (up to 30%) 
will be allowed to use no more than 1 
concomitant preventive migraine 
medication (see Table 4.1.2-1) at a stable 
dose and regimen during the trial if the 
medication was 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 informed 
consent. 
 
ADDITIONAL RISK TO THE SUBJECT: 
There is no additional risk to the subjects. 
 


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(English translation, 06 Aug 2019) 
Amendment Number: 
2 
Issue Date: 
18 Jun 2018 
 
PURPOSE: 
To clarify the text, correct errors, resolve inconsistencies throughout the text, reflect 
changes in the statistical analysis plan, etc. 
BACKGROUND: 
Revisions were made because unclear text, errors, etc, were found.  Furthermore, on the 
basis of results from global studies, it was considered that stratified analysis would not be 
applicable. 
MODIFICATIONS TO PROTOCOL: 
Sectional Revisions: 
Protocol Section 
Before Revision 
After Revision 
Protocol Synopsis, 
Trial Duration 
Overall trial period:  Aug 2017 through 
Apr 2019 (planned) 
Overall trial period:  Aug 2017 through 
Sep 2019 (planned) 
1.1 
Pathology and 
Treatment of 
Migraine 
Currently available drug therapies  ... 
include ..., angiotensin receptor blockers, 
angiotensin-converting enzyme 
inhibitors, and calcium channel blockers. 
Currently available drug therapies ...  
include ..., angiotensin receptor blockers, 
angiotensin-converting enzyme 
inhibitors*, and calcium channel 
blockers. 
(Note*: A minor revision was made in 
the Japanese original, but no changes 
are required in the English 
translation.) 
2.1 
Trial Rationale 
It is considered necessary to ...... and to 
demonstrate that the efficacy and safety 
of TEV-48125 in Japanese patients is 
similar to the efficacy and safety 
observed in the multinational phase 3 
confirmatory trials (Trials TV48125-
CNS-30049 and TV48125-CNS-30050), 
which warrants the implementation of 
this clinical trial. 
It is considered necessary* to ...... and to 
demonstrate that the efficacy and safety 
of TEV-48125 in Japanese patients is 
similar to the efficacy and safety 
observed in the multinational phase 3 
confirmatory trials (Trials TV48125-
CNS-30049 and TV48125-CNS-30050), 
which warrants the implementation of 
this clinical trial. 
(Note*: A minor revision was made in 
the Japanese original, but no changes 
are required in the English translation) 
2.1 
Trial Rationale 
Prior to the implementation of this 
trial, ... . 
*Prior to the implementation of this 
trial, ... . 
(Note*: A minor revision was made in 
the Japanese original, but no changes 
are required in the English 
translation.) 
2.3 
Dosing Rationale 
Both TEV-48125 dose groups showed 
improvement compared to the placebo 
group from Week 1, ... . 
Both TEV-48125 dose groups showed 
improvement compared to the placebo 
group from Month 1, ... . 


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Protocol Section 
Before Revision 
After Revision 
3.1 
Type/Design of 
Trial 
For subjects who are lost to follow up, 
the end of trial date for individual subject 
is defined as the date of their last 
visit/contact or the date of the last 
attempt to contact them. 
 
Following ... for the purpose of 
evaluating ADA at 225 days 
(approximate equivalent of 5 half-lives) 
after the final dose of IMP (V4/Month 2) 
in this trial. 
For *subjects who are lost to follow up*, 
the end of trial date for individual subject 
is defined as the date of their last 
visit/contact or the date of the last 
attempt to contact them. 
 
*Following ... for the purpose of 
evaluating ADA at 225 days 
(approximate equivalent of 5 half-lives) 
after the final dose of IMP (V4/Month 2) 
in this trial. 
(Note*: Minor revisions were made in 
the Japanese original, but no changes 
are required in the English 
translation.) 
3.4.3 
Exclusion Criteria 
Screen failure subjects who fall under 
any of the exclusion criteria 1 to 5, 12, 
19, and 20 during the screening period 
(including V1/Screening) may be 
rescreened only once if the characteristics 
of the exclusion criteria 1 to 5, 12, 19, 
and 20 have changed.  In the event that a 
subject is rescreened, a new ICF must be 
signed, and a new subject identification 
number must be assigned prior to the 
rescreening.  However, if it cannot be 
confirmed that a subject meets all the 
inclusion criteria and does not fall under 
any of the exclusion criteria at 
V2/Baseline, the subject will not be 
eligible for rescreening. 
Screen failure subjects may be rescreened 
if prior agreement is obtained from the 
sponsor.  If a subject is to be rescreened, 
informed consent must be newly 
obtained, and a new subject identification 
number must be assigned to the subject 
prior to performing the rescreening 
examination. 
Protocol Synopsis, 
Criteria for 
Evaluation; 
 
3.5.2.1 
Efficacy Endpoints 
 
Mean change from baseline in the 
monthly average number of days of 
use of any acute migraine 
medications during the 12-week 
period after the first dose of IMP 
 
Mean change from baseline in the 
monthly average number of days 
with use of any acute headache 
medications during the 12-week 
period after the first dose of IMP 
Protocol Synopsis, 
Criteria for 
Evaluation; 
 
3.5.2.1 
Efficacy Endpoints 
 
Mean change from baseline in the 
number of migraine days during the 
4-week period after the first dose of 
IMP 
(Deleted) 
3.5.3 
Exploratory 
Endpoints 
 
Number of days of use of any acute 
headache medications  
 
 
Number of subjects discontinuing 
concomitant preventive migraine 
medications during the treatment 
period 
 
Number of days with use of any 
acute headache medications 
 
 
(Deleted) 
3.5.5 
Immunogenicity 
Endpoints 
 
Impact of serum anti-TEV-48125 
antibodies on pharmacokinetics, 
efficacy, and safety 
(Deleted) 


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Protocol Section 
Before Revision 
After Revision 
3.6 
Measures to 
Minimize/Avoid 
Bias 
In the event that a medical emergency 
occurs to a subject and knowledge of the 
IMP assignment code is considered 
essential to adequately treat the 
subject, ... . 
In the event that a subject experiences a 
medical emergency or the safety of a 
subject needs to be confirmed 
immediately and knowledge of the IMP 
assignment code is considered essential 
to adequately treat the subject, ... . 
3.7 
Trial Procedure,  
Table 3.7-1 
dProcedure will be performed before 
other assessments (eg., blood draws and 
administration of questionnaires). 
dProcedure will be performed before 
other assessments (blood draws and 
administration of questionnaires). 
3.7.1.1.1 
Visit 1/Screening 
(Day −28; 
Acceptable 
Window:  −3 Days) 
 
Vital signs (systolic and diastolic 
blood pressure, pulse rate, 
temperature, and respiratory rate) 
(should precede other scheduled 
assessments including blood 
sampling and questionnaires) 
 
Triplicate 12-lead ECGs (should 
precede other scheduled assessments 
including blood sampling and 
questionnaires) 
 
Vital signs (systolic and diastolic 
blood pressure, pulse rate, 
temperature, and respiratory rate) 
(should precede blood sampling) 
 
Triplicate 12-lead ECGs (should 
precede blood sampling) 
3.7.1.2.1.1 
Visit 2/Baseline 
(Day 1) 
If it cannot be confirmed that a subject 
meets all the inclusion criteria and does 
not fall under any of the exclusion 
criteria at V2/Baseline, the subject will 
not be eligible for rescreening. 
(Deleted) 
3.7.1.2.1.1 
Visit 2/Baseline 
(Day 1); 
 
3.7.1.2.3 
Visit 5/End of 
Treatment (Day 85; 
Acceptable 
Window:  ±3 Days) 
and Withdrawal 
(Acceptable 
Window:  Day of 
Withdrawal 
Decision + 7 Days) 
 
Vital signs (systolic and diastolic 
blood pressure, pulse rate, 
temperature, and respiratory rate) 
(should precede other scheduled 
assessments including blood 
sampling and questionnaires) 
 
Triplicate 12-lead ECGs (should 
precede other scheduled assessments 
including blood sampling and 
questionnaires) 
 
Vital signs (systolic and diastolic 
blood pressure, pulse rate, 
temperature, and respiratory rate) 
(should precede blood sampling and 
questionnaires) 
 
Triplicate 12-lead ECGs (should 
precede blood sampling and 
questionnaires) 
3.7.1.2.2 
Visit 3/Month 1 
(Day 29; 
Acceptable 
Window:  ±3 Days) 
and Visit 4/Month 
2 (Day 57; 
Acceptable 
Window:  ±3 Days) 
 
Vital signs (systolic and diastolic 
blood pressure, pulse rate, 
temperature, and respiratory rate) 
(should precede other scheduled 
assessments including blood 
sampling and questionnaires) 
 
Vital signs (systolic and diastolic 
blood pressure, pulse rate, 
temperature, and respiratory rate) 
(should precede blood sampling and 
questionnaires) 
3.7.1.3 
Two Additional 
Visits for 
Pharmacokinetic 
Analysis (3 to 10 
Days and 14 to 21 
 
Triplicate 12-lead ECGs (should 
precede other scheduled assessments 
including blood sampling and 
questionnaires) 
 
Triplicate 12-lead ECGs (should 
precede blood sampling) 


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Protocol Section 
Before Revision 
After Revision 
Days After One of 
the IMP 
Administrations at 
Either Visit 
2/Baseline, Visit 
3/Month 1, or Visit 
4/Month 2) 
3.7.2.1 
Electronic 
Headache Diary 
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 
migraine medications). 
 
If a subject has not entered the headache 
data by the end of the next day, the 
subject will be reminded to enter the data 
on the following day. 
 
Subjects will also record the presence or 
absence of photophobia, phonophobia, 
nausea, or vomiting, and the status of use 
of any acute migraine medications. 
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). 
 
If a subject has not entered the headache 
data by 8 PM of the next day, the subject 
will be reminded to enter the data. 
 
Subjects will also record the presence or 
absence of photophobia, phonophobia, 
nausea, or vomiting, and the status of use 
of any acute headache medications. 
3.7.3.2 
Clinical Laboratory 
Assessments 
Table 3.7.3.2-1 
Creatine phosphokinase 
Creatine* phosphokinase 
(Note*: A minor revision was made in 
the Japanese original, but no changes 
are required in the English 
translation.)  
3.7.3.5 
Vital Signs 
As vital signs, systolic and diastolic 
blood pressure, pulse rate, temperature, 
and respiratory rate will be measured 
before other assessments (eg, blood 
draws and questionnaires). 
 
The same position and arm should be 
used each time vital signs are measured 
for a given subject. 
As vital signs, systolic and diastolic 
blood pressure, pulse rate, temperature, 
and respiratory rate will be measured 
before other assessments (blood draws 
and questionnaires). 
 
The same position and arm should be 
used each time vital signs are measured 
for a given subject (however, if it is 
difficult to use the same position and arm 
due to the occurrence of an AE, the use 
of a different position or arm is 
acceptable. 
3.7.3.6 
Twelve-lead 
Electrocardiography 
Using 12-lead ECG equipment provided 
by the central laboratory selected by the 
sponsor, ECGs will be conducted before 
other assessments (eg, blood draws and 
questionnaires). 
Using 12-lead ECG equipment provided 
by the central laboratory selected by the 
sponsor, ECGs will be conducted before 
other assessments (blood draws and 
questionnaires). 
3.7.3.7 
Electronic 
Columbia-Suicide 
Severity Rating 
Scale 
Any positive findings on the eC-SSRS 
Since Last Visit version requires 
evaluation by the investigator. 
Any positive findings on the eC-SSRS 
Baseline/Screening version or the eC-
SSRS Since Last Visit version require 
evaluation by the investigator. 
4.1 
Prohibited/Restricted 
Subjects will be allowed to use acute 
migraine medication to treat acute 
Subjects will be allowed to use acute 
headache medication only at the time of 


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Protocol Section 
Before Revision 
After Revision 
Medications 
migraine attacks, as needed, but will not 
be allowed to use it as preventive 
medication. 
occurrence of a headache attack, as 
needed, but will not be allowed to use it 
as preventive medication. 
4.1.1 
Prohibited 
Medications 
(Preventive 
Migraine 
Medications), 
Table 4.1.1-1 
Angiotensin receptor blockers 
Angiotensin receptor blockers/ 
angiotensin converting enzyme inhibitors 
4.2 
Prohibited 
Concomitant 
Therapies 
Use of an intervention/device (eg, 
scheduled nerve blocks and transcranial 
magnetic stimulation) for treating CM 
will be prohibited. 
Use of an intervention/device (eg, 
scheduled nerve blocks and transcranial 
magnetic stimulation) for treating 
migraine will be prohibited. 
5.1 
Definitions 
 
...or the development of drug 
dependency or drug abuse. 
 
Any potential ... . 
 
...or the development of drug 
dependency or drug abuse.  Any 
potential ... . 
6.1.1 
Pharmacokinetic 
Analysis Set 
The pharmacokinetic analysis set will 
include all subjects in whom at least 1 
dose of IMP is administered, and 
effective plasma drug concentration is 
measured for at least 1 time point after 
IMP dosing.  However, subjects whose 
entire data are rejected in Section 6.1.2 
(3), Analysis Method 1), will be excluded 
from the pharmacokinetic analysis set. 
The pharmacokinetic analysis set will 
include all subjects in whom at least 1 
dose of IMP is administered, and 
effective plasma drug concentration is 
measured for at least 1 time point after 
IMP dosing.   
6.3.2 
Immunogenicity 
Analysis 
The impact of immunogenicity on the 
pharmacokinetics, efficacy, and safety 
will be evaluated. 
(Deleted) 
7.4.2 
Secondary 
Endpoint Analysis 
3) Mean change from baseline in the 
monthly average number of days of use 
of any acute migraine medications during 
the 12-week period after the first dose of 
IMP 
3) Mean change from baseline in the 
monthly average number of days with 
use of any acute headache medications 
during the 12-week period after the first 
dose of IMP 
7.4.2 
Secondary 
Endpoint Analysis 
4) Mean change from baseline in the 
number of migraine days during the 4-
week period after the first dose of IMP 
(Deleted) 
 
The numbers that followed 4) were 
shifted up to replace 4) onward. 
7.4.2 
Secondary 
Endpoint Analysis 
The same analysis used for the primary 
efficacy endpoint will be performed for 
the above endpoints, 1), 3), 4), 5), and 6), 
using an ANCOVA model. 
The same analysis used for the primary 
efficacy endpoint will be performed for 
the above endpoints, 1), 3), 4), and 5), 
using an ANCOVA model. 
7.4.3 
Exploratory 
Efficacy Endpoint 
Analysis 
 
Number of days of use of acute 
headache medications  
 
 
Number of subjects discontinuing 
concomitant preventive migraine 
medications during the treatment 
period 
 
Number of days of use of any acute 
headache medications  
 
 
(Deleted) 
7.6.4 
Electrocardiogram 
Data 
For the results of assessments (normal or 
abnormal), a shift table from baseline 
will be displayed. 
For the results of assessments, a shift 
table from baseline will be displayed. 


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ADDITIONAL RISK TO THE SUBJECT: 
There is no additional risk to the subjects. 
 
 
 


Protocol 406-102-00001 
Confidential - Proprietary Information 
100 
Version 5.0, 08 Jul 2019 
 
 
(English translation, 06 Aug 2019) 
Amendment Number: 
3 
Issue Date: 
28 Feb 2019 
 
PURPOSE: 
To reflect the extension of the trial duration 
BACKGROUND: 
Revisions were made because the trial period was extended.  
MODIFICATIONS TO PROTOCOL: 
Sectional Revisions: 
Protocol Section 
Before Revision 
After Revision 
Protocol Synopsis, 
Trial Duration 
Overall trial period:  Aug 2017 through 
Sep 2019 (planned) 
Overall trial period:  Aug 2017 through 
Jan 2020 (planned) 
 
ADDITIONAL RISK TO THE SUBJECT: 
There is no additional risk to the subjects. 
 
 


Protocol 406-102-00001 
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101 
Version 5.0, 08 Jul 2019 
 
 
(English translation, 06 Aug 2019) 
Amendment Number: 
4 
Issue Date: 
08 Jul 2019 
 
PURPOSE: 
To reflect the extension of the trial duration and to clarify wording and correct errors in 
the text. 
BACKGROUND: 
Revisions were made because the trial period was extended.  Revisions were also made 
because unclear wording and errors in the text were found. 
MODIFICATIONS TO PROTOCOL: 
Sectional Revisions: 
Protocol Section 
Before Revision 
After Revision 
Protocol Synopsis, 
Trial Duration 
Overall trial period:  Aug 2017 through 
Jan 2020 (planned) 
Overall trial period:  Aug 2017 through 
Mar 2020 (planned) 
3.7.2.5. 
EuroQol-5 
Dimension,  
5 Response Level 
Version 
Questionnaire 
The EQ-5D-5L questionnaire consists of 
2 parts.  In Part 1, subjects rate their 
health state in 5 domains:  mobility, self-
care, usual activities, pain/discomfort, 
and anxiety/depression, using a scale of 1 
to 5, where 1 = no problems, 2 = slight 
problems, 3 = moderate problems, 4 = 
severe problems, and 5 = extreme 
problems. 
The EQ-5D-5L questionnaire consists of 
2 parts.  In Part 1, subjects rate their 
health state in 5 domains:  mobility, self-
care, usual activities, pain/discomfort, 
and anxiety/depression, using a scale of 1 
to 5, where 1 = no problems, 2 = slight 
problems, 3 = moderate problems, 
4 = severe problems, and 5 = extreme 
problems. 
(Note*:  A minor revision was made in 
the Japanese original, but no changes 
are required in the English translation.) 
5.3 Immediately 
Reportable Events 
(IREs) 
An IRE form must be completed and sent 
by e-mail, fax, or overnight courier to the 
sponsor.  (Please note that the IRE form 
is not the AE page of the CRF.) 
An IRE form must be completed and sent 
by e-mail, fax, or overnight courier to the 
sponsor.  (Please note that the IRE form 
is not the AE page of the CRF.)  When 
sending an IRE form by e-mail, etc, 
sufficient care and attention must be 
taken to protect subject privacy. 
11 
Ethics and 
Responsibility 
Further, in preparing and handling CRFs, 
the investigator and their staff will .... 
Further, in preparing and handling CRFs, 
IRE forms, etc, the investigator and their 
staff will .... 
15  
References 
Reference No. 19 
Silberstein SD. Practice parameter: 
evidence-based guidelines for migraine 
headache (an evidence-based review). 
Report of the quality standards 
subcommittee of american academy of 
neurology. Neurology. 2000;55:754-62. 
Silberstein SD. Practice parameter: 
evidence-based guidelines for migraine 
headache (an evidence-based review). 
Report of the quality standards 
subcommittee of American Academy of 
Neurology. Neurology. 2000;55:754-62. 
 
ADDITIONAL RISK TO THE SUBJECT: 
There is no additional risk to the subjects. 

SAP_001.pdf: 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
A Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group Trial 
Evaluating the Efficacy and Safety of Subcutaneous Administration of TEV-48125 for 
the Preventive Treatment of Chronic Migraine 
 
 
 
 
NCT Number: NCT03303079 
PRT NO.: 406-102-00001 
Version Date: 12 December 2019 (Version 1.0) 


Otsuka Pharmaceutical Co., Ltd.
Investigational Medicinal Product
TEV-48125
Protocol No. 406-102-00001
A Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group Trial 
Evaluating the Efficacy and Safety of Subcutaneous Administration of TEV-48125 for 
the Preventive Treatment of Chronic Migraine
Statistical Analysis Plan
Version: 1.0
Date: 12 Dec 2019
Protocol Date: 8 Jul 2019
Confidential
May not be used, divulged, published, or otherwise disclosed without the prior written 
consent of Otsuka Pharmaceutical Co., Ltd.


Protocol 406-102-00001
Statistical Analysis Plan 
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Table of Contents
Table of Contents...........................................................................................2
List of Appendices..........................................................................................5
List of Abbreviations and Definition of Terms...........................................6
1
Introduction ..........................................................................................7
2
Trial Objectives.....................................................................................7
3
Trial Design...........................................................................................7
3.1
Type/Design of Trial ...........................................................................................7
3.2
Trial Treatments ..................................................................................................8
3.3
Trial Population...................................................................................................9
3.3.1
Number of Subjects and Description of Population .........................................9
4
Sample Size..........................................................................................10
5
Statistical Analysis Datasets ..............................................................10
5.1
Analysis Sets .....................................................................................................10
5.2
Handling of Missing Data .................................................................................11
6
Primary and Secondary Endpoints: .................................................11
6.1
Primary Endpoints.............................................................................................11
6.2
Secondary Outcome Variables ..........................................................................11
7
Disposition and Demographic Analysis............................................11
7.1
Subject Disposition............................................................................................12
7.2
Demographic and Baseline Characteristics.......................................................12
7.3
Baseline Disease Evaluation .............................................................................12
7.4
Treatment Compliance ......................................................................................13
7.5
Prior and Concomitant Medications..................................................................13
7.6
Protocol Deviations...........................................................................................14
8
Efficacy Analysis.................................................................................14
8.1
Primary Endpoint ..............................................................................................14
8.1.1
Primary Analysis ............................................................................................14
8.1.2
Sensitivity Analyses........................................................................................15
8.1.2.1
Wilcoxon Rank-sum Test............................................................................15
8.1.2.2
Analysis With Multiple Imputation Method...............................................15


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8.1.3
Supplementary Analyses ................................................................................16
8.1.4
Technical Computational Details for Primary Analysis.................................17
8.2
Secondary Endpoint ..........................................................................................18
8.2.1
Secondary Analysis ........................................................................................18
8.2.2
Technical Computational Details for Secondary Analysis.............................19
8.3
Exploratory Endpoints.......................................................................................20
8.3.1
Number of Headache Days of at Least Moderate Severity ............................20
8.3.2
Number of Migraine Days..............................................................................21
8.3.3
Other Headache-related Endpoints.................................................................21
8.3.4
Other Efficacy Endponts.................................................................................22
8.3.5
Technical Computational Details for Exploratory Analysis...........................24
8.4
Subgroup Analyses............................................................................................25
9
Safety Analyses ...................................................................................25
9.1
Extent of Exposure............................................................................................25
9.2
Adverse Events..................................................................................................25
9.3
Clinical Laboratory Data...................................................................................26
9.4
Vital Sign and Weight Data...............................................................................27
9.5
Physical Examination Data ...............................................................................27
9.6
Electrocardiogram Data.....................................................................................27
9.7
Injection Site Reactions.....................................................................................28
9.8
Electronic Columbia-Suicide Severity Rating Scale.........................................28
10
Pharmacokinetic Analyses.................................................................28
10.1
Endpoint ............................................................................................................28
10.2
Dataset for Analysis ..........................................................................................28
10.3
Handling of Data ...............................................................................................28
10.4
Statistical Analysis Method...............................................................................28
11
Pharmacodynamic Analyses..............................................................29
12
Pharmacogenomic Analyses ..............................................................29
13
Interim Analysis..................................................................................29
14
Changes in the Planned Analyses......................................................29
15
References............................................................................................30


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List of Appendices
Appendix 1
Logics for Migraine Day Derivation............................................. 31
Appendix 2
Scoring Instructions for MSQ....................................................... 31
Appendix 3
Criteria for Identifying Laboratory Values of Potentially
Clinically Significant .................................................................... 32
Appendix 4
Criteria for Identifying Vital Signs of Potentially Clinically 
Significant..................................................................................... 33
Appendix 5
List of Summary Tables and Figures............................................ 34
Appendix 6
List of Subject Data Listings......................................................... 45


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Statistical Analysis Plan 
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List of Abbreviations and Definition of Terms
Abbreviation
Definition
ADA
Antidrug antibody
AE
Adverse event
ANCOVA
Analysis of covariance
CM
Chronic migraine
CMH
Cochran-Mantel-Haenszel
ECG
Electrocardiogram
EM
Episodic migraine
EOT
End of Treatment
ePRO
Electronic patient-reported outcome
EQ-5D-5L
EuroQol-5 Dimension, 5 response level version
ES
Enrolled Set
FAS
Full Analysis Set
HIT-6
6-Item Headache Impact Test
IMP
Investigational medicinal product
IRT
Interactive response technology
LS mean
Least Square Mean
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
Mixed-effects model for repeated measures
MSQOL
Migraine-Specific Quality of Life
PCS
Potentially Clinically Significant
PGIC
Patient Global Impression of Change
PHQ-2
2-Item Patient Health Questionnaire
PHQ-9
9-Item Patient Health Questionnaire
PT
Preferred Term
RS
Randomized Set
SAP
Statistical Analysis Plan
SC
Subcutaneous
SD
Standard deviation
SE
Standard error
SMQ
Standardized MedDRA Queries
SOC
System Organ Class
SS
Safety Set
TEAE
Treatment-emergent adverse event
WPAI
Work Productivity and Activity Impairment


Protocol 406-102-00001
Statistical Analysis Plan 
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Version Date: 12 Dec 2019
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 406-102-00001. Analysis of 
immunogenicity is described in the bioanalytical protocol. All amendments to the 
protocol are taken into consideration in developing the SAP.
2
Trial Objectives
To evaluate the efficacy and safety of subcutaneous (SC) administration of TEV-48125 
(monthly TEV-48125 225 mg [loading dose only:  675 mg] and TEV-48125 675 mg once 
over a period of 3 months) compared with placebo for preventive treatment in chronic
migraine (CM) patients.
3
Trial Design
3.1
Type/Design of Trial
This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial 
in CM patients.  The schematic of the trial design is shown in Figure 3.1-1.
The trial consists of a 4-week screening period and a 12-week double-blind treatment 
period.
After obtaining written informed consent from patients, the investigator will screen them 
for eligibility (Visit [V] 1/Screening).  Subjects who have been diagnosed with CM, and 
who meet all the inclusion criteria and do not fall under any of the exclusion criteria will 
be randomized in a 1:1:1 ratio to one of the following 3 treatment groups (V2/Baseline).  
The investigational medicinal product (IMP) will be administered at V2/Baseline, 
V3/Month 1, and V4/Month 2 as specified in the protocol Section 3.2, Trial Treatments.  
Subjects will also visit the trial site at 3 to 10 days and at 14 to 21 days (twice) after one 
of IMP administrations at either V2/Baseline, V3/Month 1, or V4/Month 2 for 
pharmacokinetic assessment.  Subjects will also return to the trial site (V5/End of 
treatment) for the final assessment at 12 weeks after the first IMP administration.  
Subjects who are withdrawn from the trial will undergo a withdrawal assessment.
The trial includes the following treatment groups.

TEV-48125 675/225/225 mg group


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
TEV-48125 675 mg/placebo/placebo group

Placebo group
The period of trial participation for each subject is defined as the period from the day that 
informed consent is obtained from the patient until the day of trial completion.
Definition of the end of trial date for individual subject:
The end of trial date for individual subject is defined as the date of V5/End of treatment 
for the final assessment/observation or the date of trial withdrawal.  The date of trial 
withdrawal is defined as the date of withdrawal assessment, the date of the final 
assessment/observation in the double-blind treatment period, or the date of withdrawal 
decision, whichever comes later.  For subjects who are lost to follow up, the end of trial 
date for individual subject is defined as the date of their last visit/contact or the date of 
the last attempt to contact them.
Following the end of treatment visit (V5/End of treatment), subjects will be offered the 
opportunity to enter a long-term trial for the purpose of evaluating antidrug antibody
(ADA) at 225 days (approximate equivalent of 5 half-lives) after the final dose of IMP 
(V4/Month 2) in this trial.
 V1
V2/Baseline
 V3
 V4
 V5
675 mg
225 mg
225 mg
Informed consent
675 mg
PBO
PBO
PBO
PBO
PBO
Screening period
(4 weeks)
Subjects will also visit the trial site at 3 to 10 days and 14 to 21 days (twice) after one of IMP administrations
at either V2/Baseline, V3, or V4 for pharmacokinetic assessment.
Double-blind treatment period
(12 weeks)
R
Figure 3.1-1
Trial Design Schematic
PBO = placebo; R = randomization.
3.2
Trial Treatments
In the trial, TEV-48125 or placebo will be subcutaneously administered once monthly for 
3 months for a total of 3 doses.  Monthly dosing refers to dosing every 4 weeks 
(acceptable window:  ± 3 days).  Subjects who visit the trial site earlier than the 
acceptable window will not receive the IMP and will be requested to return to the trial 
site within the acceptable window.  The IMP will be administered by trial personnel 
responsible for administration of injections.


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The dosing regimens for treatment groups are shown below.

TEV-48125 675/225/225 mg group:
Subjects will receive 675 mg of TEV-48125 as 3 active injections (225 mg/1.5 mL) at 
V2/Baseline and 225 mg of TEV-48125 as a single active injection (225 mg/1.5 mL) 
at V3/Month 1 and V4/Month 2.

TEV-48125 675 mg/placebo/placebo group:
Subjects will receive 675 mg of TEV-48125 as 3 active injections (225 mg/1.5 mL) at 
V2/Baseline and placebo as a single 1.5-mL injection at V3/Month 1 and 
V4/Month 2.

Placebo group:
Subjects will receive three 1.5-mg placebo injections at V2/Baseline and a single 1.5-
mL placebo injection at V3/Month 1 and V4/Month 2.
At the time of each visit, the interactive response technology (IRT) will be queried and 
trial personnel will retrieve and administer a 1.5-mL volume from each syringe contained 
in the appropriately numbered kit(s).
Recommended SC injection sites follow the National Institutes of Health clinical center 
patient education materials:  Giving a subcutaneous injection.1  The suggested sites of 
injection are the outside of upper arms, back of upper arms, abdomen, or front of thighs.  
At each visit and when 3 injections are administered at a visit, each of the injections 
should be given in a different location (eg, not in precisely the same place).  Trial 
personnel responsible for administration of injections should inspect previous injection 
sites to ensure that they are free from bruising and tenderness and that proper rotation of 
sites is performed.
IMP should be removed from the refrigerator and allowed to equilibrate at room 
temperature for 45 to 60 minutes before IMP administration.
The date and time of SC injections and their locations will be recorded for each dosing 
visit (V2/Baseline, V3/Month 1, and V4/Month 2).
3.3
Trial Population
3.3.1
Number of Subjects and Description of Population
A total of 540 male or female (180 per group, a total of 3 groups) with CM aged 18 to 70
years, inclusive, will be enrolled in the trial.  The plan is to enroll at least approximately 
half of the subjects in Japan.  The enrollment procedure will be continued until the 
number of enrolled subjects reaches 540.


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Continued concomitant use of some preventive migraine medications (Table 4.1.2-1 in 
the protocol) may be permitted, so long as a stable dose and regimen have been 
maintained for at least 2 consecutive months prior to informed consent, in which case the 
subject will be allowed to continue using no more than 1 preventive medication.  
However, the total number of subjects receiving concomitant preventive medication 
during the trial will not exceed 30% of the total sample size of the trial.
4
Sample Size 
In a phase 2b trial in CM patients (Trial LBR-101-021), concerning the mean change 
from baseline in the monthly average number of headache days of at least moderate 
severity during the 12-week period after the first dose of IMP, the difference between the 
TEV-48125 675/225/225 mg group and the placebo group was 1.7 days and the standard 
deviation was 4.9 days.  On the assumption that this trial will also yield a similar result to 
the phase 2b trial (Trial LBR-101-021), a sample size of 176 subjects per group gives 
more than 90% power for the trial to succeed at a significance level of 0.05 (two-sided).  
Based on the above and taking into account a small percentage of subjects who may be 
excluded from the FAS, the target sample size was determined to be 180 subjects per 
group and 540 subjects as the overall total included in the trial.
5
Statistical Analysis Datasets
5.1
Analysis Sets

Enrolled set (ES):
Subjects from whom informed consent has been obtained (including screen failures)

Randomized set (RS):
Randomized subjects in the ES

Safety set (SS):
Subjects in the RS who receive the IMP at least once

Full Analysis set (FAS):
Subjects in the SS who have at least 10 days of baseline and post baseline efficacy 
assessment data on monthly average number of headache days of at least moderate 
severity

Pharmacokinetic Analysis set:
The pharmacokinetic analysis set will include all subjects in whom at least 1 dose of 
TEV-48125 is administered, and date and time of blood sampling for plasma drug 
concentration is recorded for at least 1 time point after TEV-48125 dosing.


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
Immunogenicity Analysis set:
The immunogenicity analysis set will include all subjects in whom at least 1 dose of 
TEV-48125 is administered, and date and time of blood sampling for serum ADA 
assessment is recorded for at least 1 time point after TEV-48125 dosing.
For all analysis sets except for ES, treatment will be assigned based on the treatment to 
which subjects are randomized regardless of which treatment they actually received.
5.2
Handling of Missing Data
Information on missing data is handled within the analysis sections.
6
Primary and Secondary Endpoints:
6.1
Primary Endpoints

Mean change from baseline in the monthly* average number of headache days of at 
least moderate severity during the 12-week period after the first dose of IMP
* “the monthly” is defined as “28-day” in this trial.
6.2
Secondary Outcome Variables

Mean change from baseline in the monthly average number of migraine days during 
the 12-week period after the first dose of IMP

Proportion of subjects reaching at least 50% reduction in the monthly average number 
of headache days of at least moderate severity during the 12-week period after the 
first dose of IMP

Mean change from baseline in the monthly average number of days with use of any 
acute headache medications during the 12-week period after the first dose of IMP

Mean change from baseline in the monthly average number of headache days of at 
least moderate severity during the 12-week period after the first dose of IMP in 
subjects not receiving concomitant preventive migraine medications

Mean change from baseline in disability score, as measured by the HIT-6, at 4 weeks 
after the final (third) dose of IMP
7
Disposition and Demographic Analysis
Descriptive statistics include number of subject (n), mean, standard deviation (SD), 
median, minimum, and maximum. 


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7.1
Subject Disposition
Data will be summarized for the overall population and by country.
The number of subjects from whom informed consent has been obtained, screen failure 
subjects and randomized subjects will be provided for the ES.
The number and percentage of subjects in whom IMP is administrated, in whom IMP is 
not administrated, who completed the trial and who are withdrawn from the trial will be 
summarized by treatment group, for all TEV-48125-treated subjects, and overall for the 
RS. The primary reason for discontinuation will also be summarized by treatment group, 
for all TEV-48125-treated subjects, and overall for the RS.
The number and percentage of subjects who are included in the SS, FAS, 
pharmacokinetic analysis set, immunogenicity analysis set, and who are excluded from 
the SS, FAS, pharmacokinetic analysis set, immunogenicity analysis set will be 
summarized by treatment group, for all TEV-48125-treated subjects, and overall for the 
RS.
7.2
Demographic and Baseline Characteristics
Data will be summarized for the overall population and by country.
The following demographic and baseline characteristics will be summarized by treatment 
group, for all TEV-48125-treated subjects, and overall for the RS. Continuous variables 
will be summarized using descriptive statistics. Categorical variables will be summarized 
using number and percentage of subjects.

Age ([45, ≥46 to 64, ≥65], [45, >45]), sex

Country, ethnicity, detailed ethnicity (Japanese, Korean), race

Weight, 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 Ver. 22.0) preferred term (PT). 
The number and percentage of subjects with medical history and complications will be 
summarized by SOC and PT for the RS. Subjects are counted only once in each SOC and 
only once in each PT.
7.3
Baseline Disease Evaluation
Data will be summarized for the overall population and by country.


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The following baseline disease evaluation will be summarized by treatment group, for all 
TEV-48125-treated subjects, and overall for the RS. Continuous variables will be 
summarized using descriptive statistics. Categorical variables will be summarized using 
number and percentage of subjects.

Number of headache days of any duration and any severity

Number of migraine days 

Number of headache days of at least moderate severity

Use of any acute headache medications (yes/no)

Use of migraine-specific acute headache medications (triptans and ergot 
compounds) (yes/no)
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 Technical 
Computational Details for Primary Analysis 8.1.4) using the electronic headache diary
data collected through the corresponding headache diary questions.
7.4
Treatment Compliance
Information for administration of IMP is described in Section 9.1
7.5
Prior and Concomitant Medications
Data will be summarized for the overall population and by country, by treatment group, 
for all TEV-48125-treated subjects, and overall for the RS.
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 
Enhanced B2 March 2017). 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 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


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
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 4.1.2-1 in the protocol)
used at baseline will also be summarized.
7.6
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 by treatment group, for all 
TEV-48125-treated subjects, and overall for the RS. 
8
Efficacy Analysis
The FAS will be used for all efficacy analyses. Summaries will be presented by treatment 
group, unless otherwise noted. Descriptive statistics for all efficacy data will be presented 
by month (or week) and overall for the 12-week period. Descriptive statistics will include 
number of subjects, mean, SD, median, minimum, and maximum.
8.1
Primary Endpoint
8.1.1
Primary Analysis
The primary efficacy endpoint is mean change from baseline in the monthly average 
number of headache days of at least moderate severity during the 12-week period after 
the first dose of IMP. 
The primary endpoint will be analyzed using an analysis of covariance (ANCOVA) 
model.  The model will include treatment, sex, country, and baseline preventive 
medication use as fixed effects and baseline number of headache days of at least 
moderate severity and years since onset of migraines as covariates.  Two-sided 95% 
confidence intervals and p-values will be constructed for the least squares (LS) mean 
differences between each TEV-48125 group and the placebo group.
The following sample SAS code pertains to the primary analysis.
proc mixed;
class TREATMENT SEX PRVMBASE CONTRY;
model CHG = BASE TTMIG PRVMBASE SEX TREATMENT CONTRY /s;


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lsmeans TREATMENT /pdiff cl alpha = 0.05;
ods output diffs = DIFFS lsmeans = LSMEANS;
run;
*PRVMBASE: Baseline preventive medication use
*TTMIG         : Years since onset of migraines
Multiplicity problems will be avoided using a closed testing procedure. If superiority of 
the TEV-48125 675/225/225 mg group to the placebo group is confirmed at a two-sided 
significance level of 0.05, then the TEV-48125 675 mg/placebo/placebo group vs the 
placebo group will be tested at a two-sided significance level of 0.05.
8.1.2
Sensitivity Analyses
8.1.2.1
Wilcoxon Rank-sum Test
The primary endpoint will be also analyzed using Wilcoxon rank-sum test to compare 
each TEV-48125 group vs the placebo group.
8.1.2.2
Analysis With Multiple Imputation Method 
Regarding the primary endpoint, when the monthly average number of headache days of 
at least moderate severity during the 12-week period after the first dose of IMP is not 
missing, but any of the monthly number of headache days of at least moderate severity 
during the 4-week period after each dose of IMP (ie, Month 1, Month 2, and Month 3) is 
missing, the multiple imputation (MI) method will be applied to impute the missing data 
for Month 1, Month 2, or Month 3 and the primary endpoint will be calculated as the 
average of Month 1, Month 2, and Month 3. The data will be processed by the following 
steps.

If a subject has partial electronic headache diary data for a month, ie, <10 days of 
data, a value for that month will be considered missing before the MI procedure.

Subjects in each TEV-48125 group who are withdrawn early for reasons of 
adverse events (AEs) or lack of efficacy will be assigned to the placebo group and
their missing values will be imputed using data from the placebo-treated subjects.

The SAS MI procedure will be run to create 100 complete datasets.

Within each imputed data set, for a subject who has partial, eg, X days (X <10) , 
electronic headache diary data for a month, the monthly value will be replaced by

The monthly average number of headache days of at least moderate severity
during the 12-week period after the first dose of IMP will be the average of the 
Month 1, Month 2, and Month 3 values.


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Each dataset including the monthly average during the 12-week period will be analyzed 
using the same ANCOVA model as described in Section 8.1.1. The LS means and 
standard errors (SE) from each analysis will be output to a SAS data set. The SAS 
MIANALYZE procedure will be used to generate the final LS means (± SE) for the 
treatment groups and the treatment differences (each TEV-48125 group −placebo group) 
as well as the p-values associated with treatment differences. The 95% confidence 
intervals for the treatment differences will also be constructed.
8.1.3
Supplementary Analyses
A mixed-effects model for repeated measures (MMRM) analysis will be used to estimate 
the mean change from baseline in the monthly number of headache days of at least 
moderate severity for the overall 3-month treatment period and by each month to support 
the primary analysis.
The MMRM will include treatment, sex, country, baseline preventive migraine 
medication use, month and treatment-by-month interaction as fixed effects and baseline 
value and years since onset of migraines as covariates. The unstructured covariance 
structure will be used for repeated observations within a subject. Kenward-Roger 
approximation will be used to estimate denominator degrees of freedom. The LS means 
for the treatment groups, LS means for the treatment differences (each TEV-48125 group 
−placebo group), and corresponding 95% confidence intervals and associated p-values 
will be calculated by month and for the overall treatment period.
The following SAS code pertains to the MMRM analysis.
proc mixed method = reml; 
class USUBJID MONTH TREATMENT SEX PRVMBASE CONTRY;
model CHG = BASE TTMIG PRVMBASE SEX TREATMENT MONTH 
TREATMENT * MONTH CONTRY /s ddfm = kr;
repeated MONTH /subject = USUBJID type = un r;
lsmeans TREATMENT TREATMENT * MONTH / pdiff cl alpha = 0.05;
ods output diffs = DIFFS lsmeans = LSMEANS;
run;
*PRVMBASE: Baseline preventive medication use
*TTMIG         : Years since onset of migraines


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If any problems in convergence status arise in the estimation of variance components, 
heterogeneous Toeplitz, heterogeneous autoregressive of order 1, and heterogeneous 
compound symmetry, which are error variance-covariance structures, will be applied in 
that order, and the first structure that achieves convergence will be used. If anything other 
than an unstructured variance-covariance structure is selected, a sandwich estimator for 
standard errors will be used.
The LS means ± SE of monthly change from baseline values estimated by MMRM will 
be plotted by month for each treatment group.
Mean change from baseline in the monthly number of headache days of at least moderate 
severity during the 4-week period after each dose (ie, for Month 1, Month 2, and Month 
3) will also be estimated and compared by the same ANCOVA model as described in
Section 8.1.1 and by Wilcoxon rank-sum test as described in Section 8.1.2.
8.1.4
Technical Computational Details for Primary Analysis

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

Variable definitions
The change from baseline in the monthly average number of headache days of at 
least moderate severity during the 12-week period after the first dose of IMP will 
be derived using the electronic headache diary data collected for the 
corresponding headache diary questions. 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).
The monthly average number of headache days of at least moderate severity
during the 12-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. 
The monthly number of headache days of at least moderate severity during the 4-
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derived and normalized to 28 days (see the following formula), where monthly 
data separated by each visit for IMP dosing will be used. 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.
8.2
Secondary Endpoint
8.2.1
Secondary Analysis
The secondary endpoints in this trial are as follows:
1) Mean change from baseline in the monthly average number of migraine days 
during the 12-week period after the first dose of IMP
2) Proportion of subjects reaching at least 50% reduction in the monthly average 
number of headache days of at least moderate severity during the 12-week period 
after the first dose of IMP
3) Mean change from baseline in the monthly average number of days with use of 
any acute headache medications during the 12-week period after the first dose of 
IMP
4) Mean change from baseline in the monthly average number of headache days of 
at least moderate severity during the 12-week period after the first dose of IMP in 
subjects not receiving concomitant preventive migraine medications
5) Mean change from baseline in disability score, as measured by the HIT-6, at 
4 weeks after the final (third) dose of IMP
For the endpoint 1), 3) and 4), will be analyzed using an ANCOVA model, Wilcoxon 
rank-sum test, and MMRM in the same manner as described in Section 8.1. The LS 
means ± SE of monthly change from baseline values estimated by the MMRM will also 
be plotted.
For the endpoint 2), each TEV-48125 group and the placebo group will be compared 
using Cochran-Mantel-Haenszel (CMH) test stratified by baseline preventive medication 
use. The difference in the endpoint 2) between each TEV-48125 group and the placebo 
group and its two-sided 95% confidence interval (a Mantel-Haenszel estimator of the 
difference and its two-sided 95% confidence interval) will be computed. Additionally, 
two-sided 95% confidence interval for the endpoint 2) in each treatment group will also 
be calculated using Clopper-Pearson method. Furthermore, proportion of subjects 
reaching at least 50% reduction in the monthly number of headache days of at least 
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and Month 3) will also be computed in the same manner. Missing data of evaluation will 
not be imputed.
For the endpoint 5), the HIT-6 total score will be used for disability score. The ANCOVA 
model and Wilcoxon rank-sum test will be performed as described in Section 8.1.
Frequency distributions will be provided by grade in each time point for each item of 
HIT-6.
8.2.2
Technical Computational Details for Secondary Analysis

Definition of migraine day
A migraine day is defined as when at least one of the following situations occurs:

A calendar day (0000 to 2359) demonstrating at least 4 consecutive hours of 
headache meeting the criteria for migraine with or without aura

A calendar day (0000 to 2359) demonstrating 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 headache of any duration that was treated 
with migraine specific-medication (triptans and ergot compounds)
The derivation logic is presented in Appendix 1.

Variable definitions

Electronic Headache Diary Data
The monthly average number of days for secondary endpoints (eg, migraine days, 
days with use of any acute headache medications, etc.) during the 12-week period 
after the first dose of IMP will be derived similar to the primary endpoint using 
the electronic headache diary data collected for the corresponding headache diary 
questions. The baseline value and monthly number of days for endpoints during 
the 4-week period after each dose (ie, for Month 1, Month 2, and Month 3) will be 
derived in the same manner (see Technical Computational Details for Primary 
Analysis 8.1.4).

6-Item Headache Impact Test (HIT-6)
The HIT-6 total score will be obtained from summation of the 6 question points. 
Each question is answered on the scale ranging with the following response 
options: 6 points (never), 8 points (rarely), 10 points (sometimes), 11 points (very 
often), and 13 points (always). If one or more items are missing, then the total 
score is missing. Baseline will be the last value prior to the first dose of IMP.
Post-baseline (4 weeks after the final [third] dose of IMP) will be the nominal 
visit.


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8.3
Exploratory Endpoints
8.3.1
Number of Headache Days of at Least Moderate Severity
The exploratory endpoints for number of headache days of at least moderate severity in 
this trial are as follows:
1) Mean change from baseline in the weekly number of headache days of at least 
moderate severity during the 4-week period after the first dose of IMP
2) Proportion of subjects reaching at least 75% reduction and total (100%) reduction 
in the monthly average number of headache days of at least moderate severity
during the 12-week period after the first dose of IMP
3) Proportion of subjects reaching at least 50% reduction and at least 75% reduction 
in the number of headache days of at least moderate severity during the 4-week 
period after the first dose of IMP for whom this level of effect is sustained 
throughout the 12-week period after the first dose of IMP
4) Mean change from baseline in the monthly average number of headache days of 
at least moderate severity during the 12-week period after the first dose of IMP in 
subjects receiving concomitant preventive migraine medications
5) Mean change from baseline in the number of headache days of at least moderate
severity during the 4-week period after the first dose of IMP
For the endpoint 1), similar to the supplementary analysis for the primary endpoint 
described in Section 8.1.3, an ANCOVA model, Wilcoxon rank-sum test, and MMRM
will be used to estimate the mean change from baseline by week (ie, for Week 1, Week 2, 
Week 3 and Week 4) after the first dose of IMP.
The endpoint 2) will be analyzed using CMH method as described in Section 8.2.1
“endpoint 2)”.
The endpoint 3) will be analyzed using CMH test stratified by baseline preventive 
migraine medication use similar to “endpoint 2)” in Section 8.2.1. If the subject shows
50% reduction or more at Month 1, Month 2, and also Month3, the level of effect is 
considered to be sustained throughout the 12-week period after the first dose of IMP for 
this subject. A subjects with a missing will be treated as a non-responder. Similar 
definition will be applied to calculate the proportion of sustained responders reaching at 
least 75% reduction.
The endpoint 4) will be analyzed using an ANCOVA model, Wilcoxon rank-sum test,
and MMRM in the same manner as described in Section 8.1. 
The endpoint 5) will be compared between the combined TEV-48125 group and the 
placebo group, since the patients randomized to both active treatment arms receive the 


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same dose of TEV-48125 675 mg at first dose of IMP. Similar analyses described in 
Section 8.1 will be used. An MMRM will be used to estimate the mean change from 
baseline by week (ie, for Week 1, Week 2, Week 3 and Week 4) after the first dose of 
IMP, and an ANCOVA model and Wilcoxon rank-sum test will be used to estimate the 
mean change from baseline for Month 1 after the first dose of IMP.
8.3.2
Number of Migraine Days
The exploratory endpoints for number of migraine days in this trial are as follows:
1) Mean change from baseline in the weekly number of migraine days during the 4-
week period after the first dose of IMP
2) Proportion of subjects reaching at least 50% reduction, at least 75% reduction, 
and total (100%) reduction in the monthly average number of migraine days
during the 12-week period after the first dose of IMP
3) Proportion of subjects reaching at least 50% reduction and at least 75% reduction 
in the number of migraine days during the 4-week period after the first dose of 
IMP for whom this level of effect is sustained throughout the 12-week period 
after the first dose of IMP
4) Mean change from baseline in the monthly average number of migraine days
during the 12-week period after the first dose of IMP in subjects not receiving 
concomitant preventive migraine medications
5) Mean change from baseline in the monthly average number of migraine days
during the 12-week period after the first dose of IMP in subjects receiving 
concomitant preventive migraine medications
6) Mean change from baseline in the number of migraine days during the 4-week 
period after the first dose of IMP
The endpoint 1) will be analyzed in the same manner as “endpoint 1)” in Section 8.3.1.
The endpoint 2) will be analyzed in the same manner as “endpoint 2)” in Section 8.3.1.
The endpoint 3) will be analyzed in the same manner as “endpoint 3)” in Section 8.3.1.
The endpoints 4) and 5) will be analyzed in the same manner as “endpoint 4)” in 
Section 8.3.1.
The endpoint 6) will be analyzed in the same manner as “endpoint 5)” in Section 8.3.1.
8.3.3
Other Headache-related Endpoints
The other exploratory headache-related endpoints in this trial are as follows:
1) Mean change from baseline in the monthly average number of headache days of 
any severity during the 12-week period after the first dose of IMP


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2) Mean change from baseline in the monthly average number of headache hours of 
any severity during the 12-week period after the first dose of IMP
3) Mean change from baseline in the monthly average number of headache hours of 
at least moderate severity during the 12-week period after the first dose of IMP
4) Mean change from baseline in the monthly average number of days with use of 
migraine-specific acute headache medications (triptans and ergot compounds) 
during the 12-week period after the first dose of IMP in subjects who used
migraine-specific acute headache medications (triptans and ergot compounds) at 
baseline
5) Mean change from baseline in the monthly average number of days with nausea 
or vomiting during the 12-week period after the first dose of IMP
6) Mean change from baseline in the monthly average number of days with 
photophobia and phonophobia during the 12-week period after the first dose of 
IMP
These endpoints will be analyzed in the same manner as Section 8.1.
8.3.4
Other Efficacy Endponts 
The other exploratory efficacy endpoints collected using Electronic Patient-Reported 
Outcomes (ePRO) in this trial are as follows:
1) Mean change from baseline in quality of life, as measured by the Migraine-
Specific Quality of Life Questionnaire (MSQOL) questionnaire, at each visit after 
IMP administration.
2) The health status quality of life, as measured by the EuroQol-5 Dimension, 5 
response level version (EQ-5D-5L) questionnaire at 4 weeks after the final (third) 
dose of IMP
3) Mean change from baseline in subject depression status, as measured by the Two-
Item Patient Health Questionnaire/Nine-Item Patient Health Questionnaire (PHQ-
2/ PHQ-9) at 4 weeks after the final (third) dose of IMP
4) Mean change from baseline in subject work productivity and activity impairment, 
as measured by the Work Productivity and Activity Impairment (WPAI) at 
4 weeks after the final (third) dose of IMP
5) Assessment of patient satisfaction, as measured by the Patient Global Impression 
of Change (PGIC) scale, at each visit after IMP administration.
For the endpoint 1), the transformed scores for the three domains (ie, Role Function-
Restrictive, Role Function-Preventive, and Emotional Function) of MSQOL will be 
derived for baseline, V3/Month 1, V4/Month 2, and V5/End of treatment (Month 3). The 
scoring instructions are presented in Appendix 2. In each domain, transformed scores will 
be analyzed in the same manner as Section 8.1. Baseline will be the last value prior to the 


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first dose of IMP. Post-baseline (V3/Month 1, V4/Month 2, and V5/End of treatment 
[Month 3]) will be the nominal visits.
For the endpoint 2), for each domain (mobility, self-care, usual activities, pain/discomfort, 
and anxiety/depression), frequency distributions will be provided by scale of 1 to 5 where 
1 = no problems, 2 = slight problems, 3 = moderate problems, 4 = severe problems, and 
5 = extreme problems for baseline and 4 weeks after the final (third) dose of IMP in each 
treatment group. The ANCOVA model and Wilcoxon rank-sum test, which are described 
in Section 8.1, will be performed for the visual analog scale. Baseline will be the last 
value prior to the first dose of IMP. Post-baseline (4 weeks after the final [third] dose of 
IMP) will be the nominal visit (V5/End of treatment [Month 3]).
For the endpoint 3), the total score will be analyzed using the ANCOVA model and 
Wilcoxon rank-sum test as described in Section 8.1. Baseline will be the last value prior 
to the first dose of IMP. Post-baseline (4 weeks after the final [third] dose of IMP) will be 
the nominal visit (V5/End of treatment [Month 3]).
For the endpoint 4), the following scores (in percentages) will be analyzed using the 
ANCOVA model and Wilcoxon rank-sum test as described in Section 8.1. Baseline will 
be the last value prior to the first dose of IMP. Post-baseline (4 weeks after the final 
[third] dose of IMP) will be the nominal visit (V5/End of treatment [Month 3]). The 
scores (in percentages) will be derived based on the WPAI questionnaire as follows:

Percent work item missed due to health:

Percent impairment while working due to health:

Percent overall work impairment due to health:   

Percent activity impairment due to health:
For the endpoint 5), the number and percentage of PGIC responders (subjects whose 
PGIC score were 5 to 7) will be derived for V3/Month 1, V4/Month 2, and V5/End of 
treatment (Month 3). The percentage of PGIC responders will be analyzed by CMH test 
stratified by baseline preventive migraine medication use as described in “endpoint 2)” in 
Section 8.2.1. Frequency distributions will also be provided by original response (scores: 
1 to 7) at each visit in each treatment group.


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8.3.5
Technical Computational Details for Exploratory Analysis

Variable definitions

Electronic Headache Diary Data
The weekly number of days for exploratory endpoints (eg, migraine days, 
headache days of at least moderate severity, etc.) during the 4-week period after 
the first dose of IMP will be derived using the electronic headache diary data 
collected for the corresponding headache diary questions. 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 7 days (see the following formula).
The weekly number of days for exploratory endpoints will be calculated for the 
subject’s first 28 calendar days of diary data after the first dose of IMP. Each 
week is defined as 7 calendar days, with Week 1 counted from the first dose date. 
If a subject has missing diary data in a week, the following method will be used to 
handle the missing data.

If the subject has ≥3 days of electronic headache diary data for a week, the 
weekly number of days of exploratory endpoints will be prorated to 7 days 
for that week (see the following formula).

If the subject has <3 days of electronic headache diary data for a week, the 
weekly number of days of efficacy variables will be considered as missing 
for that week.
The monthly average number of days/hours for exploratory endpoints (eg,
headache hours of any severity, headache hours of at least moderate severity, days 
with use of migraine-specific acute headache medications [triptans and ergot 
compounds], days with nausea or vomiting, days with photophobia and
phonophobia, etc.) during the 12-week period after the first dose of IMP will be 
derived similar to the primary endpoint using the electronic headache diary data 
collected for the corresponding headache diary questions. The baseline value and 
monthly number of days/hours for endpoints during the 4-week period after each 
dose (ie, for Month 1, Month 2, and Month 3) will be derived in the same manner
(see Technical Computational Details for Primary Analysis 8.1.4). In the case of 
hours, the numerator of formula will be hours instead of days.

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.


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8.4
Subgroup Analyses
The following subgroups for the change from baseline in the monthly average number of 
migraine days during the 12-week period after the first dose of IMP and the monthly 
average number of headache days of at least moderate severity during the 12-week period 
after the first dose of IMP will be analyzed in the same manner as Section 8.1.

Country

Age (45, >45)

Sex
9
Safety Analyses
The SS will be used for all safety analyses. Summaries will be presented by treatment 
group and all TEV-48125 groups unless specified otherwise. Descriptive statistics will
include number of subjects, mean, SD, median, minimum, and maximum.
9.1
Extent of Exposure
Data will be summarized for overall population and by country. Duration of treatment 
(days treated) is the number of days on treatment based on the first dose of IMP day and 
end of treatment (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, 2 doses, and 3 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, ≥2 
months, ≥3 months). One month will be defined as 28 days. The total exposure of IMP 
allocated at in each visit (V2/Baseline, V3/Month 1, and V4/Month 2) will also be 
summarized.
9.2
Adverse Events 
All AEs will be coded by SOC and MedDRA PT. The incidence of the following events 
will be summarized:

Treatment-emergent AEs (TEAEs)

TEAEs by severity 

TEAEs with an outcome of death

Serious TEAEs

TEAEs leading to discontinuation of the IMP

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The above summaries will also be prepared for TEAEs potentially drug related, and for 
the overall population (SS) and by country. In addition, TEAEs will be summarized by 
age (<65, ≥65), sex and use of preventive migraine medication at baseline (yes, no).

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 in any treatment group
9.3
Clinical Laboratory Data
Descriptive statistics will be calculated for clinical laboratory data and changes from 
baseline at each time point (V3/Month 1, V4/Month 2, V5/End of treatment [Month 3],
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 3.
Shift tables (except qualitative urinalysis) will be created for baseline and post-baseline at 
each time point values classified into normal, high, or low based on the reference range.
Baseline will be the last value prior to the first dose of IMP. Each visit for post-baseline
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(including scheduled, unscheduled, and withdrawal visits). Summaries of PCS values will 
include all post-baseline data.
9.4
Vital Sign and Weight Data
Descriptive statistics will be calculated for vital sign and weight measurements and 
changes from baseline at each time point (V3/Month 1, V4/Month 2, V5/End of treatment 
[Month 3], and final evaluation). 
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. Listing of subjects with 
PCS values will be prepared. The criteria are presented in Appendix 4.
Baseline will be the last value prior to the first dose of IMP. Each visit for post-baseline
will be the Nominal visits. Final evaluation will be the last observed all post-baseline data
(including scheduled, unscheduled, and withdrawal visits). Summaries of PCS values will 
include all post-baseline data.
9.5
Physical Examination Data
A list will be prepared for subjects with physical examination.
9.6
Electrocardiogram Data
Descriptive statistics will be calculated for electrocardiogram (ECG) measurements and 
changes from baseline at each time point (V5/End of treatment [Month 3], additional 
visits for pharmacokinetic [at 3 to 10 days and at 14 to 21 days postdose at V2/Baseline,
V3/Month 1, and V4/Month 2], and at 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.
For QTcB and QTcF, frequency distributions with the numbers and percentages of 
subjects will be presented for the following criteria: 

Subject who attains a value >450 msec post-baseline* 

Subject who attains a value >480 msec post-baseline* 

Subject who attains a value >500 msec post-baseline*

Increase in change from baseline value >30 msec at post-baseline*

Increase in change from baseline value >60 msec at post-baseline*
* “post-baseline” in the above criteria are at final evaluation and worst value. 


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The ECGs will be performed in triplicate. The average of the recorded measurements will 
be calculated for each visit. Baseline will be the last value prior to the first dose of IMP.
Each visit for post-baseline will be the Nominal visits. Final evaluation will be the last 
observed all post-baseline data (including scheduled, unscheduled, additional visits for 
pharmacokinetic assessments, and withdrawal visits). Worst value will also be derived 
using all post-baseline data.
9.7
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/Baseline, 
V3/Month 1, and V4/Month 2) and time point (immediately postdose and 1 hour 
postdose).
9.8
Electronic Columbia-Suicide Severity Rating Scale
Frequency distributions will be provided by response (positive/negative) for baseline and 
post-baseline scores. Post-baseline will include all post-baseline data, and if at least one
time point is positive, post-baseline will be positive. Subjects having positive findings 
will be listed.
10
Pharmacokinetic Analyses
10.1
Endpoint
Plasma TEV-48125 concentration
10.2
Dataset for Analysis
Pharmacokinetic analysis set
10.3
Handling of Data

The plasma concentrations below lower limit of quantitation will be imputed to 
0 (ng/mL). Lower limit of quantitation of TEV-48125 is 250 ng/mL.

No imputation will be performed for missing data.
10.4
Statistical Analysis Method
Concerning 10.1Endpoint, descriptive statistics will be calculated by treatment group for 
each blood sampling time point. Descriptive statistics include the number of subjects, 


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arithmetic mean, standard deviation, coefficient of variation, minimum, median, and 
maximum.
11
Pharmacodynamic Analyses
There were no pharmacodynamic analyses in this trial.
12
Pharmacogenomic Analyses
There were no pharmacogenomic analyses in this trial.
13
Interim Analysis
None
14
Changes in the Planned Analyses

Wilcoxon rank-sum test is conducted as the sensitivity analysis for normality 
assumption of the residuals in the primary efficacy analysis.

The sensitivity analysis based on multiple imputation method is conducted to 
explore the impact of missing data in the primary efficacy analysis.

MMRM analysis is added to estimate the mean change from baseline in the 
monthly number of headache days of at least moderate severity for the overall 3 
months treatment period and by each month.

The definitions of pharmacokinetic analysis set and immunogenicity analysis set
were changed as described in Section 5.1. Pharmacokinetic analysis set and 
immunogenicity analysis set will be determined based on the TEV-48125 dosing 
and the presence of recording of the date and time of blood sampling, not based 
on the IMP dosing and the presence of the measured values as described in the 
protocol.


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15
References
1
NIH clinical center patient education materials. Giving a subcutaneous injection. 
[Internet]. [cited 2017 Jul 3]. Available from: 
http://www.cc.nih.gov/ccc/patient_education/pepubs/subq.pdf.


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Appendix 1
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 and 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
A2 = 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
Appendix 2
Scoring Instructions for MSQ
The scoring of the MSQ is completed in 3 steps:
1.
Recoding of MSQ items (final item value assignment)
The precoded and final item values for each MSQ item response is shown in Table 
15-1. All item values range from 1 to 6.
2.
Computation of raw dimension scores
Once a final item value has been assigned to each item, a raw score can be computed 
for each MSQ dimension. The raw score for each dimension is simply the algebraic 
sum of the final item value for all items in that dimension. The range of each raw 
dimension score is shown in Table 15-2.
3.
Transformation of raw dimension scores to a 0 to 100 scale
After the raw score for each MSQ dimension is computed, the each score is 
transformed to a 0 to 100 scale. The transformation formula for each dimension is 
provided in Table 15-2. The transformation process allows each dimension score to 


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reflect the percentage of the total possible score achieved (since 100 equal the 
highest score).
Table 15-1
Precoded and final item values for MSQ item responses
Response categories
Precoded items value
Final item value
None of the time
1
6
A little bit of the time
2
5
Some of the time
3
4
A good bit of the time
4
3
Most of the time
5
2
All of the time
6
1
Table 15-2
Raw score and transformation formula for each MSQ 
dimension
MSQ dimension
Item No.
Raw score range
Transformation formula
Role Function - Restrictive
1-7
7 to 42
((raw score − 7) × 100) / 35
Role Function - Preventive
8-11
4 to 24
((raw score − 4) × 100) / 20
Emotional Function
12-14
3 to 18
((raw score − 3) × 100) / 15
Handling of missing data:
In the event that responses on one or more items within a dimension are missing, a 
missing item value may be estimated using the average of the other items within the same 
dimension. If a respondent answered at least half of the items in a multi item scale (or 
half plus one in the case of scales with an odd number of items), a missing item value can 
be estimated.
Appendix 3
Criteria for Identifying Laboratory Values of Potentially
Clinically Significant
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


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Laboratory Tests
Criteria
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
Appendix 4
Criteria for Identifying Vital Signs of Potentially Clinically 
Significant 
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 5
List of Summary Tables and Figures
CT-1
Subject Disposition by Country (Enrolled set)
CT-2
Reasons for Discontinuation by Country (RS)
CT-3.1.1
Demographics and Baseline Characteristics, All Countries (RS)
CT-3.1.2
Demographics and Baseline Characteristics in Japan (RS)
CT-3.1.3
Demographics and Baseline Characteristics in Korea (RS)
CT-3.2.1
Medical History by MedDRA SOC and PT, All Countries (RS)
CT-3.2.2
Medical History by MedDRA SOC and PT in Japan (RS)
CT-3.2.3
Medical History by MedDRA SOC and PT in Korea (RS)
CT-3.3.1
Complications by MedDRA SOC and PT, All Countries (RS)
CT-3.3.2
Complications by MedDRA SOC and PT in Japan (RS)
CT-3.3.3
Complications by MedDRA SOC and PT in Korea (RS)
CT-3.4.1
Baseline Disease Evaluation - Electronic Headache Diary Data, All Countries (RS)
CT-3.4.2
Baseline Disease Evaluation - Electronic Headache Diary Data in Japan (RS)
CT-3.4.3
Baseline Disease Evaluation - Electronic Headache Diary Data in Korea (RS)
CT-4.1.1.1
Prior Medications by WHO Drug Medication Class and Preferred Name, All 
Countries (RS)
CT-4.1.1.2
Prior Medications by WHO Drug Medication Class and Preferred Name in Japan 
(RS)
CT-4.1.1.3
Prior Medications by WHO Drug Medication Class and Preferred Name in Korea 
(RS)
CT-4.1.2.1
Prior Medications for Migraine by WHO Drug Medication Class and Preferred 
Name, Prohibited and Restricted Medications for Preventive Treatment of Migraine 
Medication, All Countries (RS)
CT-4.1.2.2
Prior Medications for Migraine by WHO Drug Medication Class and Preferred 
Name, Prohibited and Restricted Medications for Preventive Treatment of Migraine 
Medication in Japan (RS)
CT-4.1.2.3
Prior Medications for Migraine by WHO Drug Medication Class and Preferred 
Name, Prohibited and Restricted Medications for Preventive Treatment of Migraine 
Medication in Korea (RS)
CT-4.1.3.1
Prior Medications for Migraine by WHO Drug Medication Class and Preferred 
Name, Triptans and Ergots for Treatment of Acute Migraine, All Countries (RS)
CT-4.1.3.2
Prior Medications for Migraine by WHO Drug Medication Class and Preferred 
Name, Triptans and Ergots for Treatment of Acute Migraine in Japan (RS)


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CT-4.1.3.3
Prior Medications for Migraine by WHO Drug Medication Class and Preferred 
Name, Triptans and Ergots for Treatment of Acute Migraine in Korea (RS)
CT-4.1.4.1
Prior Medications for Migraine by WHO Drug Medication Class and Preferred 
Name, NSAIDs for Treatment of Acute Migraine, All Countries (RS)
CT-4.1.4.2
Prior Medications for Migraine by WHO Drug Medication Class and Preferred 
Name, NSAIDs for Treatment of Acute Migraine in Japan (RS)
CT-4.1.4.3
Prior Medications for Migraine by WHO Drug Medication Class and Preferred 
Name, NSAIDs for Treatment of Acute Migraine in Korea (RS)
CT-4.1.5.1
Prior Medications for Migraine by WHO Drug Medication Class and Preferred 
Name, Opioids for Treatment of Acute Migraine, All Countries (RS)
CT-4.1.5.2
Prior Medications for Migraine by WHO Drug Medication Class and Preferred 
Name, Opioids for Treatment of Acute Migraine in Japan (RS)
CT-4.1.5.3
Prior Medications for Migraine by WHO Drug Medication Class and Preferred 
Name, Opioids for Treatment of Acute Migraine in Korea (RS)
CT-4.2.1.1
Concomitant Medications by WHO Drug Medication Class and Preferred Name, All 
Countries (RS)
CT-4.2.1.2
Concomitant Medications by WHO Drug Medication Class and Preferred Name in 
Japan (RS)
CT-4.2.1.3
Concomitant Medications by WHO Drug Medication Class and Preferred Name in 
Korea (RS)
CT-4.2.2.1
Concomitant Medications for Migraine by WHO Drug Medication Class and 
Preferred Name, Prohibited and Restricted Medications for Preventive Treatment of 
Migraine, All Countries (RS)
CT-4.2.2.2
Concomitant Medications for Migraine by WHO Drug Medication Class and 
Preferred Name, Prohibited and Restricted Medications for Preventive Treatment of 
Migraine in Japan (RS)
CT-4.2.2.3
Concomitant Medications for Migraine by WHO Drug Medication Class and 
Preferred Name, Prohibited and Restricted Medications for Preventive Treatment of 
Migraine in Korea (RS)
CT-4.2.3.1
Concomitant Medications for Migraine by WHO Drug Medication Class and 
Preferred Name, Triptans and Ergots for Treatment of Acute Migraine, All 
Countries (RS)
CT-4.2.3.2
Concomitant Medications for Migraine by WHO Drug Medication Class and 
Preferred Name, Triptans and Ergots for Treatment of Acute Migraine in Japan (RS)
CT-4.2.3.3
Concomitant Medications for Migraine by WHO Drug Medication Class and 
Preferred Name, Triptans and Ergots for Treatment of Acute Migraine in Korea (RS)
CT-4.2.4.1
Concomitant Medications for Migraine by WHO Drug Medication Class and 


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Preferred Name, NSAIDs for Treatment of Acute Migraine, All Countries (RS)
CT-4.2.4.2
Concomitant Medications for Migraine by WHO Drug Medication Class and
Preferred Name, NSAIDs for Treatment of Acute Migraine in Japan (RS)
CT-4.2.4.3
Concomitant Medications for Migraine by WHO Drug Medication Class and 
Preferred Name, NSAIDs for Treatment of Acute Migraine in Korea (RS)
CT-4.2.5.1
Concomitant Medications for Migraine by WHO Drug Medication Class and 
Preferred Name, Opioids for Treatment of Acute Migraine, All Countries (RS)
CT-4.2.5.2
Concomitant Medications for Migraine by WHO Drug Medication Class and 
Preferred Name, Opioids for Treatment of Acute Migraine in Japan (RS)
CT-4.2.5.3
Concomitant Medications for Migraine by WHO Drug Medication Class and 
Preferred Name, Opioids for Treatment of Acute Migraine in Korea (RS)
CT-4.3.1
Restricted Preventive Migraine Medications at Baseline by WHO Drug Medication 
Class and Preferred Name, All Countries (RS)
CT-4.3.2
Restricted Preventive Migraine Medications at Baseline by WHO Drug Medication 
Class and Preferred Name in Japan (RS)
CT-4.3.3
Restricted Preventive Migraine Medications at Baseline by WHO Drug Medication 
Class and Preferred Name in Korea (RS)
CT-4.4
Major Protocol Deviations (RS)
CT-5.1
Change from Baseline in Monthly Number of Headache Days of at Least Moderate 
Severity, ANCOVA and Wilcoxon Rank Sum Test (FAS)
CT-5.2
Change from Baseline in Monthly Number of Headache Days of at Least Moderate 
Severity with Multiple Imputation ANCOVA (FAS)
CT-5.3
Change from Baseline in Monthly Number of Headache Days of at Least Moderate 
Severity, MMRM (FAS)
CT-6.1.1.1
Change from Baseline in Monthly Number of Migraine Days, ANCOVA and 
Wilcoxon Rank Sum Test (FAS)
CT-6.1.1.2
Change from Baseline in Monthly Number of Migraine Days, MMRM (FAS)
CT-6.1.2
Proportion of Subjects with >=50% Reduction in Monthly Number of Headache 
Days of at Least Moderate Severity (FAS)
CT-6.1.3.1
Change from Baseline in Monthly Number of Days With Use of Any Acute 
Headache Medication, ANCOVA and Wilcoxon Rank Sum Test (FAS)
CT-6.1.3.2
Change from Baseline in Monthly Number of Days With Use of Any Acute 
Headache Medication, MMRM (FAS)
CT-6.1.4.1
Change from Baseline in Monthly Number of Headache Days of at Least Moderate 
Severity in Subjects Not Receiving Concomitant Preventive Migraine Medication,
ANCOVA and Wilcoxon Rank Sum Test (FAS)


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CT-6.1.4.2
Change from Baseline in Monthly Number of Headache Days of at Least Moderate 
Severity in Subjects Not Receiving Concomitant Preventive Migraine Medication,
MMRM (FAS)
CT-6.1.5.1
Change from Baseline in Disability Score as Measured by HIT-6, ANCOVA and 
Wilcoxon Rank Sum Test (FAS)
CT-6.1.5.2.1
HIT-6 Disability Grade - Pain Severity (FAS)
CT-6.1.5.2.2
HIT-6 Disability Grade - Limit ability daily activities (FAS)
CT-6.1.5.2.3
HIT-6 Disability Grade - Lie down (FAS)
CT-6.1.5.2.4
HIT-6 Disability Grade - Feel Tired work/daily activity (FAS)
CT-6.1.5.2.5
HIT-6 Disability Grade - Felt Fed up or irritated (FAS)
CT-6.1.5.2.6
HIT-6 Disability Grade - Limit ability/concentrate work (FAS)
CT-6.2.1.1
Change from Baseline in Weekly Number of Headache Days of at Least Moderate 
Severity, ANCOVA and Wilcoxon Rank Sum Test (FAS)
CT-6.2.1.2
Change from Baseline in Weekly Number of Headache Days of at Least Moderate 
Severity, MMRM (FAS)
CT-6.2.2.1
Proportion of Subjects with >=75% Reduction in Monthly Number of Headache 
Days of at Least Moderate Severity (FAS)
CT-6.2.2.2
Proportion of Subjects with 100% Reduction in Monthly Number of Headache Days 
of at Least Moderate Severity (FAS)
CT-6.2.3.1
Proportion of Subjects with >=50% Reduction in Monthly Number of Headache 
Days of at Least Moderate Severity During First 4 Weeks and Sustained Throughout 
the 12-Week Treatment Period (FAS)
CT-6.2.3.2
Proportion of Subjects with >=75% Reduction in Monthly Number of Headache 
Days of at Least Moderate Severity During First 4 Weeks and Sustained Throughout 
the 12-Week Treatment Period (FAS)
CT-6.2.4.1
Change from Baseline in Monthly Number of Headache Days of at Least Moderate 
Severity in Subjects Receiving Concomitant Preventive Migraine Medication,
ANCOVA and Wilcoxon Rank Sum Test (FAS)
CT-6.2.4.2
Change from Baseline in Monthly Number of Headache Days of at Least Moderate 
Severity in Subjects Receiving Concomitant Preventive Migraine Medication,
MMRM (FAS)
CT-6.2.5.1
Change from Baseline in Number of Headache Days of at Least Moderate Severity -
Combined TEV-48125 Treatment Groups, ANCOVA and Wilcoxon Rank Sum Test 
(FAS)
CT-6.2.5.2
Change from Baseline in Weekly Number of Headache Days of at Least Moderate 
Severity - Combined TEV-48125 Treatment Groups, MMRM (FAS)


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CT-6.3.1.1
Change from Baseline in Weekly Number of Migraine Days, ANCOVA and 
Wilcoxon Rank Sum Test (FAS)
CT-6.3.1.2
Change from Baseline in Weekly Number of Migraine Days, MMRM (FAS)
CT-6.3.2.1
Proportion of Subjects with >=50% Reduction in Monthly Number of Migraine 
Days (FAS)
CT-6.3.2.2
Proportion of Subjects with >=75% Reduction in Monthly Number of Migraine 
Days (FAS)
CT-6.3.2.3
Proportion of Subjects with 100% Reduction in Monthly Number of Migraine Days 
(FAS)
CT-6.3.3.1
Proportion of Subjects with >=50% Reduction in Monthly Number of Migraine 
Days During First 4 Weeks and Sustained Throughout the 12-Week Treatment 
Period (FAS)
CT-6.3.3.2
Proportion of Subjects with >=75% Reduction in Monthly Number of Migraine 
Days During First 4 Weeks and Sustained Throughout the 12-Week Treatment 
Period (FAS)
CT-6.3.4.1
Change from Baseline in Monthly Number of Migraine Days in Subjects Not 
Receiving Concomitant Preventive Migraine Medication, ANCOVA and Wilcoxon 
Rank Sum Test (FAS)
CT-6.3.4.2
Change from Baseline in Monthly Number of Migraine Days in Subjects Not 
Receiving Concomitant Preventive Migraine Medication, MMRM (FAS)
CT-6.3.5.1
Change from Baseline in Monthly Number of Migraine Days in Subjects Receiving 
Concomitant Preventive Migraine Medication, ANCOVA and Wilcoxon Rank Sum 
Test (FAS)
CT-6.3.5.2
Change from Baseline in Monthly Number of Migraine Days in Subjects Receiving 
Concomitant Preventive Migraine Medication, MMRM (FAS)
CT-6.3.6.1
Change from Baseline in Number of Migraine Days - Combined TEV-48125 
Treatment Groups, ANCOVA and Wilcoxon Rank Sum Test (FAS)
CT-6.3.6.2
Change from Baseline in Weekly Number of Migraine Days - Combined TEV-
48125 Treatment Groups, MMRM (FAS)
CT-6.4.1.1
Change from Baseline in Monthly Number of Headache Days of Any Severity,
ANCOVA and Wilcoxon Rank Sum Test (FAS)
CT-6.4.1.2
Change from Baseline in Monthly Number of Headache Days of Any Severity,
MMRM (FAS)
CT-6.4.2.1
Change from Baseline in Monthly Number of Headache Hours of Any Severity,
ANCOVA and Wilcoxon Rank Sum Test (FAS)
CT-6.4.2.2
Change from Baseline in Monthly Number of Headache Hours of Any Severity,
MMRM (FAS)


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CT-6.4.3.1
Change from Baseline in Monthly Number of Headache Hours of at Least Moderate 
Severity, ANCOVA and Wilcoxon Rank Sum Test (FAS)
CT-6.4.3.2
Change from Baseline in Monthly Number of Headache Hours of at Least Moderate 
Severity, MMRM (FAS)
CT-6.4.4.1
Change from Baseline in Monthly Number of Days of Use of Migraine-Specific 
Acute Headache Medication (Triptans and Ergot Compounds) in Subjects Who 
Used Migraine-specific Acute Headache Medication at Baseline, ANCOVA and 
Wilcoxon Rank Sum Test (FAS)
CT-6.4.4.2
Change from Baseline in Monthly Number of Days of Use of Migraine-Specific 
Acute Headache Medication (Triptans and Ergot Compounds) in Subjects Who 
Used Migraine-specific Acute Headache Medication at Baseline, MMRM (FAS)
CT-6.4.5.1
Change from Baseline in Monthly Number of Days with Nausea or Vomiting,
ANCOVA and Wilcoxon Rank Sum Test (FAS)
CT-6.4.5.2
Change from Baseline in Monthly Number of Days with Nausea or Vomiting,
MMRM (FAS)
CT-6.4.6.1
Change from Baseline in Monthly Number of Days with Photophobia and 
Phonophobia, ANCOVA and Wilcoxon Rank Sum Test (FAS)
CT-6.4.6.2
Change from Baseline in Monthly Number of Days with Photophobia and 
Phonophobia, MMRM (FAS)
CT-6.5.1.1.1
Change from Baseline in MSQOL - Role Function - Restrictive, ANCOVA and 
Wilcoxon Rank Sum Test (FAS)
CT-6.5.1.1.2
Change from Baseline in MSQOL - Role Function - Preventive, ANCOVA and 
Wilcoxon Rank Sum Test (FAS)
CT-6.5.1.1.3
Change from Baseline in MSQOL - Emotional Function, ANCOVA and Wilcoxon 
Rank Sum Test (FAS)
CT-6.5.1.2.1
Change from Baseline in MSQOL - Role Function - Restrictive, MMRM (FAS)
CT-6.5.1.2.2
Change from Baseline in MSQOL - Role Function - Preventive, MMRM (FAS)
CT-6.5.1.2.3
Change from Baseline in MSQOL - Emotional Function, MMRM (FAS)
CT-6.5.2.1.1
EQ-5D-5L Questionnaire - Mobility (FAS)
CT-6.5.2.1.2
EQ-5D-5L Questionnaire - Self-Care (FAS)
CT-6.5.2.1.3
EQ-5D-5L Questionnaire - Usual Activities (FAS)
CT-6.5.2.1.4
EQ-5D-5L Questionnaire - Pain / Discomfort (FAS)
CT-6.5.2.1.5
EQ-5D-5L Questionnaire - Anxiety / Depression (FAS)
CT-6.5.2.2
Change from Baseline in EQ-5D-5L Questionnaire Visual Analog Scale, ANCOVA 
and Wilcoxon Rank Sum Test (FAS)


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CT-6.5.3
Change from Baseline in PHQ-9 Total Score, ANCOVA and Wilcoxon Rank Sum 
Test (FAS)
CT-6.5.4.1
Change from Baseline in WPAI-Percent work item missed due to health, ANCOVA 
and Wilcoxon Rank Sum Test (FAS)
CT-6.5.4.2
Change from Baseline in WPAI-Percent impairment while working due to health,
ANCOVA and Wilcoxon Rank Sum Test (FAS)
CT-6.5.4.3
Change from Baseline in WPAI-Percent overall work impairment due to health,
ANCOVA and Wilcoxon Rank Sum Test (FAS)
CT-6.5.4.4
Change from Baseline in WPAI-Percent activity impairment due to health,
ANCOVA and Wilcoxon Rank Sum Test (FAS)
CT-6.5.5.1
Proportion of Subjects with Responder in PGIC (FAS)
CT-6.5.5.2
PGIC (FAS)
CT-6.6.1.1.1
Change from Baseline in Monthly Number of Migraine Days, ANCOVA and 
Wilcoxon Rank Sum Test, in Japan (FAS)
CT-6.6.1.1.2
Change from Baseline in Monthly Number of Migraine Days, ANCOVA and 
Wilcoxon Rank Sum Test, in Korea (FAS)
CT-6.6.1.2.1
Change from Baseline in Monthly Number of Migraine Days, MMRM, in Japan 
(FAS)
CT-6.6.1.2.2
Change from Baseline in Monthly Number of Migraine Days, MMRM, in Korea 
(FAS)
CT-6.6.2.1.1
Change from Baseline in Monthly Number of Migraine Days, ANCOVA and 
Wilcoxon Rank Sum Test, in Age 18-45 years (FAS)
CT-6.6.2.1.2
Change from Baseline in Monthly Number of Migraine Days, ANCOVA and 
Wilcoxon Rank Sum Test, in Age >45 years (FAS)
CT-6.6.2.2.1
Change from Baseline in Monthly Number of Migraine Days, MMRM, in Age 18-
45 years (FAS)
CT-6.6.2.2.2
Change from Baseline in Monthly Number of Migraine Days, MMRM, in Age >45 
years (FAS)
CT-6.6.3.1.1
Change from Baseline in Monthly Number of Migraine Days, ANCOVA and 
Wilcoxon Rank Sum Test, in Male (FAS)
CT-6.6.3.1.2
Change from Baseline in Monthly Number of Migraine Days, ANCOVA and 
Wilcoxon Rank Sum Test, in Female (FAS)
CT-6.6.3.2.1
Change from Baseline in Monthly Number of Migraine Days, MMRM, in Male 
(FAS)
CT-6.6.3.2.2
Change from Baseline in Monthly Number of Migraine Days, MMRM, in Female 
(FAS)


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CT-6.7.1.1.1
Change from Baseline in Monthly Number of Headache Days of at Least Moderate 
Severity, ANCOVA and Wilcoxon Rank Sum Test, in Japan (FAS)
CT-6.7.1.1.2
Change from Baseline in Monthly Number of Headache Days of at Least Moderate 
Severity, ANCOVA and Wilcoxon Rank Sum Test, in Korea (FAS)
CT-6.7.1.2.1
Change from Baseline in Monthly Number of Headache Days of at Least Moderate 
Severity, MMRM, in Japan (FAS)
CT-6.7.1.2.2
Change from Baseline in Monthly Number of Headache Days of at Least Moderate 
Severity, MMRM, in Korea (FAS)
CT-6.7.2.1.1
Change from Baseline in Monthly Number of Headache Days of at Least Moderate 
Severity, ANCOVA and Wilcoxon Rank Sum Test, in Age 18-45 years (FAS)
CT-6.7.2.1.2
Change from Baseline in Monthly Number of Headache Days of at Least Moderate 
Severity, ANCOVA and Wilcoxon Rank Sum Test, in Age >45 years (FAS)
CT-6.7.2.2.1
Change from Baseline in Monthly Number of Headache Days of at Least Moderate 
Severity, MMRM, in Age 18-45 years (FAS)
CT-6.7.2.2.2
Change from Baseline in Monthly Number of Headache Days of at Least Moderate 
Severity, MMRM, in Age >45 years (FAS)
CT-6.7.3.1.1
Change from Baseline in Monthly Number of Headache Days of at Least Moderate 
Severity, ANCOVA and Wilcoxon Rank Sum Test, in Male (FAS)
CT-6.7.3.1.2
Change from Baseline in Monthly Number of Headache Days of at Least Moderate 
Severity, ANCOVA and Wilcoxon Rank Sum Test, in Female (FAS)
CT-6.7.3.2.1
Change from Baseline in Monthly Number of Headache Days of at Least Moderate 
Severity, MMRM, in Male (FAS)
CT-6.7.3.2.2
Change from Baseline in Monthly Number of Headache Days of at Least Moderate 
Severity, MMRM, in Female (FAS)
CT-7.1
Duration of Treatment (Days) and Extent of Exposure to Trial Medication by 
Country (SS)
CT-7.2
Number of Doses of Trial Medication by Country (SS)
CT-7.3
Duration of treatment, n (%) by Country (SS)
CT-8.1
Summary of AEs by Country (SS)
CT-8.2.1.1
TEAEs by MedDRA SOC and PT, All Countries (SS)
CT-8.2.1.2
TEAEs by MedDRA SOC and PT in Japan (SS)
CT-8.2.1.3
TEAEs by MedDRA SOC and PT in Korea (SS)
CT-8.2.2.1
Potentially Drug-related TEAEs by MedDRA SOC and PT, All Countries (SS)
CT-8.2.2.2
Potentially Drug-related TEAEs by MedDRA SOC and PT in Japan (SS)
CT-8.2.2.3
Potentially Drug-related TEAEs by MedDRA SOC and PT in Korea (SS)


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CT-8.3.1.1
TEAEs by Severity by MedDRA SOC and PT, All Countries (SS)
CT-8.3.1.2
TEAEs by Severity by MedDRA SOC and PT in Japan (SS)
CT-8.3.1.3
TEAEs by Severity by MedDRA SOC and PT in Korea (SS)
CT-8.3.2.1
Potentially Drug-related TEAEs by Severity by MedDRA SOC and PT, All 
Countries (SS)
CT-8.3.2.2
Potentially Drug-related TEAEs by Severity by MedDRA SOC and PT in Japan 
(SS)
CT-8.3.2.3
Potentially Drug-related TEAEs by Severity by MedDRA SOC and PT in Korea 
(SS)
CT-8.4.1.1
TEAEs with an outcome of death by MedDRA SOC and PT, All Countries (SS)
CT-8.4.1.2
TEAEs with an outcome of death by MedDRA SOC and PT in Japan (SS)
CT-8.4.1.3
TEAEs with an outcome of death by MedDRA SOC and PT in Korea (SS)
CT-8.4.2.1
Potentially Drug-related TEAEs with an outcome of death by MedDRA SOC and 
PT, All Countries (SS)
CT-8.4.2.2
Potentially Drug-related TEAEs with an outcome of death by MedDRA SOC and 
PT in Japan (SS)
CT-8.4.2.3
Potentially Drug-related TEAEs with an outcome of death by MedDRA SOC and 
PT in Korea (SS)
CT-8.5.1.1
Serious TEAEs by MedDRA SOC and PT, All Countries (SS)
CT-8.5.1.2
Serious TEAEs by MedDRA SOC and PT in Japan (SS)
CT-8.5.1.3
Serious TEAEs by MedDRA SOC and PT in Korea (SS)
CT-8.5.2.1
Potentially Drug-related Serious TEAEs by MedDRA SOC and PT, All Countries
(SS)
CT-8.5.2.2
Potentially Drug-related Serious TEAEs by MedDRA SOC and PT in Japan (SS)
CT-8.5.2.3
Potentially Drug-related Serious TEAEs by MedDRA SOC and PT in Korea (SS)
CT-8.6.1.1
TEAEs leading to discontinuation of the IMP by MedDRA SOC and PT, All 
Countries (SS)
CT-8.6.1.2
TEAEs leading to discontinuation of the IMP by MedDRA SOC and PT in Japan 
(SS)
CT-8.6.1.3
TEAEs leading to discontinuation of the IMP by MedDRA SOC and PT in Korea 
(SS)
CT-8.6.2.1
Potentially Drug-related TEAEs leading to discontinuation of the IMP by MedDRA 
SOC and PT, All Countries (SS)
CT-8.6.2.2
Potentially Drug-related TEAEs leading to discontinuation of the IMP by MedDRA 
SOC and PT in Japan (SS)


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CT-8.6.2.3
Potentially Drug-related TEAEs leading to discontinuation of the IMP by MedDRA 
SOC and PT in Korea (SS)
CT-8.7.1.1
TEAEs reported in at least 2% of subjects at Any Group by MedDRA SOC and PT, 
All Countries (SS)
CT-8.7.1.2
TEAEs reported in at least 2% of subjects at Any Group by MedDRA SOC and PT 
in Japan (SS)
CT-8.7.1.3
TEAEs reported in at least 2% of subjects at Any Group by MedDRA SOC and PT 
in Korea (SS)
CT-8.7.2.1
Potentially Drug-related TEAEs reported in at least 2% of subjects at Any Group by 
MedDRA SOC and PT, All Countries (SS)
CT-8.7.2.2
Potentially Drug-related TEAEs reported in at least 2% of subjects at Any Group by 
MedDRA SOC and PT in Japan (SS)
CT-8.7.2.3
Potentially Drug-related TEAEs reported in at least 2% of subjects at Any Group by 
MedDRA SOC and PT in Korea (SS)
CT-8.7.3.1
TEAEs by MedDRA SOC and PT in Age <65 years (SS)
CT-8.7.3.2
TEAEs by MedDRA SOC and PT in Age >=65 years (SS)
CT-8.7.3.3
TEAEs by MedDRA SOC and PT in Male (SS)
CT-8.7.3.4
TEAEs by MedDRA SOC and PT in Female (SS)
CT-8.7.3.5
TEAEs by MedDRA SOC and PT in using preventive migraine medication at 
baseline (SS)
CT-8.7.3.6
TEAEs by MedDRA SOC and PT in not using preventive migraine medication at 
baseline (SS)
CT-8.8.1
Injection Site Reaction TEAEs by MedDRA SOC and PT, All Countries (SS)
CT-8.8.2
Ophthalmic TEAEs of at least moderate severity by MedDRA SOC and PT, All 
Countries (SS)
CT-8.8.3
Drug-related Hepatic TEAEs by MedDRA SOC and PT, All Countries (SS)
CT-8.8.4
Anaphylaxis and severe hypersensitivity reaction TEAEs by MedDRA SOC and PT, 
All Countries (SS)
CT-8.8.5
Cardiovascular-related TEAEs by MedDRA SOC and PT, All Countries (SS)
CT-8.8.6
Non-Serious TEAEs Greater Than or Equal to 5% in Any Group by MedDRA SOC 
and PT, All Countries (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)


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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)
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)
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)


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CT-13.5.1
Electronic Columbia-Suicide Severity Rating Scale (eC-SSRS) Assessment 
Outcome Responses (SS)
CT-13.5.2
Subjects with Positive Responses for Electronic Columbia-Suicide Severity Rating 
Scale (eC-SSRS) Assessment (SS)
CF-1
LS Mean Change from Baseline in Monthly Number of Headache Days of at Least 
Moderate Severity Using MMRM (FAS)
CF-2
LS Mean Change from Baseline in Monthly Number of Migraine Days Using 
MMRM (FAS)
CF-3
LS Mean Change from Baseline in Monthly Number of Days with Use of Any 
Acute Headache Medication Using MMRM (FAS)
CF-4
LS Mean Change from Baseline in Monthly Number of Headache Days of at Least 
Moderate Severity in Subjects Not Receiving Concomitant Preventive Migraine 
Medication Using MMRM (FAS)
PKT-X.1.4.1
Individual and Summary of Plasma Trough Concentration
Appendix 6
List of Subject Data Listings
PDATA-1
Subject Disposition (RS)
PDATA-2
Analysis Population Flag (RS)
PDEV-1
Major Protocol Deviations (RS)
DEMOG-1
Demographics (RS)
DEMOG-2
Initial Migraine Diagnosis Date (RS)
DEMOG-3
Childbearing Potential (Females Only) (RS)
PDATA-3
Medical History (RS)
PDATA-4
Complications (RS)
PDATA-5.1
Prior and Concomitant Medications and Therapy (RS)
PDATA-5.2
Past Preventive Migraine Medications (RS)
SMED-1
Study Drug Administration (RS)
SMED-2
Extent of Exposure (RS)
PDATA-6
Vital Signs Values (RS)
PDATA-7.1
Electrocardiogram Measurement (RS)
PDATA-7.2
Electrocardiogram Interpretation (RS)
PDATA-7.3
Electrocardiogram Findings (RS)
PDATA-7.4
Electrocardiogram Technical (RS)


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PDATA-8
Physical Examination Findings (RS)
PDATA-9
Electronic Columbia-Suicide Severity Rating Scale (eC-SSRS) Assessment (RS)
PDATA-10
Injection Site Assessment (RS)
PDATA-11
Screen Failures (Screen Failure)
PDATA-12
Subjects Who Did Not Meet Inclusion Criteria or Meet Exclusion Criteria (Screen 
Failure)
PDATA-13
Pharmacokinetic Blood Draw Date and Times (RS)
PDATA-14
Anti-drug Antibodies Blood Draw Date and Times (RS)
PDATA-15
Biomarker Sampling Date and Times (RS)
PDATA-16
Subjects Who Did Not Meet Inclusion Criteria or Meet Exclusion Criteria (RS)
PDATA-17
Information on Subjects Lost to Follow-up (RS)
EFF-1.1
Electronic Headache Diary Questionnaire - Questions List
EFF-1.2
Electronic Headache Diary Questionnaire - Results (RS)
EFF-1.3
Electronic Headache Diary Questionnaire - Derived (RS)
EFF-2.1
6-Item Headache Impact Test (HIT-6) - Questions List
EFF-2.2
6-Item Headache Impact Test (HIT-6) - Results (RS)
EFF-3.1
Migraine-Specific Quality of Life (MSQOL) Questionnaire - Questions List
EFF-3.2
Migraine-Specific Quality of Life (MSQOL) Questionnaire - Results (RS)
EFF-4.1
EuroQoL-5 Dimension (EQ-5D-5L) Questionnaire - Questions List
EFF-4.2
EuroQoL-5 Dimension (EQ-5D-5L) Questionnaire - Results (RS)
EFF-5.1
Patient Health Questionnaire-9 (PHQ-9) - Questions List
EFF-5.2
Patient Health Questionnaire-9 (PHQ-9) - Results (RS)
EFF-6.1
Work Productivity and Activity Impairment (WPAI) Questionnaire - Questions List
EFF-6.2
Work Productivity and Activity Impairment (WPAI) Questionnaire - Results (RS)
EFF-7
Patients Global Impression of Change (PGIC) Scale (RS)
AE-1
Treatment-Emergent Adverse Events (RS)
AE-2
Prior to Treatment Adverse Events (RS)
LAB-1
Serum Chemistry Laboratory Tests Results (RS)
LAB-2
Hematology Laboratory Tests Results (RS)
LAB-3
Coagulation Laboratory Tests Results (RS)
LAB-4
Urinalysis Laboratory Tests Results (RS)


Protocol 406-102-00001
Statistical Analysis Plan 
47 of 47
Version Date: 12 Dec 2019
LAB-5
Pregnancy Test Results (Females Only) (RS)