A Multicenter, Randomized, Double-Blind, Parallel-Group Study Evaluating the Long-Term Safety, Tolerability, and Efficacy of Subcutaneous Administration of Fremanezumab (TEV-48125) for the Preventive Treatment of Migraine
Phase: PHASE3
Conditions: Migraine
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc.

 
 
 
 
Clinical Study Protocol with Amendment 01 
 
 
A Multicenter, Randomized, Double-Blind, Parallel-Group Study Evaluating the Long-
Term Safety, Tolerability, and Efficacy of Subcutaneous Administration of TEV 48125 for 
the Preventive Treatment of Migraine 
 
 
Study Number TV48125-CNS-30051 
 
NCT02638103 
 
Protocol with Amendment 01 Approval Date: 30 March 2016  
 

 
Long-Term Study–Chronic and Episodic Migraine 
Clinical Study Protocol with Amendment 01 
 
Study TV48125-CNS-30051 
 
1 
 
 
 
Clinical Study Protocol with Amendment 01 
Study Number TV48125-CNS-30051 
A Multicenter, Randomized, Double-Blind, Parallel-Group Study Evaluating the 
Long-Term Safety, Tolerability, and Efficacy of Subcutaneous Administration of 
TEV-48125 for the Preventive Treatment of Migraine 
Phase 3 
IND number: 106,533 
EudraCT number: 2015-004550-18 
Protocol Approval Date:  30 March 2016 
Sponsor 
Monitors 
Teva Branded Pharmaceutical  
Products R&D, Inc. 
41 Moores Road 
Frazer, Pennsylvania 19355 
United States 
NCGS, Inc. 
288 Meeting Street 
Suite 400 
Charleston, South Carolina 29401 
United States 
PRA 
4130 Parklake Avenue 
Suite 400 
Raleigh, NC 27612 
Authorized Representative 
Teva Branded Pharmaceutical Products R&D, Inc. 
Sponsor’s Medical Expert 
Sponsor’s Safety Representative  
Teva Pharmaceuticals 
 
Confidentiality Statement 
This clinical study will be conducted in accordance with current Good Clinical Practice (GCP), as directed by the 
provisions of the International Conference on Harmonisation (ICH); United States (US) Code of Federal 
Regulations (CFR) and European Union (EU) Directives (as applicable in the region of the study); local country 
regulations; and the sponsor’s Standard Operating Procedures (SOPs).  
This document contains confidential and proprietary information (including confidential commercial information 
pursuant to 21CFR§20.61) and is a confidential communication of Teva Branded Pharmaceutical Products R&D, 
Inc. and/or its affiliates. The recipient agrees that no information contained herein may be published or disclosed 
without written approval from the sponsor. 
© 2016 Teva Branded Pharmaceutical Products R&D, Inc. All rights reserved. 

 
Long-Term Study–Chronic and Episodic Migraine 
Clinical Study Protocol with Amendment 01 
 
Study TV48125-CNS-30051 
 
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AMENDMENT HISTORY 
The protocol for Study TV48125-CNS-30051 (dated 02 November 2015) has been amended and 
reissued as follows: 
Amendment 01 
30 March 2016 
3 patients enrolled to date 
Administrative Letter 02: 
Suspected Anaphylaxis 
01 March 2016 
0 patients enrolled to date 
Administrative Letter 01: 
Drug Administration, Patient-
Reported Outcome Measures, 
and Laboratory Tests 
22 January 2016 
0 patients enrolled to date 
Details about the changes and reason/justification for each change are provided in Section 17. 
 

 
Long-Term Study–Chronic and Episodic Migraine 
Clinical Study Protocol with Amendment 01 
 
Study TV48125-CNS-30051 
 
 
INVESTIGATOR AGREEMENT 
Clinical Study Protocol with Amendment 01 
Original Protocol Dated 02 November 2015 
IND number: 106,533 
EudraCT number: 2015-004550-18 
A Multicenter, Randomized, Double-Blind, Parallel-Group Study Evaluating the 
Long-Term Safety, Tolerability, and Efficacy of Subcutaneous Administration of 
TEV-48125 for the Preventive Treatment of Migraine 
Phase 3 
 
Principal Investigator: __________________________________________ 
Title: _________________________________________________ 
Address of Investigational Center: __________________________________ 
 
__________________________________ 
 
__________________________________ 
Tel: ______________ 
I have read the protocol with Amendment 01 and agree that it contains all necessary details for 
carrying out this study. I am qualified by education, experience, and training to conduct this 
clinical research study. The signature below constitutes approval of this protocol and 
attachments, and provides assurance that this study will be conducted according to all 
stipulations of the protocol, including all statements regarding confidentiality, and according to 
national or local legal and regulatory requirements and applicable regulations and guidelines. 
I will make available the protocol and all information on the drug that were furnished to me by 
the sponsor to all physicians and other study personnel responsible to me who participate in this 
study and will discuss this material with them to ensure that they are fully informed regarding the 
drug and the conduct of the study. I agree to keep records on all patient information, study drug 
shipment and return forms, and all other information collected during the study, in accordance 
with national and local Good Clinical Practice (GCP) regulations. 
 
Principal Investigator 
Signature 
Date 
 
SPONSOR PROTOCOL APPROVAL 

 
Long-Term Study–Chronic and Episodic Migraine 
Clinical Study Protocol with Amendment 01 
 
Study TV48125-CNS-30051 
 
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COORDINATING INVESTIGATOR AGREEMENT 
 

 
Long-Term Study–Chronic and Episodic Migraine 
Clinical Study Protocol with Amendment 01 
 
Study TV48125-CNS-30051 
 
5 
 
CLINICAL LABORATORY AND OTHER DEPARTMENTS AND 
INSTITUTIONS 
Central Institutional Review Board 
 
 
 
Central Clinical Laboratory 
PPD Global Central Laboratories  
2 Tesseneer Drive 
Highland Heights, KY 41076 
 
Electronic Data Capture 
Medidata Rave 
 
Data Management 
PRA 
4130 Parklake Avenue 
Suite 400 
Raleigh, NC 27612 
 
Electronic Clinical Outcome Assessment 
eResearch Technology, Inc. 
1818 Market Street 
Philadelphia, PA 19103 
 
Central Electrocardiogram Evaluation 
eResearch Technology, Inc. 
1818 Market Street 
Philadelphia, PA 19103 
 
Web and Phone Integrated Interactive Response Technology 
Y-Prime 
 

 
Long-Term Study–Chronic and Episodic Migraine 
Clinical Study Protocol with Amendment 01 
 
Study TV48125-CNS-30051 
 
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Bioanalytical Pharmacokinetics Evaluation  
Teva Branded Pharmaceuticals R&D, Inc. 
Teva Branded Pharmaceuticals R&D, Inc. 
 
Bioanalytical Immunogenicity Evaluation  
Teva Branded Pharmaceuticals R&D, Inc. 
 
Biomarker Evaluation 
Teva Branded Pharmaceuticals R&D, Inc. 
 
Pharmacogenomic and Biomarker Sample Storage 
BioStorage Technologies, Inc.  
2910 Fortune Circle West, Suite E  
Indianapolis, IN 46241 USA 
 
BioStorage Technologies, GmbH  
Im Leuschnerpark 1b  
64347 Griesheim, Germany 
 

 
Long-Term Study–Chronic and Episodic Migraine 
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Study TV48125-CNS-30051 
 
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CLINICAL STUDY PERSONNEL CONTACT INFORMATION 
For medical issues, contact the physician listed below:  
Teva Branded Pharmaceuticals 
R&D, Inc. 
 
For operational issues, contact the operational leads listed below:  
 Teva Branded Pharmaceuticals R&D, Inc. 
 
 
For serious adverse events: 
Send by e-mail to the local safety officer/contract research organization (LSO/CRO). The email 
address will be provided in the serious adverse event form. In the event of difficulty transmitting 
the form, contact the sponsor’s study personnel identified above for further instruction. 

 
Long-Term Study–Chronic and Episodic Migraine 
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CLINICAL STUDY PROTOCOL SYNOPSIS 
Study TV48125-CNS-30051 
Title of Study: A Multicenter, Randomized, Double-Blind, Parallel-Group Study Evaluating the Long-Term Safety, 
Tolerability, and Efficacy of Subcutaneous Administration of TEV-48125 for the Preventive Treatment of Migraine 
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc. 
IND Number: 106,533 
EudraCT Number: 2015-004550-18 
Name of Active Ingredient: Humanized anti-calcitonin gene-related peptide (CGRP) monoclonal antibody 
Name of Investigational Product: TEV-48125 
Phase of Clinical Development: 3 
Number of Investigational Centers Planned: Approximately 140 
Countries Planned: Approximately 15 
Planned Study Period: 1Q/2016 (first patient in) to 2Q/2018 (last patient last visit)  
Number of Patients Planned: A total of 1842 patients, including approximately 867 patients with chronic migraine 
(CM) and 675 patients with episodic migraine (EM) from the pivotal efficacy studies (Studies TV48125-CNS-30049 
and TV48125-CNS-30050, respectively) and approximately 300 patients (approximately half of whom have a 
diagnosis of CM and half of whom have a diagnosis of EM) who have not participated in the pivotal efficacy 
studies, are eligible for enrollment in this study. A 30% drop-out rate is anticipated.  
Study Population: The study population will be composed of 3 subgroups of patients as follows: 
• 
Patients rolling over from the pivotal efficacy studies 
• 
Patients not rolling over from the pivotal efficacy studies (new patients) 
• 
Patients rolling over from the pivotal efficacy studies for antidrug antibody (ADA) evaluation only 
Female and male patients must be 18 to 70 years of age (inclusive) at the time of screening with a history of 
migraine (as defined by International Classification of Headache Disorders, 3rd revision [ICHD-3] criteria 
[Classification Committee of the IHS, 2013]) or clinical judgement suggests a migraine diagnosis for at least 
12 months prior to screening and a diagnosis of CM or EM. For new patients, the diagnosis will be prospectively 
documented via review of headache data recorded daily in an electronic headache diary device during a 28-day run-
in period.  
New patients (not rolling over from the pivotal efficacy studies) will be allowed to remain on up to 2 concomitant 
preventive medications for migraine, provided that they are on stable doses for at least 2 months of consecutive use 
prior to study entry. Similarly, patients rolling over from the pivotal efficacy studies using concomitant preventive 
medications (up to 30% of the patients in the pivotal efficacy studies may be using no more than 1 preventive 
medication for migraine) will be allowed to continue taking the medication during this study. Those not using 
preventive medications for migraine will be asked not to initiate preventive medications de novo during the safety 
extension study. Medications in scope as concomitant preventive medications are those with at least moderate 
evidence of efficacy for migraine (Silberstein et al 2012). A list of preventive medications is presented in  
Appendix A.  
Patients on acceptable concomitant preventive migraine medication(s) at study entry will be encouraged to continue 
their preventive medication regimen without change for the duration of the study. If discontinuation is clinically 

 
Long-Term Study–Chronic and Episodic Migraine 
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Study TV48125-CNS-30051 
 
9 
 
indicated by the investigator (eg, due to no further need or safety concerns), the medication may be stopped, and the 
reason must be recorded.  
Primary Objective: The primary objective of this study is to evaluate the long-term safety and tolerability of 
subcutaneous (sc) TEV-48125 in the preventive treatment of migraine. 
Secondary Objectives: There are no secondary objectives.  
Exploratory Objectives: The exploratory objectives of the study are as follows: 
• 
to evaluate the efficacy of sc TEV-48125 in patients with migraine, as assessed by the reduction of the 
number of migraine days 
• 
to evaluate the efficacy of sc TEV-48125 in patients with migraine, as assessed by the reduction in the 
number of headache days of at least moderate severity 
• 
to evaluate the efficacy of sc TEV-48125 in patients with migraine, as assessed by the reduction in the 
number of migraine days in patients not receiving concomitant migraine preventive medications at 
baseline 
• 
to evaluate the efficacy of sc TEV-48125 in patients with migraine, as assessed by the reduction in the 
number of headache days of at least moderate severity in patients not receiving concomitant migraine 
preventive medications at baseline 
• 
to evaluate the efficacy of sc TEV-48125 in patients with migraine, as assessed by the reduction in the 
number of migraine days for new patients and placebo-treated rollover patients 
• 
to evaluate the efficacy of sc TEV-48125 in patients with migraine, as assessed by the reduction in the 
number of headache days of at least moderate severity for new patients and placebo-treated rollover 
patients 
• 
to evaluate the efficacy of sc TEV-48125 in patients with migraine, as assessed by the reduction of the 
number of headache days of any severity  
• 
to evaluate the efficacy of sc TEV-48125 in patients with migraine, as assessed by the reduction of the 
use of any acute headache medications  
• 
to evaluate the efficacy of sc TEV-48125 in patients with migraine, as assessed by the discontinuation 
of use of concomitant preventive medications 
• 
to evaluate the efficacy of sc TEV-48125 in patients with migraine, as assessed by the reduction of 
migraine-related disability and change in quality of life  
• 
to evaluate the immunogenicity of TEV-48125 and the impact of ADAs on clinical outcome in patients 
exposed to sc TEV-48125 
• 
to explore the correlation between pharmacokinetic parameters and drug efficacy  
• 
to explore the relationship between genetic polymorphisms within the CGRP receptor-ligand complex 
(eg, CALCA, CALCB, CALCRL, CRCP, and RAMP) and migraine-associated genes (eg, PRDM16, 
AJAP1, TSPAN2, MEF2D, TRPM8, TGFBR2, PHACTR1, FHL5, C7orf10, MMP16, ASTN2, LRP1, 
APOA1BP, TBC1D7, FUT9, STAT6, ATP5B, and MTHFR) and mode-of-action-related pathways 
versus hypertension, migraine severity, and safety and efficacy responses 

 
Long-Term Study–Chronic and Episodic Migraine 
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Study TV48125-CNS-30051 
 
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• 
to explore the relationship between biofluid bone, angiogenic, and inflammatory biomarkers with 
TEV-48125 concentrations and efficacy responses 
Study Endpoints: 
Primary Endpoints: The safety and tolerability endpoints for this study are as follows: 
• 
occurrence of adverse events throughout the study 
• 
changes from baseline in clinical laboratory (serum chemistry, hematology, coagulation, and 
urinalysis) test results 
• 
abnormal standard 12-lead electrocardiogram (ECG) findings 
• 
changes from baseline in vital signs (pulse, systolic and diastolic blood pressure, body temperature, 
and respiratory rate) measurements  
• 
abnormal physical examination findings 
• 
abnormal local injection site tolerability findings (ie, erythema, induration, and ecchymosis) and 
occurrence of injection site pain  
• 
suicidal ideation and behavior as suggested by the electronic Columbia-Suicide Severity Rating Scale 
(eC-SSRS) 
Secondary Endpoints: There are no secondary endpoints. 
Exploratory Endpoints: Exploratory endpoints are as follows: 
• 
mean change from baseline (28-day run-in period) in the number of migraine days during the 4-week 
periods after visits 4, 7, and 13 
• 
mean change from baseline (28-day run-in period) in the number of headache days of at least moderate 
severity during the 4-week periods after visits 4, 7, and 13 
• 
mean change from baseline (28-day run-in period) in the number of migraine days during the 4-week 
periods after visits 4, 7, and 13 in patients not receiving concomitant migraine preventive medications 
at baseline 
• 
mean change from baseline (28-day run-in period) in the number of headache days of at least moderate 
severity during the 4-week periods after visits 4, 7, and 13 in patients not receiving concomitant 
migraine preventive medications at baseline 
• 
mean change from baseline (28-day run-in period) in the number of migraine days during the 4-week 
period after the 1st dose of study drug for new patients and placebo-treated rollover patients 
• 
mean change from baseline (28-day run-in period) in the number of headache days of at least moderate 
severity during the 4-week period after the 1st dose of study drug for new patients and placebo-treated 
rollover patients 
• 
mean change from baseline (28-day run-in period) in the number of headache days of any severity 
during the 4-week periods after visits 4, 7, and 13 
• 
mean change from baseline (28-day run-in period) in the number of days of use of any acute headache 
medications during the 4-week periods after visits 4, 7, and 13 

 
Long-Term Study–Chronic and Episodic Migraine 
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• 
proportion of patients reaching at least 50%, 75%, and total (100%) reduction in the number of 
headache days of at least moderate severity during the 4-week periods after visits 4, 7, and 13 
• 
proportion of patients reaching at least 50% and 75% reduction in the number of headache days of at 
least moderate severity during the 4-week periods after visit 4 who sustain the same level of response 
during the 4-week periods after visits 7 and 13 
• 
proportion of patients reaching at least 50%, 75%, and total (100%) reduction in the number of 
migraine days during the 4-week periods after visits 4, 7, and 13 
• 
proportion of patients reaching at least 50% and 75% reduction in the number of migraine days during 
the 4-week periods after visit 4 who sustain the same level of response during the 4-week periods after 
visits 7 and 13 
• 
proportion of patients discontinuing concomitant preventive medications during the treatment period  
• 
mean change from baseline (day 0) in disability score in patients with CM, as measured by the 
Headache Impact Test (HIT-6), at visits 8 and 14  
• 
mean change from baseline (day 0) in disability score in patients with EM, as measured by the 
Migraine Disability Assessment (MIDAS) questionnaire, at visits 8 and 14 
• 
mean change from baseline (day 0) in quality of life, as measured by the Migraine-Specific Quality of 
Life (MSQOL) questionnaire, at visits 8 and 14 
• 
mean change from baseline (day 0) in patient health status, as measured by the EuroQol-5 Dimension, 
5 response level version (EQ-5D-5L) questionnaire, at visits 8 and 14 
• 
assessment of patient satisfaction, as measured by the Patient Global Impression of Change (PGIC) 
scale at visits 3, 5, 8, 11, and 14 
• 
mean change from baseline (day 0) in patient depression status, as measured by the 2-item Patient 
Health Questionnaire (PHQ-2) and 9-item Patient Health Questionnaire (PHQ-9), at visits 8 and 14  
• 
mean change from baseline (day 0) in patient work productivity and activity impairment, as measured 
by the Work Productivity and Activity Impairment (WPAI) questionnaire, at visits 8 and 14 
• 
immunogenicity of TEV-48125 and the impact of ADAs on clinical outcome after sc doses of 
TEV-48125 and at 7.5 months after stopping treatment 
• 
exploratory correlation of specific genetic polymorphisms and headache response, specific migraine 
clinical features, and adverse events to medication 
• 
mean changes from baseline in biofluid biomarkers versus treatment, migraine onset/severity, and 
response status (ie, responders versus nonresponders) 
• 
correlation of exploratory biofluid biomarkers with TEV-48125 concentrations 
General Design and Methodology: This is an approximately 19-month, multicenter, randomized, double-blind, 
parallel-group study to evaluate the long-term safety, tolerability, and efficacy of sc TEV-48125 in adult patients 
with migraine.  
Female and male patients with CM and EM who complete the pivotal efficacy studies 
(Studies TV48125-CNS-30049 and TV48125-CNS-30050) and approximately 300 patients (approximately half of 
whom have a diagnosis of CM and half of whom have a diagnosis of EM) who have not participated in the pivotal 

 
Long-Term Study–Chronic and Episodic Migraine 
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Study TV48125-CNS-30051 
 
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efficacy studies may enter this long-term safety, tolerability, and efficacy study if they meet the inclusion/exclusion 
criteria and provide informed consent. In addition, patients who do not complete the pivotal efficacy studies and 
those patients who complete the pivotal efficacy studies but do not wish to continue treatment during this long-term 
safety, tolerability, and efficacy study may attend a follow-up visit during this study for the purpose of ADA 
assessment approximately 7.5 months after their last dose of study drug.  
Participation in this study for new patients (ie, patients not rolling over from the pivotal efficacy studies) will begin at 
visit 1 (screening), and those who are eligible will complete a 28-day run-in period before returning to the study center 
at visit 2 (day 0) for randomization and baseline assessments. Participation in this study for patients who rollover from 
the pivotal efficacy studies will begin at visit 2. For patients who begin this study on the same day as the end-of-
treatment (EOT) visit for the pivotal efficacy studies, EOT visit procedures/assessments must be completed before 
beginning visit 2 procedures/assessments. Baseline for patients who rollover from the pivotal efficacy studies refers to 
the 28-day run-in period (for headache variables) and visit 2 (day 0) of the pivotal efficacy studies.  
Patients randomized to the active treatment groups in the pivotal efficacy studies who continue receiving study drug in 
the current study will receive the same treatment throughout the current study. Thus, patients with CM who received a 
loading dose of TEV-48125 at 675 mg followed by monthly sc TEV-48125 at 225 mg and patients with EM who 
received monthly sc TEV-48125 at 225 mg will continue receiving monthly sc TEV-48125 at 225 mg, and patients 
with CM or EM who received sc TEV-48125 at 675 mg once in 3 months will continue receiving quarterly sc TEV-
48125 at 675 mg. 
Patients with CM randomized to the placebo treatment group in the pivotal efficacy study who continue receiving study 
drug in the current study and patients with CM who are not rolling over from the pivotal efficacy study will be 
randomized at visit 2 in a 1:1 ratio to receive 1 of 2 treatments: 
• 
sc TEV-48125 at 675 mg (loading dose) followed by 11 monthly sc doses of TEV-48125 at 225 mg 
• 
sc TEV-48125 at 675 mg once every 3 months for 12 months for a total of 4 doses 
Patients with EM randomized to the placebo treatment group in the pivotal efficacy study who continue receiving study 
drug in the current study and patients with EM who are not rolling over from the pivotal efficacy study will be 
randomized at visit 2 in a 1:1 ratio to receive 1 of 2 treatments: 
• 
monthly sc TEV-48125 at 225 mg for 12 months 
• 
sc TEV-48125 at 675 mg once every 3 months for 12 months for a total of 4 doses 
(Note: For this study and the pivotal efficacy studies, monthly dosing refers to dosing approximately every 4 weeks 
[28 days].) 
First treatment administration will occur at visit 2, and additional doses will be administered at each visit 
(approximately every 4 weeks) through visit 13. Patients will return for the EOT visit (visit 14) approximately 4 weeks 
after administration of the final dose of study drug, and they will return approximately 7.5 months (225 days [the 
approximate equivalent of 5 half-lives]) after administration of the final dose of the study drug for collection of adverse 
event and concomitant medication information and samples for pharmacokinetic, immunogenicity, and biomarker 
analyses.  
Headache information will be captured using an electronic headache diary device as follows: 
• 
For patients rolling over from the pivotal efficacy studies, headache information will be captured daily 
during the first 3 months, during the 4-week period after visit 7, and during the 4-week period after 
visit 13.  

 
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• 
For patients not rolling over from the pivotal efficacy studies, headache information will be captured 
daily during the first 4 months, during the 4-week period after visit 7, and during the 4-week period 
after visit 13. 
Assessments of migraine-related disability and change in quality of life, safety evaluations, and collection of 
pharmacokinetic, immunogenicity, and biomarker samples will be performed throughout the study at prespecified time 
points. 
Method of Blinding and Randomization: The sponsor, investigators, study staff (except for staff involved in 
bioanalytical analyses), and patients will be blinded to treatment assignment. A computer-generated master 
randomization list will be provided to drug packaging facilities. Packaging vendor(s) will package study drug into 
kits according to Good Manufacturing Practice procedures. Kits will be identical in appearance and contain a 
prefilled syringe with active drug or placebo.  
Patients will be stratified by gender, country, and baseline preventive medication use (yes, no) during the pivotal 
efficacy studies or this study if they are not rolling over from the pivotal efficacy study. 
Patients rolling over from the pivotal efficacy studies who were randomized to the active treatment groups will 
continue receiving the same treatment throughout this study. Patients rolling over from the pivotal efficacy studies 
who received placebo and patients not rolling over from the pivotal efficacy studies will be randomly assigned in a 
1:1 ratio to receive quarterly TEV-48125 at 675 mg or monthly TEV-48125 at 225 mg (Note: Patients with CM will 
receive a 675-mg loading dosing at visit 2 and TEV-48125 at 225 mg at each subsequent visit.).  
The interactive response technology (IRT) will manage initial drug supply, maintenance of adequate study drug 
supplies on site, and study randomization centrally. At the time of each study visit, the IRT will be queried, and site 
personnel will retrieve and administer a 1.5-mL volume from each syringe contained in the appropriately numbered 
kit(s). 
Study Drug Dose, Mode of Administration, and Administration Rate: Prefilled syringes (active or placebo) will 
be contained in uniquely numbered kits and stored (refrigerated at 2ºC to 8ºC) on site. Active syringes will contain 
150 mg/mL of TEV-48125, and placebo syringes will contain the same vehicle and excipients as those for active 
injections. Each kit will contain 1 prefilled syringe.   
Study drug will be administered by qualified study personnel as sc injections approximately every 4 weeks 
(28 days). In order to maintain the study blind, all patients will receive 3 injections at visits 2, 5, 8, and 11 and 
1 injection at all other visits as detailed in the table below. 
Summary of Study Drug Administration 
Treatment group in this study 
Visit 2 
Visits 5, 8, and 11 
Visits 3, 4, 6, 7, 9, 10, 
12, and 13 
Loading dose of TEV-48125 at 
675 mg followed by monthly 
TEV-48125 at 225 mg 
3 active injections 
(225 mg/1.5 mL) 
1 active injection 
(225 mg/1.5 mL) and two 
1.5-mL placebo injections 
1 active injection 
(225 mg/1.5 mL) 
Monthly TEV-48125 at 225 mg 
1 active injection 
(225 mg/1.5 mL) and two 
1.5-mL placebo injections 
1 active injection 
(225 mg/1.5 mL) and two 
1.5-mL placebo injections 
1 active injection 
(225 mg/1.5 mL) 
Quarterly TEV-48125 at 675 mg 
3 active injections 
(225 mg/1.5 mL) 
3 active injections 
(225 mg/1.5 mL) 
one 1.5-mL placebo 
injection 
The recommended sc injection sites follow the National Institutes of Health Patient Education Guidelines of 
June 2012, which are available in Appendix C of this document and at the following website: 

 
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http://www.cc nih.gov/ccc/patient_education/pepubs/subq.pdf. The suggested sites of injection are back of upper 
arms, lower abdomen/belly/waistline, and front of thighs. At visits 2, 5, 8, and 11, the injections should be given in a 
different location (eg, not in precisely the same place), and study staff member(s) responsible for administration of 
injections should inspect previous injection sites to ensure that they are free of bruising and tenderness and that 
proper rotation of sites is performed. 
The total number of sc injections and their locations will be recorded for each dosing visit. A 1.5-mL volume from 
each syringe in each visit’s kit(s) must be injected sc for dosing to be considered complete.  
Investigational Product: TEV-48125 
Duration of Patient Participation: Study participation for patients rolling into this study from the pivotal efficacy 
studies will last approximately 18.5 months (including a 12-month treatment period and a follow-up period lasting 
6.5 months). Study participation for patients not rolling into this study from the pivotal efficacy studies will last 
approximately 19.5 months (including a 28-day run-in period, a treatment period lasting 12 months, and a follow-up 
period lasting 6.5 months). Patients rolling over from the pivotal efficacy studies for ADA evaluation only will 
participate in the current study for approximately 7.5 months. 
Criteria for Inclusion:  
Patients Rolling Over from the Pivotal Efficacy Studies: Patients may be included in this study only if they meet all 
of the following criteria: 
a. 
Patient signs and dates the informed consent document. 
b. Patient must have completed the pivotal efficacy study without major protocol violations. 
c. 
Patients may continue with a stable dose/regimen of the preventive medication they were taking during 
the pivotal efficacy studies. 
d. Patient must be willing and able to comply with study restrictions, to remain at the clinic for the 
required duration during the study period, and to return to the clinic for the follow-up evaluation as 
specified in this protocol. 
Patients Not Rolling Over from the Pivotal Efficacy Studies: Patients may be included in this study only if they meet 
all of the following criteria: 
a. 
Males or females aged 18 to 70 years, inclusive, with migraine onset at ≤50 years of age. 
b. Patient signs and dates the informed consent document. 
c. 
Patient has history of migraine (according to ICHD-3 criteria [Classification Committee of the 
IHS, 2013]) or clinical judgment suggests a migraine diagnosis (not better accounted for by another 
ICHD-3 diagnosis) for ≥12 months prior to screening. 
d. Patient fulfills the following criteria for EM or CM with prospectively collected baseline information 
during the 28-day run-in period: 
− 
Patients with EM: 
○ 
headache occurring on ≥4 and ≤14 days  
○ 
on ≥4 days, fulfilling any of the following: 
 
ICHD-3 diagnostic criteria C and D for 1.1 Migraine without aura (Appendix D) 
 
ICHD-3 criteria B and C for 1.2 Migraine with aura (Appendix D) 

 
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 
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. 
− 
Patients with CM: 
○ 
headache occurring on ≥15 days 
○ 
on ≥8 days, fulfilling any of the following: 
 
ICHD-3 diagnostic criteria C and D for 1.1 Migraine without aura (Appendix D) 
 
ICHD-3 criteria B and C for 1.2 Migraine with aura (Appendix D) 
 
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. 
e. 
Not using preventive medications (presented in Appendix B) (ie, at least 5 half-lives have passed since 
last use) or using no more than 1 preventive medication (presented in Appendix A) 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 beginning the 28-day run-in period.    
f. 
Body mass index of 17.5 to 37.5 kg/m2 and a total body weight between 45 and 120 kg, inclusive 
g. All patients must be of nonchildbearing potential, defined as: 
− 
women surgically sterile by documented complete hysterectomy, bilateral oophorectomy, or 
bitubal ligations or confirmed to be postmenopausal (at least 1 year since last menses and 
follicle-stimulating hormone above 35 U/L) 
− 
men surgically sterile by documented vasectomy 
or 
if of childbearing potential, patients must meet any of the following criteria: 
− 
Patients must simultaneously use 2 forms of highly effective contraception methods (defined in 
Section 5.2) with their partners during the entire study period and for 7.5 months after the last dose 
of study drug. 
− 
Sexual abstinence is only considered a highly effective method if defined as refraining from 
heterosexual intercourse in the defined period. The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the 
subject. Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods), 
declaration of abstinence for the duration of a study, and withdrawal are not acceptable methods of 
contraception. 
h. Female patients of childbearing potential must have a negative serum beta-human chorionic 
gonadotropin (β-HCG) pregnancy test at screening (confirmed by urine dipstick β-HCG pregnancy test 
at baseline). 
i. 
The patient demonstrated compliance with the electronic headache diary during the run-in period by 
entry of headache data on a minimum of 24 out of 28 days (~85% diary compliance). 
j. 
The patient is in good health as determined by a medical and psychiatric history, medical examination, 
12-lead ECG, serum chemistry, hematology, coagulation, and urinalysis.  

 
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k. The patient must be willing and able to comply with study restrictions, to remain at the clinic for the 
required duration during the study period, and to return to the clinic for the follow-up evaluation as 
specified in this protocol. 
Patients Rolling Over from the Pivotal Efficacy Studies for ADA Assessment Only: Patients may be included in this 
study if they sign and date the informed consent document. 
Criteria for Exclusion:  
Patients Rolling Over from the Pivotal Efficacy Studies: Patients will be excluded from participating in this study if 
they meet any of the following criteria:  
a. 
Any finding that, in the judgment of the investigator, is clinically significantly abnormal, including 
hematology values, serum chemistry, coagulation tests, or urinalysis (abnormal tests may be repeated 
for confirmation) 
b. Pregnant or nursing females 
c. 
Any finding in the baseline 12-lead ECG considered clinically significant in the judgment of the 
investigator 
d. Compliance with daily diary entry lower than 75% at the last month of the double-blind treatment 
period of the pivotal efficacy study  
Patients Not Rolling Over from the Pivotal Efficacy Studies: Patients will be excluded from participating in this 
study if they meet any of the following criteria:  
a. 
Clinically significant hematological, cardiac, renal, endocrine, pulmonary, gastrointestinal, 
genitourinary, neurologic, hepatic, or ocular disease, at the discretion of the investigator 
b. 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 
c. 
History of clinically significant cardiovascular disease or vascular ischemia (such as myocardial, 
neurological [eg, cerebral ischemia], 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 
d. Known infection or history of human immunodeficiency virus, tuberculosis, or chronic hepatitis B or C 
infection  
e. 
Past or current history of cancer in the past 5 years, except for appropriately treated nonmelanoma skin 
carcinoma  
f. 
Pregnant or nursing females 
g. History of hypersensitivity reactions to injected proteins, including monoclonal antibodies 
h. Participation in a clinical study of a new chemical entity or a prescription medicine within 2 months 
before study drug administration or 5 half-lives, whichever is longer 
i. 
Any finding in the baseline 12-lead ECG considered clinically significant in the judgment of the 
investigator 

 
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j. 
Any finding that, in the judgment of the investigator, is a clinically significant abnormality, including 
serum chemistry, hematology, coagulation, and urinalysis test values (abnormal tests may be repeated 
for confirmation) 
k. Hepatic enzymes (alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase) 
>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 
l. 
Serum creatinine >1.5 × the ULN, clinically significant proteinuria, or evidence of renal disease at 
screening 
m. History of alcohol or drug abuse during the past 2 years, or alcohol or drug dependence during the past 
5 years 
n. The patient cannot participate or successfully complete the study, in the opinion of their healthcare 
provider or the investigator, for any of the following reasons: 
− 
mentally or legally incapacitated or unable to give consent for any reason 
− 
in custody due to an administrative or a legal decision, under guardianship, or institutionalized 
− 
unable to be contacted in case of emergency 
− 
has any other condition, which, in the opinion of the investigator, makes the patient inappropriate 
for inclusion in the study 
o. Patient is a study center or sponsor employee who is directly involved in the study or the relative of 
such an employee. 
Patients Rolling Over from the Pivotal Efficacy Studies for ADA Assessment Only: Not applicable. 
Measures and Time Points:  
Primary Efficacy Measure and Time Point: There is no primary efficacy measure. 
Secondary Efficacy Measures and Time Points: There are no secondary efficacy measures. 
Exploratory Efficacy Measures and Time Points: Efficacy will be assessed at time points specified in 
Table 1 (patients rolling over from the pivotal efficacy studies) and Table 2 (patients not rolling over from the 
pivotal efficacy studies) using the following exploratory efficacy measures: 
• 
exploratory efficacy endpoints derived from headache data (ie, occurrence of headache, duration of 
headache, maximum severity of headache, and acute migraine-specific medication use), which will be 
collected using an electronic headache diary device 
• 
HIT-6 (patients with CM only) 
• 
MIDAS questionnaire (patients with EM only) 
• 
PHQ-2/PHQ-9 (Note: Patients will first respond 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  
• 
EQ-5D-5L questionnaire 
• 
PGIC scale 
• 
WPAI questionnaire 

 
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Safety and Tolerability Measures and Time Points: Safety and tolerability will be assessed at time points 
specified in Table 1 (patients rolling over from the pivotal efficacy studies), Table 2 (patients not rolling over 
from the pivotal efficacy studies), and Table 3 (patients rolling over from the pivotal efficacy studies for ADA 
assessment only) using the following measures, as applicable: 
• 
inquiries about adverse events 
• 
inquiries about concomitant medication usage 
• 
vital signs measurements (systolic and diastolic blood pressure, pulse, temperature, and respiratory 
rate) 
• 
12-lead ECGs 
• 
physical examination, including weight 
• 
safety laboratory tests (serum chemistry, hematology, coagulation, and urinalysis)  
• 
serum/urine β-HCG tests (women of childbearing potential only) 
• 
injection site reaction (ie, erythema, induration, ecchymosis, and pain) assessments  
• 
eC-SSRS  
Pharmacokinetics/Biomarkers/Immunogenicity Measures and Time Points:  
Pharmacokinetic Measures and Time Points: Blood samples for pharmacokinetic analysis of TEV-48125 
will be collected from all patients for the purpose of pharmacokinetic/pharmacodynamic relationship 
assessment at time points specified in Table 1 (patients rolling over from the pivotal efficacy studies) and 
Table 2 (patients not rolling over from the pivotal efficacy studies). The pharmacodynamic parameters will be 
the efficacy responses.  
The actual date and time of each blood sample, as well as the date and time of the last study drug dose prior to 
each sample, will be recorded in the case report form. 
Immunogenicity Measures and Time Points: Blood samples for immunogenicity analysis will be collected at 
time points specified in Table 1 (patients rolling over from the pivotal efficacy studies), Table 2 (patients not 
rolling over from the pivotal efficacy studies), and Table 3 (patients rolling over from the pivotal efficacy 
studies for ADA assessment only). 
Biomarkers Measures and Time Points: Biomarker blood and urine samples will be collected at time points 
specified in Table 1 (patients rolling over from the pivotal efficacy studies) and Table 2 (patients not rolling 
over from the pivotal efficacy studies). 
A blood sample for pharmacogenomic analysis will be collected from patients who consent to 
pharmacogenomic analysis and who have not already had a sample collected during the pivotal efficacy studies 
at the baseline visit or any visit thereafter. 
Allowed and Disallowed Medications Before and During the Study: 
Concomitant (Current) Therapy: Patients will be allowed to remain on stable doses of up to 1 (patients rolling over 
from the pivotal efficacy studies) or 2 (patients not rolling over from the pivotal efficacy studies) concomitant 
preventive migraine medication for the duration of the study provided the medication has at least moderate evidence 
of efficacy as defined by guidelines (Silberstein et al 2012) and presented in Appendix A. Patients on preventive 
medication must be on a stable dose and regimen for at least 2 months of consecutive use prior to study entry. 

 
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Alternatively, patients must have discontinued the preventive medication at least 5 half-lives prior to screening. If 
discontinuation of preventive medication is clinically indicated by the investigator (eg, due to no further need or 
safety concerns), the medications may be stopped, and the reason must be recorded.  
Patients will be allowed to use acute medications to treat acute migraine attacks, as needed.  
All concomitant medications taken during the study must be recorded with indication, daily dose, and start and stop 
dates of administration. All patients will be questioned about concomitant medication use at each visit. 
Statistical Considerations:  
Sample Size Rationale: There are no statistical considerations for this sample size. A total of 1842 patients 
(867 patients from Study TV48125-CNS-30049, 675 patients from Study TV48125-CNS-30050, and approximately 
300 patients who did not participate in the pivotal efficacy studies) are planned for enrollment, and a 30% drop-out 
rate is anticipated.  
Analysis of Efficacy: Individuals with CM often complain of continuous levels of very low severity headache, 
which is typically not modified during the earlier stages of treatment. Accordingly, and following the Classification 
Committee of the International Headache Society guidelines (Silberstein et al 2008), headache days of at least 
moderate severity for both CM and EM patients will be defined for the purpose of this study as a calendar day 
(0:00 to 23:59) when the patient reports: 
• 
a day with headache pain that lasts ≥4 hours with a peak severity of at least moderate severity  
or 
• 
a day when the patient used an acute migraine-specific medication (triptans or ergots) to treat a 
headache of any severity or duration 
Migraine day is endorsed based on the same criteria as described in the pivotal studies. For CM patients, a migraine 
day is endorsed when at least 1 of the following situations occur: 
• 
a calendar day (0:00 to 23:59) demonstrating ≥4 consecutive hours of a headache meeting criteria for 
migraine with or without aura 
• 
a calendar day (0:00 to 23:59) demonstrating ≥4 consecutive hours of a headache meeting criteria for 
probable migraine, a migraine subtype where only 1 migraine criterion is missing 
• 
a calendar day (0:00 to 23:59) demonstrating a headache of any duration that was treated with 
migraine-specific medications (triptans and ergot compounds) 
For EM patients, a migraine day is endorsed when at least 1 of the following situations occur:  
• 
a calendar day (0:00 to 23:59) demonstrating ≥2 consecutive hours of a headache meeting criteria for 
migraine with or without aura 
• 
a calendar day (0:00 to 23:59) demonstrating ≥2 consecutive hours of a headache meeting criteria for 
probable migraine, a migraine subtype where only 1 migraine criterion is missing 
• 
a calendar day (0:00 to 23:59) demonstrating a headache of any duration that was treated with 
migraine-specific medications (triptans and ergot compounds) 
Analysis of Primary Efficacy Endpoint: There is no primary efficacy endpoint.  
Analysis of Secondary Efficacy Endpoints: There are no secondary endpoints for this study. 
Multiple Comparisons and Multiplicity: Not applicable  

 
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Analysis of Exploratory Efficacy Endpoints: All efficacy variables will be summarized descriptively overall, by 
indication, and by treatment group. For continuous variables, descriptive statistics (number [n] of patients, mean, 
standard deviation [SD], standard error of mean, median, minimum, and maximum) will be provided for actual 
values and changes from baseline to each visit. For categorical variables, frequency and percentage will be provided. 
For rollover patients, their baseline is defined as the baseline in the pivotal efficacy studies.  
Safety and Tolerability Analyses: All adverse events will be coded using the Medical Dictionary for Regulatory 
Activities. Each patient will be counted only once in each preferred term or system organ class category for the 
analyses of safety. Summaries will be presented for all adverse events (overall and by severity), adverse events 
determined by the investigator to be related to study treatment, defined as related or with missing relationship 
(overall and by severity), serious adverse events, and adverse events causing withdrawal from the study. Patient 
listings of serious adverse events and adverse events leading to withdrawal will be presented. 
Local tolerability findings will be listed and summarized descriptively. 
Changes in laboratory and vital signs measurement data will be summarized descriptively. All values will be 
compared with prespecified boundaries to identify potentially clinically significant changes or values, and such 
values will be listed. 
The use of concomitant medications will be summarized by therapeutic class using descriptive statistics. 
Concomitant medications will include all medications taken while the patient is treated with study drug. 
Safety data will be summarized descriptively overall, by diagnosis, and by treatment group. For continuous 
variables, descriptive statistics (n, mean, SD, median, minimum, and maximum) will be provided for actual values 
and changes from baseline to each time point. For categorical variables, patient counts and percentages will be 
provided. 
Descriptive summaries of serious adverse events, patient withdrawals due to adverse events, and potentially 
clinically significant abnormal values (clinical laboratory or vital signs) based on predefined criteria will also be 
provided. 
If any patient dies during the study, a listing of deaths will be provided, and all relevant information will be 
discussed in the patient narrative included in the clinical study report. 
Pharmacokinetic Analysis: Pharmacokinetic plasma concentration results (TEV-48125) will be tabulated 
descriptively at each planned sampling time point by indication and treatment group. 
Pharmacokinetic/Pharmacodynamic Analysis: The pharmacokinetic/pharmacodynamic relationship will be 
estimated by compartmental techniques. The pharmacokinetic parameters will be based on TEV-48125 
measurements. The pharmacodynamic parameters will be the efficacy responses.  
The pharmacokinetic/pharmacodynamic relationship will be estimated using the most appropriate model after 
comparing different candidate models for their quality of fit. Covariates that may affect the 
pharmacokinetic/pharmacodynamic relationship will be tested for inclusion in the model. This analysis will be 
reported separately. 
Immunogenicity Analysis: Summary of immunogenicity results will be provided, and the incidence of 
immunogenicity will be calculated. The impact of immunogenicity on the pharmacokinetic profile, drug efficacy, 
and clinical safety will be evaluated. This impact analysis will be reported separately. 
Biomarkers Analysis: Biomarker analysis will include logistic regression, receiver operating characteristic curves, 
and summary statistics. Results will be reported separately.  

 
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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
AMENDMENT HISTORY .............................................................................................................2 
INVESTIGATOR AGREEMENT...................................................................................................3 
COORDINATING INVESTIGATOR AGREEMENT ...................................................................4 
CLINICAL LABORATORY AND OTHER DEPARTMENTS AND INSTITUTIONS ..............5 
CLINICAL STUDY PERSONNEL CONTACT INFORMATION ...............................................7 
CLINICAL STUDY PROTOCOL SYNOPSIS...............................................................................8 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................30 
1. 
BACKGROUND INFORMATION ...........................................................................32 
1.1. 
Introduction .................................................................................................................32 
1.2. 
Name and Description of Investigational Product ......................................................33 
1.3. 
Findings from Nonclinical and Clinical Studies .........................................................33 
1.3.1. 
Nonclinical Studies .....................................................................................................33 
1.3.2. 
Clinical Studies ...........................................................................................................34 
1.3.2.1. 
Clinical Pharmacology Studies ...................................................................................34 
1.3.2.2. 
Clinical Safety and Efficacy Studies ..........................................................................35 
1.4. 
Known and Potential Risks and Benefits to Human Patients .....................................36 
1.4.1. 
Known and Potential Risks and Benefits of TEV-48125 ...........................................36 
1.4.1.1. 
Risks of TEV-48125 ...................................................................................................36 
1.4.1.2. 
Benefits of TEV-48125 ...............................................................................................36 
1.4.2. 
Overall Risk and Benefit Assessment for This Study ................................................37 
1.5. 
Selection of Drugs and Dosages .................................................................................37 
1.6. 
Compliance Statement ................................................................................................38 
1.7. 
Population to be Studied and Justification ..................................................................38 
1.8. 
Location and Timing of Study ....................................................................................39 
2. 
PURPOSE OF THE STUDY AND STUDY OBJECTIVES .....................................40 
2.1. 
Purpose of the Study ...................................................................................................40 
2.2. 
Study Objectives .........................................................................................................40 
2.2.1. 
Primary Objective .......................................................................................................40 
2.2.2. 
Secondary Objectives .................................................................................................40 
2.2.3. 
Exploratory Objectives ...............................................................................................40 

 
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2.3. 
Study Endpoints ..........................................................................................................41 
2.3.1. 
Primary Efficacy Endpoint .........................................................................................41 
2.3.2. 
Secondary Efficacy Endpoints ....................................................................................41 
2.3.3. 
Exploratory Efficacy Endpoints .................................................................................41 
2.3.4. 
Safety and Tolerability Endpoints ..............................................................................43 
2.3.5. 
Pharmacokinetic/Immunogenicity/Biomarker Endpoints ..........................................43 
2.3.5.1. 
Pharmacokinetic Endpoints ........................................................................................43 
2.3.5.2. 
Immunogenicity Endpoint ..........................................................................................43 
2.3.5.3. 
Biomarker Endpoints ..................................................................................................43 
3. 
STUDY DESIGN .......................................................................................................44 
3.1. 
General Design and Study Schema.............................................................................44 
3.2. 
Justification for Study Design ....................................................................................49 
3.3. 
Primary and Secondary Efficacy Measures and Time Points .....................................49 
3.3.1. 
Primary Efficacy Measure and Time Points ...............................................................49 
3.3.2. 
Secondary Efficacy Measures and Time Points .........................................................49 
3.4. 
Safety and Tolerability Measures and Time Points ....................................................49 
3.5. 
Pharmacokinetic/Immunogenicity/Biomarker Measures and Time Points ................50 
3.5.1. 
Pharmacokinetic Measures and Time Points ..............................................................50 
3.5.2. 
Immunogenicity Measures and Time Points ..............................................................50 
3.5.3. 
Biomarker Measures and Time Points ........................................................................50 
3.6. 
Exploratory Measures and Time Points ......................................................................50 
3.7. 
Randomization and Blinding ......................................................................................51 
3.8. 
Maintenance of Randomization and Blinding ............................................................51 
3.8.1. 
Randomization ............................................................................................................51 
3.8.2. 
Blinding/Unblinding ...................................................................................................51 
3.8.3. 
Data Monitoring Committee .......................................................................................52 
3.9. 
Drugs Used in the Study .............................................................................................52 
3.10. 
Drug Supply and Accountability ................................................................................53 
3.10.1. 
Drug Storage and Security ..........................................................................................53 
3.10.2. 
Drug Accountability ...................................................................................................53 
3.11. 
Duration of Patient Participation and Justification .....................................................53 
3.12. 
Stopping Rules and Discontinuation Criteria .............................................................53 
3.13. 
Source Data Recorded on the Case Report Form .......................................................54 

 
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3.14. 
Study Procedures ........................................................................................................54 
3.14.1. 
Procedures for Screening of Patients Not Rolling Over from the Pivotal 
Efficacy Studies (Visit 1 [Day -28]) ...........................................................................62 
3.14.2. 
Procedures Before Study Drug Treatment ..................................................................63 
3.14.2.1. 
Patients Not Rolling Over from the Pivotal Efficacy Studies ....................................63 
3.14.2.2. 
Patients Rolling Over from the Pivotal Efficacy Studies (Visit 2 [Day 0]) ................65 
3.14.2.3. 
Patients Rolling Over from the Pivotal Efficacy Studies for Antidrug 
Antibody Assessment Only (Visit 2 [Day 0]) .............................................................66 
3.14.3. 
Procedures During Study Drug Treatment .................................................................66 
3.14.3.1. 
Treatment Period (Days 0 Through 336 ± 5 Days [Visits 2 Through 14]) .................66 
3.14.4. 
Procedures After Study Drug Treatment ....................................................................74 
3.14.4.1. 
Patients Rolling Over from the Pivotal Efficacy Studies and New Patients 
(Final Visit [Visit 15 (Day 533)]) ...............................................................................74 
3.14.4.2. 
Patients Rolling Over from the Pivotal Efficacy Studies for Antidrug 
Antibody Assessment Only (Visit 16 [Antidrug Antibody Collection]) ....................75 
3.14.5. 
Unscheduled Visits .....................................................................................................75 
4. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................76 
4.1. 
Patient Inclusion Criteria ............................................................................................76 
4.1.1. 
Patients Rolling Over from the Pivotal Efficacy Studies ...........................................76 
4.1.2. 
Patients Not Rolling Over from the Pivotal Efficacy Studies ....................................76 
4.2. 
Patient Exclusion Criteria ...........................................................................................78 
4.2.1. 
Patients Rolling Over from the Pivotal Efficacy Studies ...........................................78 
4.2.2. 
Patients Not Rolling Over from the Pivotal Efficacy Studies ....................................78 
4.3. 
Justification for Key Inclusion and Exclusion Criteria...............................................79 
4.4. 
Withdrawal Criteria and Procedures ...........................................................................80 
5. 
TREATMENT OF PATIENTS ..................................................................................81 
5.1. 
Drugs Administered During the Study .......................................................................81 
5.2. 
Restrictions .................................................................................................................82 
5.3. 
Prior and Concomitant Therapy or Medication ..........................................................82 
5.4. 
Procedures for Monitoring Patient Compliance .........................................................83 
5.5. 
Total Blood Volume ...................................................................................................83 
6. 
ASSESSMENT OF EFFICACY ................................................................................85 
6.1. 
Primary Efficacy Measure and Justification ...............................................................85 
6.2. 
Electronic Headache Diary .........................................................................................85 

 
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6.3. 
Six-Item Headache Impact Test ..................................................................................85 
6.4. 
Migraine Disability Assessment Questionnaire ..........................................................86 
6.5. 
Two-Item Patient Health Questionnaire/9-Item Patient Health Questionnaire ..........86 
6.6. 
Migraine-Specific Quality of Life Questionnaire .......................................................86 
6.7. 
EuroQol-5 Dimension Questionnaire .........................................................................87 
6.8. 
Patient Global Impression of Change Scale ...............................................................87 
6.9. 
Work Productivity and Activity Impairment Questionnaire ......................................87 
7. 
ASSESSMENT OF SAFETY .....................................................................................89 
7.1. 
Adverse Events ...........................................................................................................89 
7.1.1. 
Definition of an Adverse Event ..................................................................................89 
7.1.2. 
Recording and Reporting Adverse Events ..................................................................90 
7.1.3. 
Severity of an Adverse Event .....................................................................................91 
7.1.4. 
Relationship of an Adverse Event to the Study Drug .................................................91 
7.1.5. 
Serious Adverse Events ..............................................................................................92 
7.1.5.1. 
Definition of a Serious Adverse Event .......................................................................92 
7.1.5.2. 
Expectedness ...............................................................................................................92 
7.1.5.3. 
Reporting a Serious Adverse Event ............................................................................93 
7.1.6. 
Protocol-Defined Adverse Events of Special Interest ................................................94 
7.1.7. 
Withdrawal Due to an Adverse Event ........................................................................95 
7.1.8. 
Overdose of Study Drug .............................................................................................95 
7.1.9. 
Protocol Deviations Because of an Adverse Event ....................................................95 
7.2. 
Pregnancy ...................................................................................................................96 
7.3. 
Clinical Laboratory Tests ...........................................................................................96 
7.3.1. 
Serum Chemistry ........................................................................................................97 
7.3.2. 
Hematology .................................................................................................................97 
7.3.3. 
Coagulation .................................................................................................................98 
7.3.4. 
Urinalysis ....................................................................................................................98 
7.3.5. 
Other Clinical Laboratory Tests .................................................................................99 
7.3.5.1. 
Human Chorionic Gonadotropin Tests .......................................................................99 
7.3.5.2. 
Follicle-Stimulating Hormone Tests ...........................................................................99 
7.4. 
Vital Signs ..................................................................................................................99 
7.5. 
Electrocardiography ....................................................................................................99 
7.6. 
Physical Examinations ..............................................................................................100 

 
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7.7. 
Electronic Columbia-Suicide Severity Rating Scale ................................................100 
7.8. 
Concomitant Therapy or Medication ........................................................................101 
7.9. 
Immunogenicity ........................................................................................................101 
7.10. 
Injection Site Assessments .......................................................................................101 
7.11. 
Methods and Timing of Assessing, Recording, and Analyzing Safety Data ............102 
8. 
ASSESSMENT OF PHARMACOKINETICS/IMMUNOGENICITY/ 
BIOMARKERS ........................................................................................................103 
8.1. 
Pharmacokinetic Variables .......................................................................................103 
8.1.1. 
Specimen Sampling and Handling ............................................................................103 
8.1.2. 
Shipment and Analysis of Samples ..........................................................................103 
8.2. 
Immunogenicity Testing ...........................................................................................104 
8.2.1. 
Blood Sampling and Handling..................................................................................104 
8.2.2. 
Shipment and Analysis of Samples ..........................................................................104 
8.3. 
Assessment of Exploratory Biomarkers ...................................................................104 
8.3.1. 
Pharmacogenomic Assessment .................................................................................105 
8.3.2. 
Specimen Sampling and Handling ............................................................................106 
8.3.3. 
Shipment and Analysis of Samples ..........................................................................106 
8.4. 
Methods and Timing of Assessing, Recording, and Analyzing Clinical 
Pharmacology Data ...................................................................................................106 
9. 
STATISTICS ............................................................................................................107 
9.1. 
Sample Size and Power Considerations ...................................................................107 
9.2. 
Analysis Sets .............................................................................................................107 
9.2.1. 
Intent-to-Treat Analysis Set ......................................................................................107 
9.2.2. 
Safety Analysis Set ...................................................................................................107 
9.2.3. 
Full Analysis Set .......................................................................................................107 
9.2.4. 
Antidrug Antibody Only Analysis Set ......................................................................107 
9.3. 
Data Handling Conventions ......................................................................................107 
9.4. 
Study Population .......................................................................................................107 
9.4.1. 
Patient Disposition ....................................................................................................108 
9.4.2. 
Demographic and Baseline Characteristics ..............................................................108 
9.5. 
Efficacy Analysis ......................................................................................................108 
9.5.1. 
Primary Endpoint ......................................................................................................109 
9.5.2. 
Secondary Endpoints ................................................................................................109 

 
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9.5.3. 
Exploratory Endpoints ..............................................................................................109 
9.5.4. 
Planned Method of Analysis .....................................................................................110 
9.5.4.1. 
Primary Efficacy Analysis ........................................................................................110 
9.5.4.2. 
Sensitivity Analysis ..................................................................................................110 
9.5.4.3. 
Secondary Efficacy Analysis ....................................................................................110 
9.5.4.4. 
Exploratory Efficacy Analysis ..................................................................................110 
9.6. 
Multiple Comparisons and Multiplicity....................................................................111 
9.7. 
Safety and Tolerability Endpoints and Analysis ......................................................111 
9.7.1. 
Safety and Tolerability Endpoints ............................................................................111 
9.7.2. 
Safety and Tolerability Analysis ..............................................................................111 
9.8. 
Pharmacokinetic Analysis ........................................................................................112 
9.9. 
Biomarker Analysis ..................................................................................................112 
9.10. 
Pharmacokinetic/Pharmacodynamic Analysis ..........................................................112 
9.11. 
Immunogenicity Analysis .........................................................................................112 
9.12. 
Planned Interim Analysis ..........................................................................................112 
9.13. 
Reporting Deviations from the Statistical Plan ........................................................113 
10. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.......................................114 
11. 
QUALITY CONTROL AND QUALITY ASSURANCE .......................................115 
11.1. 
Protocol Amendments and Protocol Deviations and Violations ..............................115 
11.1.1. 
Protocol Amendments ..............................................................................................115 
11.1.2. 
Protocol Violations ...................................................................................................115 
11.2. 
Information to Study Personnel ................................................................................115 
11.3. 
Study Monitoring ......................................................................................................116 
11.4. 
Clinical Product Complaints .....................................................................................116 
11.4.1. 
Product Complaint Information Needed from the Investigational Center ................117 
11.4.2. 
Handling the Study Drug at the Investigational Center ............................................117 
11.4.3. 
Adverse Events or Serious Adverse Events Associated with a Product 
Complaint .................................................................................................................118 
11.4.4. 
Documenting a Product Complaint ..........................................................................118 
11.5. 
Audit and Inspection .................................................................................................118 
12. 
ETHICS ....................................................................................................................119 
12.1. 
Informed Consent .....................................................................................................119 

 
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12.2. 
Health Authorities and Independent Ethics Committees/Institutional Review 
Boards .......................................................................................................................119 
12.3. 
Confidentiality Regarding Study Patients ................................................................119 
12.4. 
Declaration of the End of the Clinical Study ............................................................120 
12.5. 
Registration of the Clinical Study.............................................................................120 
13. 
DATA HANDLING, DATA QUALITY CONTROL, AND RECORD 
KEEPING .................................................................................................................121 
13.1. 
Data Collection .........................................................................................................121 
13.2. 
Data Quality Control .................................................................................................121 
13.3. 
Archiving of Case Report Forms and Source Documents ........................................122 
13.3.1. 
Sponsor Responsibilities ...........................................................................................122 
13.3.2. 
Investigator Responsibilities .....................................................................................122 
14. 
FINANCING AND INSURANCE ...........................................................................124 
15. 
REPORTING AND PUBLICATION OF RESULTS ..............................................125 
16. 
REFERENCES .........................................................................................................126 
17. 
SUMMARY OF CHANGES TO PROTOCOL .......................................................129 
17.1. 
Amendment 01 Dated 30 March 2016 ......................................................................129 
17.2. 
Administrative Letter Dated 01 March 2016 ............................................................165 
17.3. 
Administrative Letter Dated 22 January 2016 ..........................................................167 
APPENDIX A. PREVENTIVE MEDICATIONS ALLOWED FOR THE DURATION 
OF THE STUDY ......................................................................................................168 
APPENDIX B. DISALLOWED MEDICATIONS FOR THE DURATION OF THE 
STUDY .....................................................................................................................169 
APPENDIX C. NATIONAL INSTITUTES OF HEALTH PATIENT EDUCATION 
GUIDELINES OF JUNE 2012 .................................................................................170 
APPENDIX D. ICHD-3 DIAGNOSTIC CRITERIA ...............................................................177 
APPENDIX E. GUIDANCE ON SAFETY MONITORING ...................................................178 
APPENDIX F. CLINICAL CRITERIA FOR DIAGNOSING ANAPHYLAXIS ...................181 

 
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LIST OF TABLES 
Table 1: 
Study Procedures and Assessments for Patients Rolling Over from the 
Pivotal Efficacy Studies ..............................................................................................55 
Table 2: 
Study Procedures and Assessments for Patients Not Rolling Over from the 
Pivotal Efficacy Studies ..............................................................................................58 
Table 3: 
Study Procedures and Assessments for Patients Rolling Over from the 
Pivotal Efficacy Studies for Antidrug Antibody Assessment Only............................62 
Table 4: 
Study Drug Administration by Treatment Group and Visit .......................................81 
Table 5: 
Blood Volumes for Patients Rolling Over from the Pivotal Efficacy Studies ...........83 
Table 6: 
Blood Volumes for Patients Not Rolling Over from the Pivotal Efficacy 
Studies.........................................................................................................................84 
Table 7: 
Severity of Pain Scale for Injection Site Assessments .............................................102 
Table 8: 
Changes to the Protocol ............................................................................................130 
 

 
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LIST OF FIGURES 
Figure 1: 
Study Schema for Patients with Chronic Migraine ....................................................47 
Figure 2: 
Study Schema for Patients with Episodic Migraine ...................................................48 
 
 

 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Table of Abbreviations 
Abbreviation 
Term 
β-HCG 
beta-human chorionic gonadotropin 
21CFR 
Title 21 Code of Federal Regulations (United States) 
ADA 
antidrug antibody 
ALP 
alkaline phosphatase  
ALT 
alanine aminotransferase  
AST 
aspartate aminotransferase  
BP 
blood pressure 
CBC 
complete blood count 
CDMS 
clinical data management system  
CGRP 
calcitonin gene-related peptide 
CM 
chronic migraine 
Cmax 
maximum observed plasma drug concentration 
CRF 
case report form (refers to any media used to collect study data [ie, paper or 
electronic]) 
CRO 
contract research organization 
DNA 
deoxyribonucleic acid 
eC-SSRS 
electronic Columbia-Suicide Severity Rating Scale 
ECG 
electrocardiography/electrocardiogram 
EDTA 
ethylenediaminetetraacetic acid  
EM 
episodic migraine 
EOT 
end-of-treatment (visit) 
EQ-5D-5L 
EuroQol-5 Dimension, 5 response level version 
EU 
European Union 
FAS 
full analysis set 
FDA 
Food and Drug Administration (United States) 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transpeptidase 
HIT-6 
6-item Headache Impact Test 
ICH 
International Conference on Harmonisation 

 
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Abbreviation 
Term 
ICHD-3 
International Classification of Headache Disorders, 3rd revision 
IEC 
Independent Ethics Committee 
IgG 
immunoglobulin G 
IgM 
immunoglobulin M 
INR 
international normalized ratio  
IRB 
Institutional Review Board 
IRT 
interactive response technology 
ITT 
intent-to-treat  
iv 
intravenous(ly) 
LSO 
local safety officer  
MIDAS 
Migraine Disability Assessment 
MSQOL 
Migraine-Specific Quality of Life  
n 
number 
NOAEL 
no-observed-adverse-effect level 
NR 
nonrollover patients 
PBO 
placebo 
PEF 
peak expiratory flow 
PGIC 
Patient Global Impression of Change 
PHQ-2 
2-item Patient Health Questionnaire 
PHQ-9 
9-item Patient Health Questionnaire 
QC 
quality control 
RBC 
red blood cell 
RNA 
ribonucleic acid 
sc 
subcutaneous(ly) 
SD 
standard deviation 
SOP 
standard operating procedure 
SUSAR 
suspected unexpected serious adverse reaction 
t½ 
terminal elimination half-life  
tmax 
time to maximum observed drug concentration 
ULN 
upper limit of the normal range 
V 
visit 
WBC 
white blood cell 
WPAI 
Work Productivity and Activity Impairment 

 
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1. 
BACKGROUND INFORMATION 
1.1. 
Introduction 
Migraine is a prevalent condition characterized by attacks of headache and associated symptoms 
(such as nausea, photophobia, or phonophobia). The 2 most common forms of migraine, 
migraine without aura and migraine with aura, occur on less than 15 days per month and are 
referred to as episodic forms of migraine (ie, EM) (Lipton et al 2007). However, approximately 
3% of individuals with EM evolve, in any given year, to a significantly more disabling condition 
called chronic migraine (CM) (Bigal et al 2008, Lipton et al 2007, Scher et al 2003). Individuals 
with CM present with headaches of any severity on 15 or more days per month and have full-
blown migraine on at least 8 days per month (Classification Committee of the International 
Headache Society [IHS], 2013). A sizable proportion of individuals with CM experiences daily 
headaches and, therefore, faces considerable disability (Bigal and Lipton 2008).  
The pathophysiology of migraine involves central and peripheral events. Activation of structures 
in the brainstem are involved in the modulation of sensory activity, which is impaired during 
migraine attacks. Chronic dysfunction in these structures predisposes migraineurs not only to 
migraine attacks, but to increased headache frequency (Goadsby and Hargreaves 2008). 
Furthermore, the activation of these structures is also associated with inflammation and protein 
extravasation at the level of the meningeal blood vessels, muscles and other structures innervated 
by the trigeminal nerve. This combination of peripheral insults (inflammation and plasma protein 
extravasation) with impairment of the inhibitory pain mechanisms at the level of brainstem is 
paramount to frequent migraines (Goadsby et al 2002).  
Calcitonin gene-related peptide (CGRP) is a well-studied neuropeptide found at the centers of 
the migraine processes, both centrally and peripherally (Eftekhari and Edvinsson 2010). Its role 
in migraine pathophysiology was suggested more than 20 years ago (Edvinsson and Goadsby 
1990, Goadsby et al 1990). Jugular levels of CGRP are increased during migraine attacks, and 
intravenous (iv) CGRP administration induces migraine-like headache in most individuals with 
migraine (Ashina et al 2000, Hansen et al 2010). Calcitonin gene-related peptide is therefore 
involved in the pathophysiology of migraine at all levels, peripherally (vasodilation, 
inflammation and protein extravasation), at the trigeminal ganglion, and inside the brain (Ho et al 
2010). Inhibition of CGRP has demonstrated efficacy in the treatment of EM (Hewitt et al 2011, 
Ho et al 2008, Olesen et al 2004). 
The goals of migraine treatment are to relieve pain, restore function, reduce headache frequency, 
and to prevent progression of EM to CM. Pharmacological interventions for the treatment of 
migraine include acute (symptomatic) treatments and daily preventive medications. The latter is 
indicated for patients with CM and may be appropriate patients with EM who have significant 
disability with migraine attacks, contraindications to triptans or other vasoactive medications, 
significant adverse effects from triptans, and patients with severe or prolonged attacks (Lipton 
and Silberstein 2015). Currently available drug therapies for preventive treatment of migraine 
include antiepileptic drugs, beta blockers, triptans, antidepressants, angiotensin receptor 
blockers, angiotensin-converting enzyme inhibitors, serotonergic agents, calcium channel 
blockers, nonsteroidal anti-inflammatory drugs, opioids, and direct vascular smooth muscle 

 
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relaxants. Although there are more than 40 medications within these classes of drugs that are 
used with varying response rates to prevent migraine, only 5 marketed drugs are approved by the 
Food and Drug Administration (FDA) in the United States (US) for the preventive treatment of 
migraine; 4 of them are approved for the prophylaxis of migraine: propranolol, timolol maleate, 
divalproex sodium, and topiramate. The clinical studies (Brandes et al 2004, Klapper 1997, 
Mathew et al 1995, Nadelmann et al 1986, Silberstein et al 2004) that supported registration of 
these drugs for this indication were conducted before the establishment of CM as a single entity 
and generally included patients with headaches on less than 15 days per month. Only 
1 medication, onabotulinumtoxinA, is approved for prophylaxis of CM (Lipton and Silberstein 
2015). 
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; these 
activities can lead to unwanted consequences such as cell lysis, opsonization, and cytokine 
release and inflammation (Armour et al 1999, Zeller et al 2008). 
The pharmacokinetics and tolerability of TEV-48125 (iv doses ranging from 0.2 to 2000 mg and 
subcutaneous [sc] doses of 225 and 900 mg) has been well-characterized in the Phase 1 
development program (see Section 1.3.2.1). Furthermore, the safety and effectiveness of 
TEV-48125 has been demonstrated in a randomized double-blind, placebo-controlled Phase 2b 
study 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 study of 2 sc dosing regimens of TEV-48125 
(monthly TEV-48125 at 675 or 225 mg) in patients with EM (see Section 1.3.2.2). The 
acceptable tolerability, long terminal elimination half-life (t½, approximately 45 days) and ability 
to administer sc make TEV-48125 an attractive therapeutic candidate for the preventive 
treatment of CM and EM. 
1.2. 
Name and Description of Investigational Product 
TEV-48125 (formerly LBR-101, PF-04427429, or RN307) is a fully humanized IgG2a/kappa 
monoclonal antibody derived from a murine precursor. TEV-48125 is being developed for 
administration by the sc route. A more detailed description of the product is given in Section 3.9.  
1.3. 
Findings from Nonclinical and Clinical Studies 
1.3.1. 
Nonclinical Studies 
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 monkey. 

 
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Safety pharmacology parameters of TEV-48125 were assessed in the pivotal 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 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 iv or sc. 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 pivotal 6-month chronic toxicity study in 
monkeys following once-weekly sc dosing at dosage levels of up to 300 mg/kg/week, achieving 
high exposure throughout the study, no microscopic findings 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 typical of a humanized 
IgG2 molecule, with low mean plasma clearance, low volume of distribution at steady state, and 
a long t½. Exposure as defined by the maximum observed plasma drug 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, pivotal 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. 
Further details may be found in the current Investigator’s Brochure.  
1.3.2. 
Clinical Studies 
To date, TEV-48125 has been studied in 6 Phase 1 studies in healthy volunteers and 
2 Phase 2b studies in patients with migraine. In total, 484 subjects (118 healthy volunteers and 
366 migraine patients) received at least 1 dose of TEV-48125 via iv or sc administration. 
A brief summary of clinical pharmacology and clinical safety and efficacy studies of TEV-48125 
follows. Further details may be found in the current Investigator’s Brochure.  
1.3.2.1. 
Clinical Pharmacology Studies 
A total of 118 subjects received at least 1 dose of TEV-48125 across 6 completed Phase 1 studies 
at doses ranging from 0.2 through 2000 mg. Studies included 2 single-dose-escalation 
pharmacokinetic and pharmacodynamic studies in healthy men (Studies B0141001 and 

 
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B0141002); a 2-cohort, placebo-controlled, cross-over study to examine the acute effects 
administration of TEV-48125 on capsaicin flare response in healthy men (Study B0141006); a 
parallel-group, repeat-dose study of TEV-48125 in healthy men and women (Study B0141007); 
a single-dose study evaluating the safety, tolerability, and pharmacokinetics of doses up to 
2000 mg administered to healthy women (Study LBR-101-008); and a single-dose study 
comparing the safety, tolerability, absolute bioavailability, and pharmacokinetics if sc and iv 
TEV-48125 in healthy men and women (Study LBR-101-011). 
Based on noncompartmental analysis, TEV-48125 exposure increases with dose in an 
approximately dose-proportional manner from 225 to 900 mg following sc administration and 
over the dose range from 100 to 2000 mg following iv infusion. The Cmax occurred near the end 
of the iv infusion (median time to Cmax [tmax] of 1 to 5 hours after the start of the infusion), and 
Cmax was prolonged as indicated by the delayed tmax (median tmax 96 to 108 hours postdose) after 
sc administration. The mean t½ following sc administration was similar to that observed after iv 
administration for each dose level. The t½ ranged from approximately 642 to 770 hours 
(approximately 27 to 32 days) at the 225-mg dose level, and the t½ ranged from approximately 
1140 to 1200 hours (approximately 48 to 50 days) at the 900-mg dose level. Absolute 
bioavailability of the sc dose was approximately 55%. 
TEV-48125 was well tolerated with favorable safety profile. The treatment-emergent adverse 
events reported in the Phase 1 studies were predominantly mild to moderate in severity. A 
specific “pattern of adverse events” that could be associated with a dose or a dose range of 
TEV-48125 has not been identified, nor has a maximally tolerated dose been identified. The 
most common treatment-emergent adverse events reported were headache, nasopharyngitis, 
gastroenteritis, and back pain. There were no deaths. One serious adverse event reported as 
“thoracic aortic aneurysm aggravated” in an individual receiving a single iv 300-mg TEV-48125 
dose resolved. 
TEV-48125 does not appear to be 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 studies. 
1.3.2.2. 
Clinical Safety and Efficacy Studies 
The safety, tolerability, and efficacy of TEV-48125 was evaluated in migraine patients in 
2 Phase 2b studies. The 1st study was a multicenter, randomized, double-blind, 
placebo-controlled, parallel-group study comparing the efficacy, safety, tolerability, and 
pharmacokinetics of 2 doses of TEV-48125 with placebo in 264 patients with CM 
(Study LBR-101-021). Following a 28-day run-in period, participants were randomized and 
treated sc once monthly for 3 months. One active group received a 1st dose of 675 mg followed 
by 225 mg on the subsequent 2 months. The other active group received 900 mg per month. The 
mean change in headache hours relative to baseline for each TEV-48125 dose arm was 
significantly different from the placebo arm at 3 months (primary endpoint), and the study was 

 
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also positive at 2 and 1 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 serious treatment-related adverse events 
were reported. Most adverse events were mild to moderate. No safety signals were observed in 
the clinical laboratory tests, vital signs, physical examination, or ECGs.  
The 2nd study was a multicenter, randomized, double-blind, placebo-controlled, parallel-group 
study comparing the efficacy, safety, tolerability, and pharmacokinetics of 2 doses of TEV-
48125 with placebo in 297 patients with EM (Study LBR-101-022). Following a 28-day run-in 
period, participants were randomized and treated sc once monthly for 3 months. Two active 
doses 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 at month 3 relative to baseline for both TEV-
48125 dose arms was significantly different from placebo at 3 (primary endpoint), 2, and 
1 months. Secondary and exploratory endpoints were also positive for the duration of the study. 
Both doses were well tolerated, and no serious treatment-related adverse events were reported. 
Most adverse events were mild to moderate and the lowest dose had a numerically lower number 
of adverse events relatively to placebo. No safety signals were observed in the clinical laboratory 
tests, vital signs, physical examination, or ECGs.  
1.4. 
Known and Potential Risks and Benefits to Human Patients  
1.4.1. 
Known and Potential Risks and Benefits of TEV-48125  
Information regarding risks and benefits of TEV-48125 to human patients may be found in the 
current Investigator’s Brochure. 
1.4.1.1. 
Risks of TEV-48125 
Identified risks (adverse drug reactions) of TEV-48125 include injection site erythema, 
administration site pain, injection site pain, injection site pruritus, injection site dermatitis, 
infusion-related reaction, and drug hypersensitivity. None of the identified risks are considered 
important risks. 
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. 
As described in Section 1.3.2.2, sc TEV-48125 has generally been well tolerated over the ranges 
of doses evaluated (single doses of 0.02 to 2000 mg in healthy volunteers, multiple doses of 
30 to 300 mg in healthy volunteers, and multiple doses of 225 to 900 mg in migraine patients). 
The most common treatment-emergent adverse events across the clinical program were mild to 
moderate transient general administration site disorders/reactions. Other commonly reported 
treatment-emergent adverse events were headache, back pain, and upper respiratory tract 
infection.  
1.4.1.2. 
Benefits of TEV-48125 
As described in Section 1.3.2.2, results from Phase 2b clinical studies have demonstrated 
statistically significant reductions in mean headache hours after 1, 2, and 3 months of 
TEV-48125 treatment in patients with CM and statistically significant reductions in monthly 

 
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migraine days after 1, 2, and 3 months of TEV-48125 treatment in patients with EM. Results for 
several secondary/exploratory endpoints also showed TEV-48125 to be superior to placebo. 
1.4.2. 
Overall Risk and Benefit Assessment for This Study 
Based on the current safety profile and the demonstrated efficacy of the sc TEV-48125 dosage 
form, the overall risk and benefit assessment for this study is favorable. 
1.5. 
Selection of Drugs and Dosages 
A detailed description of study drug administration is presented in Section 5.1. 
This study is a multi-arm evaluation of the long-term safety, tolerability, and efficacy of the 
TEV-48125 doses and regimens administered in the pivotal efficacy studies. The doses and 
regimens for the pivotal efficacy studies are supported by data gathered from animal and human 
(healthy volunteer) pharmacokinetic studies, in vivo pharmacodynamic neurogenic inflammation 
experiments in primates, safety and efficacy results of the Phase 2b studies in patients with CM 
and EM, and population pharmacokinetic and pharmacokinetic/pharmacodynamic models and 
simulations.  
This study will include patients who are rolling over from the pivotal efficacy studies, patients 
who are not rolling over from the pivotal efficacy studies, and patients who are rolling over from 
the pivotal efficacy studies for ADA assessment only (ie, these patients will not receive study 
drug during the current study). Treatments for patients receiving study drug during the current 
study will be as follows: 
• Patients who complete the pivotal efficacy studies and who received active study drug 
will continue the dose and regimen they received in those studies for 12 months.  
• Patients rolling over from the pivotal efficacy studies who received placebo and 
patients not rolling over will be randomly assigned in a 1:1 ratio to receive monthly 
TEV-48125 at 225 mg (Note: Patients with CM will receive a 675-mg loading dosing 
at visit 2 and TEV-48125 at 225 mg at each subsequent visit) or quarterly TEV-48125 
at 675 mg.  
The doses and regimens selected for the long-term safety study enable a long-term safety 
evaluation of the doses administered in the pivotal studies as well as examine the maintenance of 
effect with increased exposure. This study provides the placebo-treated patients from pivotal 
studies and new patients the opportunity to receive potential benefit from therapeutic doses, and 
it is the customary way to conduct a long-term safety study by which patients are allowed to 
continue on their current dose and regimen. 
In general, all patients will receive at least 12 months exposure to TEV-48125 in accordance 
with the International Conference on Harmonisation (ICH) E1 guideline: "the extent of 
population exposure to assess clinical safety for drugs intended for long-term treatment of 
non life-threatening conditions". This long-term exposure is supported by the long-term 
(6-month) chronic toxicity study in monkeys. In this study, male and female cynomolgus 
monkeys received a weekly sc administration of TEV-48125 at a dose of 0, 10, 100, or 
300 mg/kg. These doses are equivalent to 290, 2900, and 6900 mg, respectively, administered 
weekly for a duration of 6 months in humans. No mortalities occurred during the conduct of the 

 
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study, and no test article-related clinical observations and alterations in body weight were noted. 
Test article-related abnormalities were noted. 
1.6. 
Compliance Statement 
This study will be conducted in full accordance with the ICH Good Clinical Practice (GCP) 
Consolidated Guideline (E6) and any applicable national and local laws and regulations 
(eg, Title 21 Code of Federal Regulations [21CFR] Parts 11, 50, 54, 56, 312, and 314, European 
Union [EU] Directive 2001/20/EC on the approximation of the laws, regulations and 
administrative provisions of the Member States relating to the implementation of GCP in the 
conduct of clinical studies on medicinal products for human use). Any episode of noncompliance 
will be documented. 
The investigator is responsible for performing the study in accordance with this protocol and the 
applicable GCP guidelines referenced above for collecting, recording, and reporting the data 
accurately and properly. Agreement of the investigator to conduct and administer this study in 
accordance with the protocol will be documented in separate study agreements with the sponsor 
and other forms as required by national authorities in the country where each investigational 
center is located.  
The investigator is responsible for ensuring the privacy, health, and welfare of the patients during 
and after the study and must ensure that trained personnel are immediately available in the event 
of a medical emergency. The investigator and the applicable study staff must be familiar with the 
background to, and requirements of, the study and with the properties of the study drug(s) as 
described in the Investigator’s Brochure or prescribing information.  
The principal investigator at each investigational center has the overall responsibility for the 
conduct and administration of the study at that center and for contacts with study management, 
with the Independent Ethics Committee/Institutional Review Board (IEC/IRB), and with local 
authorities. 
1.7. 
Population to be Studied and Justification 
The study population will be composed of 3 subgroups of patients as follows: 
• Patients rolling over from the pivotal efficacy studies 
• Patients not rolling over from the pivotal efficacy studies (new patients) 
• Patients rolling over from the pivotal efficacy studies for ADA evaluation only 
Female and male patients must be 18 to 70 years of age (inclusive) at the time of screening with 
a history of migraine (as defined by International Classification of Headache Disorders, 
3rd revision [ICHD-3] criteria [Classification Committee of the IHS, 2013]) or clinical judgement 
suggests a migraine diagnosis for at least 12 months prior to screening and a diagnosis of CM or 
EM. For new patients, the diagnosis will be prospectively documented via review of headache 
data recorded daily in an electronic headache diary device during a 28-day run-in period. 
New patients (not rolling over from the pivotal efficacy studies) will be allowed to remain on up 
to 2 concomitant preventive medications for migraine, provided that they were on a stable doses 
for at least 2 months prior to study entry. Similarly, patients rolling over from the pivotal 
efficacy studies using concomitant preventive medications (up to 30% of the patients in the 

 
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pivotal efficacy studies may be using no more than 1 preventive medication for migraine) will be 
allowed to continue taking the medication during this study. Those not using preventive 
medications for migraine will be asked not to initiate preventive medications de novo during the 
safety extension study. Medications in scope as concomitant preventive medications are those 
with at least moderate evidence of efficacy for migraine (Silberstein et al 2012). A list of 
preventive medications is presented in Appendix A.  
Patients on acceptable concomitant preventive medication(s) at study entry will be encouraged to 
continue their preventive medication regimen without change for the duration of the study. If 
discontinuation is clinically indicated by the investigator (eg, due to no further need or safety 
concerns), the medication may be stopped, and the reason must be recorded.  
Episodic migraine is a highly prevalent condition and a significant cause of disability, especially 
in patients with high frequency EM. Furthermore, 3% to 6% of patients with EM evolve in any 
given year to CM, which is significantly more disabling (Scher et al 2003). Risk factors for 
evolution from EM to CM include high headache frequency and the use of specific classes of 
acute medication, including barbiturates and opiates (Bigal et al 2008).  
Aside from limiting migraine-associated disability, it is expected that effective preventive 
migraine medications should decrease the likelihood that a patient with EM will evolve to CM. 
However, available preventive medications have variable response rates and are associated with 
adverse effects. In addition, only 4 are approved for preventive treatment of EM (Lipton and 
Silberstein 2015, Shamliyan et al 2013). 
Patients with CM have significant disability despite availability of many pharmacological 
(approved and off label) and nonpharmacological treatments. The persistence of CM-associated 
disability likely reflects variable response rates, adverse effects of available preventive 
treatments, and the paucity of approved preventive treatments (Lipton and Silberstein 2015, 
Shamliyan et al 2013). 
1.8. 
Location and Timing of Study  
This study is planned to be conducted in approximately 15 countries, including North and South 
America, the European Union, and Asia Pacific, at approximately 140 centers. It is expected to 
start in 1Q 2016 and have a duration of approximately 2.5 years. Additional centers will be 
added, if needed. Expected duration of the study may also be extended dependent on enrollment 
speed and other factors. 

 
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2. 
PURPOSE OF THE STUDY AND STUDY OBJECTIVES 
2.1. 
Purpose of the Study 
This study is being conducted to evaluate the long-term safety, tolerability, and efficacy of sc 
administration of TEV-48125 in adult patients with CM or EM. Results of this study may 
contribute to the registration of TEV-48125 for these indications.  
2.2. 
Study Objectives 
2.2.1. 
Primary Objective 
The primary objective of the study is to evaluate the long-term safety and tolerability of sc 
TEV-48125 in the preventive treatment of migraine.  
2.2.2. 
Secondary Objectives 
There are no secondary objectives. 
2.2.3. 
Exploratory Objectives 
The exploratory objectives of the study are as follows: 
• to evaluate the efficacy of sc TEV-48125 in patients with migraine, as assessed by the 
reduction of the number of migraine days  
• to evaluate the efficacy of sc TEV-48125 in patients with migraine, as assessed by the 
reduction in the number of headache days of at least moderate severity 
• to evaluate the efficacy of sc TEV-48125 in patients with migraine, as assessed by the 
reduction in the number of migraine days in patients not receiving concomitant 
migraine preventive medications at baseline 
• to evaluate the efficacy of sc TEV-48125 in patients with migraine, as assessed by the 
reduction in the number of headache days of at least moderate severity in patients not 
receiving concomitant migraine preventive medications at baseline 
• to evaluate the efficacy of sc TEV-48125 in patients with migraine, as assessed by the 
reduction in the number of migraine days for new patients and placebo-treated 
rollover patients 
• to evaluate the efficacy of sc TEV-48125 in patients with migraine, as assessed by the 
reduction in the number of headache days of at least moderate severity for new 
patients and placebo-treated rollover patients 
• to evaluate the efficacy of sc TEV-48125 in patients with migraine, as assessed by the 
reduction of the number of headache days of any severity  
• to evaluate the efficacy of sc TEV-48125 in patients with migraine, as assessed by the 
reduction of the use of any acute headache medications  

 
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• to evaluate the efficacy of sc TEV-48125 in patients with migraine, as assessed by the 
discontinuation of use of concomitant preventive medications 
• to evaluate the efficacy of sc TEV-48125 in patients with migraine, as assessed by the 
reduction of migraine-related disability and change in quality of life  
• to evaluate the immunogenicity of TEV-48125 and the impact of ADAs on clinical 
outcome in patients exposed to sc TEV-48125 
• to explore the correlation between pharmacokinetic parameters and drug efficacy 
• to explore the relationship between genetic polymorphisms within the CGRP 
receptor-ligand complex (eg, CALCA, CALCB, CALCRL, CRCP, and RAMP) and 
migraine-associated genes (eg, PRDM16, AJAP1, TSPAN2, MEF2D, TRPM8, 
TGFBR2, PHACTR1, FHL5, C7orf10, MMP16, ASTN2, LRP1, APOA1BP, 
TBC1D7, FUT9, STAT6, ATP5B, and MTHFR) and mode-of-action-related 
pathways versus hypertension, migraine severity, and safety and efficacy responses 
• to explore the relationship between biofluid bone, angiogenic, and inflammatory 
biomarkers with TEV-48125 concentrations and efficacy responses 
2.3. 
Study Endpoints  
2.3.1. 
Primary Efficacy Endpoint 
There is no primary efficacy endpoint. 
2.3.2. 
Secondary Efficacy Endpoints  
There are no secondary efficacy endpoints. 
2.3.3. 
Exploratory Efficacy Endpoints 
Exploratory efficacy endpoints are as follows: 
• mean change from baseline (28-day run-in period) in the number of migraine days 
during the 4-week periods after visits 4, 7, and 13 
• mean change from baseline (28-day run-in period) in the number of headache days of 
at least moderate severity during the 4-week periods after visits 4, 7, and 13 
• mean change from baseline (28-day run-in period) in the number of migraine days 
during the 4-week periods after visits 4, 7, and 13 in patients not receiving 
concomitant migraine preventive medications at baseline 
• mean change from baseline (28-day run-in period) in the number of headache days of 
at least moderate severity during the 4-week periods after visits 4, 7, and 13 in 
patients not receiving concomitant migraine preventive medications at baseline 
• mean change from baseline (28-day run-in period) in the number of migraine days 
during the 4-week period after the 1st dose of study drug for new patients and 
placebo-treated rollover patients 

 
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• mean change from baseline (28-day run-in period) in the number of headache days of 
at least moderate severity during the 4-week period after the 1st dose of study drug for 
new patients and placebo-treated rollover patients 
• mean change from baseline (28-day run-in period) in the number of headache days of 
any severity during the 4-week periods after visits 4, 7, and 13 
• mean change from baseline (28-day run-in period) in the number of days of use of 
any acute headache medications during the 4-week periods after visits 4, 7, and 13 
• proportion of patients reaching at least 50%, 75%, and total (100%) reduction in the 
number of headache days of at least moderate severity during the 4-week periods 
after visits 4, 7, and 13 
• proportion of patients reaching at least 50% and 75% reduction in the number of 
headache days of at least moderate severity during the 4-week periods after visit 4 
who sustain the same level of response during the 4-week periods after visits 7 and 13 
• proportion of patients reaching at least 50%, 75%, and total (100%) reduction in the 
number of migraine days during the 4-week periods after visits 4, 7, and 13 
• proportion of patients reaching at least 50% and 75% reduction in the number of 
migraine days during the 4-week periods after visit 4 who sustain the same level of 
response during the 4-week periods after visits 7 and 13 
• proportion of patients discontinuing concomitant preventive medications during the 
treatment period  
• mean change from baseline (day 0) in disability score in patients with CM, as 
measured by the 6-item Headache Impact Test (HIT-6), at visits 8 and 14  
• mean change from baseline (day 0) in disability score in patients with EM, as 
measured by the Migraine Disability Assessment (MIDAS) questionnaire, at visits 8 
and 14 
• mean change from baseline (day 0) in quality of life, as measured by the 
Migraine-Specific Quality of Life (MSQOL) questionnaire, at visits 8 and 14 
• mean change from baseline (day 0) in patient health status, as measured by the 
EuroQol-5 Dimension, 5 response level version (EQ-5D-5L) questionnaire, at visits 8 
and 14 
• assessment of patient satisfaction, as measured by the Patient Global Impression of 
Change (PGIC) scale at visits 3, 5, 8, 11, and 14 
• mean change from baseline (day 0) in patient depression status, as measured by the 
2-item Patient Health Questionnaire (PHQ-2) and 9-item Patient Health 
Questionnaire (PHQ-9), at visits 8 and 14  
• mean change from baseline (day 0) in patient work productivity and activity 
impairment, as measured by the Work Productivity and Activity Impairment (WPAI) 
questionnaire, at visits 8 and 14 

 
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2.3.4. 
Safety and Tolerability Endpoints 
The safety and tolerability endpoints for this study are as follows: 
• occurrence of adverse events throughout the study 
• changes from baseline in clinical laboratory (serum chemistry, hematology, 
coagulation, and urinalysis) test results 
• abnormal standard 12-lead ECG findings 
• changes from baseline in vital signs (pulse, systolic and diastolic blood pressure, body 
temperature, and respiratory rate) measurements  
• abnormal physical examination findings 
• abnormal local injection site tolerability findings (ie, erythema, induration, and 
ecchymosis) and occurrence of injection site pain  
• suicidal ideation and behavior as suggested by the electronic Columbia-Suicide 
Severity Rating Scale (eC-SSRS) 
2.3.5. 
Pharmacokinetic/Immunogenicity/Biomarker Endpoints 
2.3.5.1. 
Pharmacokinetic Endpoints 
There are no prespecified pharmacokinetic endpoints. 
2.3.5.2. 
Immunogenicity Endpoint 
The immunogenicity endpoint is the immunogenicity of TEV-48125 and the impact of ADAs on 
clinical outcome after sc doses of TEV-48125 and at 7.5 months after stopping treatment. 
2.3.5.3. 
Biomarker Endpoints 
The biomarker endpoints are as follows: 
• exploratory correlation of specific genetic polymorphisms and headache response, 
specific migraine clinical features, and adverse events to medication 
• mean changes from baseline in biofluid biomarkers versus treatment, migraine 
onset/severity, and response status (ie, responders versus nonresponders) 
• correlation of exploratory biofluid biomarkers with TEV-48125 concentrations 

 
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3. 
STUDY DESIGN 
3.1. 
General Design and Study Schema 
This is an approximately 19-month, multicenter, randomized, double-blind, parallel-group study 
to evaluate the long-term safety, tolerability, and efficacy of sc TEV-48125 in adult patients with 
migraine. For patients who complete the pivotal efficacy studies of TEV-48125 
(Studies TV48125-CNS-30049 and TV48125-CNS-30050), the study will consist of a 12-month 
treatment period and a 6.5-month follow-up period. For patients who have not participated in a 
pivotal efficacy study, the study will consist of a screening visit and 28-day run-in period, a 
12-month treatment period, and a 6.5-month follow-up period. 
Female and male patients 18 to 70 years of age, inclusive, with CM and EM who complete the 
pivotal efficacy studies (Studies TV48125-CNS-30049 and TV48125-CNS-30050) and 
approximately 300 patients (approximately half of whom have a diagnosis of CM and half of 
whom have a diagnosis of EM) who have not participated in the pivotal efficacy studies may 
enter this long-term safety, tolerability, and efficacy study if they meet the inclusion/exclusion 
criteria and provide informed consent. In addition, patients who do not complete the pivotal 
efficacy studies and those patients who complete the pivotal efficacy studies but do not wish to 
continue treatment during this long-term safety, tolerability, and efficacy study may attend a 
follow-up visit during this study for the purpose of ADA assessment approximately 7.5 months 
after their last dose of study drug.  
New patients (not rolling over from the pivotal efficacy studies) using up to 2 preventive 
medications at the time of the screening visit will be allowed to remain on the medications if the 
medications have at least moderate evidence of efficacy for migraine (Silberstein et al 2012) and 
provided that they are on stable doses for at least 2 months prior to study entry. Similarly, 
patients rolling over from the pivotal efficacy studies using concomitant preventive medications 
(up to 30% of the patients in the pivotal efficacy studies may be using no more than 1 preventive 
medication for migraine) will be allowed to continue taking the medication during this study. 
Patients will be encouraged to continue their preventive medication regimen without change for 
the duration of the study. If discontinuation is clinically indicated by the investigator (eg, due to 
no further need or safety concerns), the medication may be stopped, and the reason must be 
recorded. A list of preventive medications is presented in Appendix A. Patients who are not 
using preventive medications for migraine at the time of study entry will be asked not to initiate 
preventive medications de novo during the safety extension study. Patients will be allowed to use 
acute medications to treat acute migraine attacks, as needed. 
Patients who have not participated in a pivotal efficacy study will complete the informed consent 
process and be screened for eligibility at visit 1. Eligible patients will enter a 28-day run-in 
period during which they will complete daily electronic headache diary entries. After completing 
the run-in period, patients will be asked to return to the study center on day 0 (visit 2). Patients 
who have confirmed CM (≥15 headache days with migraine on ≥8 days) or EM with headache 
days on ≥4 and ≤14 days with migraine on ≥3 days and meet all other eligibility criteria 
(including electronic headache diary compliance criteria during the 28-day run-in period) at 
visit 2 will complete baseline assessments/procedures before beginning study treatment. 

 
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Patients who rollover from the pivotal efficacy studies and are eligible to participate in this study 
will begin this study at visit 2 after completing the informed consent process. Visit 2 may 
correspond with the end-of-treatment (EOT) visit (visit 5) or it may be a separate visit. For 
patients who begin this study on the same day as EOT visit (visit 5) for the pivotal efficacy studies, 
EOT visit procedures/assessments must be completed before beginning visit 2 
procedures/assessments. Baseline for patients rolling over from the pivotal efficacy studies refers 
to the 28-day run-in period (for headache variables only) and visit 2 (day 0) of the pivotal 
efficacy studies. 
Patients randomized to the active treatment groups in the pivotal efficacy studies who continue 
receiving study drug in the current study will receive the same treatment throughout the current 
study. Thus, patients with CM who received a loading dose of TEV-48125 at 675 mg followed 
by monthly sc TEV-48125 at 225 mg and patients with EM who received monthly sc 
TEV-48125 at 225 mg will continue receiving monthly sc TEV-48125 at 225 mg, and patients 
with CM or EM who received sc TEV-48125 at 675 mg once in 3 months will continue receiving 
quarterly sc TEV-48125 at 675 mg.  
Patients with CM randomized to the placebo treatment group in the pivotal efficacy study who 
continue receiving study drug in the current study and patients with CM who are not rolling over 
from the pivotal efficacy study will be randomized at visit 2 in a 1:1 ratio to receive 1 of 
2 treatments: 
• sc TEV-48125 at 675 mg (loading dose) followed by 11 monthly sc doses of 
TEV-48125 at 225 mg 
• sc TEV-48125 at 675 mg once every 3 months for 12 months for a total of 4 doses 
Patients with EM randomized to the placebo treatment group in the pivotal efficacy study who 
continue receiving study drug in the current study and patients with EM who are not rolling over 
from the pivotal efficacy study will be randomized at visit 2 in a 1:1 ratio to receive 1 of 
2 treatments: 
• monthly sc TEV-48125 at 225 mg for 12 months 
• sc TEV-48125 at 675 mg once every 3 months for 12 months for a total of 4 doses 
(Note: For this study and the pivotal efficacy studies, monthly dosing refers to dosing 
approximately every 4 weeks [28 days].) 
First treatment administration (ie, for this study) will occur at visit 2, and additional doses will be 
administered at each visit (approximately every 4 weeks) through visit 13. Patients will return for 
the EOT visit (visit 14) approximately 4 weeks after administration of the final dose of study 
drug, and they will return approximately 7.5 months (225 days [the approximate equivalent of 
5 half-lives]) after administration of the final dose of the study drug for collection of adverse 
event and concomitant medication information and samples for pharmacokinetic, 
immunogenicity, and biomarker analyses.  
Headache information will be captured using an electronic headache diary device as follows: 
• For patients rolling over from the pivotal efficacy studies, headache information will 
be captured daily during the first 3 months, during the 4-week period after visit 7, and 
during the 4-week period after visit 13.  

 
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• For patients not rolling over from the pivotal efficacy studies, headache information 
will be captured daily during the first 4 months, during the 4-week period after visit 7, 
and during the 4-week period after visit 13. 
Assessments of migraine-related disability and change in quality of life (using the HIT-6 or 
MIDAS questionnaire, PHQ-2/PHQ-9, PGIC scale, MSQOL questionnaire, EQ-5D-5L 
questionnaire, and WPAI questionnaire), safety evaluations, and collection of pharmacokinetic, 
immunogenicity, and biomarker samples will be performed throughout the study according to the 
schedules of assessments (Table 1, Table 2, and Table 3) and Section 3.14.  
Patients who withdraw from the study before completing the 12-month treatment period will 
have EOT visit (visit 14) procedures and assessments performed at their final visit, and they will 
be asked to return for the follow-up visit approximately 7.5 months (225 days [the approximate 
equivalent of 5 half-lives]) after their last dose of study drug.  
The study schemas for patients with CM and EM who receive study drug in the current study are 
presented in Figure 1 and Figure 2, respectively. 
The end of the study is defined as the date the last patient attends the follow-up visit (visit 15). 
A total of 1842 patients, including approximately 867 patients with CM and 675 patients with 
EM from the pivotal efficacy studies and approximately 300 patients (approximately half of 
whom have a diagnosis of CM and half of whom have a diagnosis of EM) who have not 
participated in the pivotal efficacy studies, are eligible for enrollment in this study.

 
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Figure 1: 
Study Schema for Patients with Chronic Migraine 
V1
V15
675 mg
225 mg
225 mg
225 mg
225 mg
225 mg
PBO
675 mg
PBO
PBO
675 mg
PBO
PBO
675 mg
PBO
PBO
675 mg
225 mg
225 mg
225 mg
225 mg
225 mg
225 mg
225 mg
225 mg
V3
V4
V5, V8, V11
V1
V2
V3
V4
V5b
Run-in
V2 
PBO
Run-in (NR)
Study TV48125-CNS-30049
Study TV48125-CNS-30051
V7, V10, V13 V14
V6, V9, V12
  PBO & NRa
 
a Patients not rolling over from the pivotal efficacy study who meet eligibility criteria after completing a 28-day run-in period and patients rolling over from the 
pivotal efficacy study who received placebo will be randomized in a 1:1 ratio at visit 2 to receive a loading dose of TEV-48125 at 675 mg followed by monthly 
TEV-48125 at 225 mg or TEV-48125 at 675 mg quarterly.  
b For patients who begin this study (visit 2) on the same day as the EOT visit (visit 5) of the pivotal efficacy studies, the EOT visit procedures/assessments for 
the pivotal efficacy study must be completed before beginning visit 2 procedures/assessments.  
EOT=end-of-treatment; NR=nonrollover patients; PBO=placebo; V=visit.  
 
 

 
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Figure 2: 
Study Schema for Patients with Episodic Migraine 
V1
V15
PBO
PBO
675 mg
PBO
PBO
675 mg
PBO
PBO
PBO
PBO
225 mg
225 mg
225 mg
225 mg
225 mg
225 mg
225 mg
225 mg
225 mg
Study TV48125-CNS-30051
V14
Run-in (NR)
675 mg
V2 
V3
V4
V5, V8, V11
V6, V9, V12
V7, V10, V13
Study TV48125-CNS-30050
  PBO & NRa
V1
V2
V3
V4
V5b
Run-in
 
a Patients rolling over from the pivotal efficacy study who received placebo and patients not rolling over from the pivotal efficacy study who meet eligibility 
criteria after completing a 28-day run-in period will be randomized in a 1:1 ratio at visit 2 to receive quarterly TEV-48125 at 675 mg or monthly TEV-48125 at 
225 mg. 
b For patients who begin this study (visit 2) on the same day as the EOT visit (visit 5) of the pivotal efficacy study, the EOT visit procedures/assessments for the 
pivotal efficacy study must be completed before beginning visit 2 procedures/assessments. 
EOT=end-of-treatment; NR=nonrollover patients; PBO=placebo; V=visit. 
 

 
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3.2. 
Justification for Study Design 
A randomized, double-blind, parallel-group design is appropriate given the objectives of this 
study.  
The dosing regimen planned for this study is consistent with the dosing regimen in the pivotal 
efficacy studies. 
In order to blind the treatment groups based on both dose-volume and number of injections, each 
patient will receive three 1.5-mL sc injections (three 1.5-mL sc injections of active drug, one 
1.5-mL sc injection of active drug and two 1.5-mL injections of placebo, or three 1.5-mL 
injections of placebo) at visits 2, 5, 8, and 11. See Section 5.1 for additional details.  
3.3. 
Primary and Secondary Efficacy Measures and Time Points 
All efficacy measures are exploratory. 
3.3.1. 
Primary Efficacy Measure and Time Points 
There is no primary efficacy measure. 
3.3.2. 
Secondary Efficacy Measures and Time Points 
There are no secondary efficacy measures. 
3.4. 
Safety and Tolerability Measures and Time Points 
Safety and tolerability will be assessed at time points specified in Table 1 (patients rolling over 
from the pivotal efficacy studies), Table 2 (patients not rolling over from the pivotal efficacy 
studies), and Table 3 (patients rolling over from the pivotal efficacy studies for ADA assessment 
only) using the following measures, as applicable: 
• inquiries about adverse events 
• inquiries about concomitant medication usage 
• vital signs measurements (systolic and diastolic blood pressure, pulse, temperature, 
and respiratory rate) 
• 12-lead ECGs 
• physical examination, including weight 
• safety laboratory tests (serum chemistry, hematology, coagulation, and urinalysis)  
• serum/urine beta-human chorionic gonadotropin (β-HCG) tests (women of 
childbearing potential only) 
• injection site reaction (ie, erythema, induration, ecchymosis, and pain) assessments  
• eC-SSRS  
A description of the safety measures is provided in Section 7. 

 
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3.5. 
Pharmacokinetic/Immunogenicity/Biomarker Measures and Time 
Points 
A description of the pharmacokinetic, biomarker, and immunogenicity measures is provided in 
Section 8. 
3.5.1. 
Pharmacokinetic Measures and Time Points 
Blood samples for pharmacokinetic analysis of TEV-48125 will be collected from all patients for 
the purpose of pharmacokinetic/pharmacodynamic relationship assessment at time points 
specified in Table 1 (patients rolling over from the pivotal efficacy studies) and Table 2 (patients 
not rolling over from the pivotal efficacy studies). The pharmacodynamic parameters will be the 
efficacy responses.  
The actual date and time of each blood sample, as well as the date and time of the last study drug 
dose prior to each sample, will be recorded in the case report form (CRF). 
3.5.2. 
Immunogenicity Measures and Time Points 
Blood samples for immunogenicity analysis will be collected at time points specified in Table 1 
(patients rolling over from the pivotal efficacy studies), Table 2 (patients not rolling over from 
the pivotal efficacy studies), and Table 3 (patients rolling over from the pivotal efficacy studies 
for ADA assessment only).  
3.5.3. 
Biomarker Measures and Time Points 
Biomarker blood and urine samples will be collected at time points specified in Table 1 (patients 
rolling over from the pivotal efficacy studies) and Table 2 (patients not rolling over from the 
pivotal efficacy studies). 
A blood sample for pharmacogenomic analysis will be collected from patients who consent to 
pharmacogenomic analysis and who have not already had a sample collected during the pivotal 
efficacy studies at the baseline visit or any visit thereafter. 
3.6. 
Exploratory Measures and Time Points 
Efficacy will be assessed at time points specified in Table 1 (patients rolling over from the 
pivotal efficacy studies) and Table 2 (patients not rolling over from the pivotal efficacy studies) 
using the following exploratory efficacy measures: 
• exploratory efficacy endpoints derived from headache data (ie, occurrence of 
headache, duration of headache, maximum severity of headache, and acute 
migraine-specific medication use), which will be collected using an electronic 
headache diary device 
• HIT-6 (patients with CM only) 
• MIDAS questionnaire (patients with EM only) 
• PHQ-2/PHQ-9 (Note: Patients will first respond 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 
• PGIC scale 
• WPAI questionnaire 
A description of the efficacy measures is provided in Section 6.  
3.7. 
Randomization and Blinding 
The sponsor, investigators, study staff (except for staff involved in bioanalytical analyses), and 
patients will be blinded to treatment assignment. The Sponsor will be unblinded when the pivotal 
efficacy studies have been unblinded. A computer-generated master randomization list will 
provided to drug packaging facilities. Packaging vendor(s) will package study drug into kits 
according to Good Manufacturing Practice procedures. Kits will be identical in appearance, and 
will contain 1 prefilled syringe with active drug or placebo. Adequate kit supply for upcoming 
study visits will be managed by interactive response technology (IRT) and kept (refrigerated at 
2°C to 8°C) on site. 
Patients will be stratified by gender, country, and baseline preventive medication use (yes, no) 
during the pivotal efficacy studies or this study if they are not rolling over from the pivotal 
efficacy study. 
Patients rolling over from the pivotal efficacy studies who were randomized to the active 
treatment groups will continue receiving the same treatment throughout the study. Patients 
rolling over from the pivotal efficacy studies who received placebo and patients not rolling over 
will be randomly assigned in a 1:1 ratio to receive quarterly TEV-48125 at 675 mg or monthly 
TEV-48125 at 225 mg (Note: Patients with CM will receive a 675-mg loading dosing at visit 2 
and TEV-48125 at 225 mg at each subsequent visit.).  
The IRT will manage initial drug supply, maintenance of adequate study drug supplies on site, 
and study randomization centrally. At the time of each study visit, the IRT will be queried, and 
site personnel will retrieve and administer a 1.5-mL volume from each syringe contained in the 
appropriately numbered kit(s). 
3.8. 
Maintenance of Randomization and Blinding 
3.8.1. 
Randomization  
Patient randomization codes will be maintained in a secure location within Teva Clinical Supply 
Chain. At the time of analysis, when treatment codes are needed, the Teva statistician assigned to 
the study will make a request to unblind and will receive the unblinded codes. 
3.8.2. 
Blinding/Unblinding 
Pharmacokinetic data may be assessed during the study. Personnel responsible for bioanalysis 
will be provided with the randomization code in order to facilitate the analysis. However, the 
personnel responsible for bioanalysis will not have access to clinical safety and efficacy data and 
will provide concentration data to other personnel in a manner that will not identify individual 
patients (ie, a dummy patient identifier will be linked to an individual patient’s concentration 
data).  

 
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For information about personnel who may be aware of treatment assignments, see Section 3.7. 
These individuals will not be involved in conduct of any study procedures or assessment of any 
adverse events. 
In case of a serious adverse event or pregnancy, or in cases when knowledge of the study drug 
assignment is needed to make treatment decisions, the investigator may unblind the patient’s 
drug assignment as deemed necessary, mainly in emergency situations. Individual treatment 
codes, indicating the treatment randomization for each randomized patient, will be available to 
the investigator(s) and/or pharmacist(s) at the study center via the IRT, both via telephone and 
internet. If possible, the sponsor should be notified of the event prior to breaking of the code. If 
this is not possible, the sponsor should be notified immediately afterwards, and the patient’s drug 
code assignment should not be revealed. Breaking of the treatment code can always be 
performed by the site without prior approval by the sponsor. 
When a blind is broken, the patient will be withdrawn from the study, and the event will be 
recorded onto the CRF. The circumstances leading to the breaking of the code should be fully 
documented in the investigator’s study files and in the patient’s source documentation. 
Treatment assignment should not be recorded in any study documents or source documents. 
In blinded studies, for adverse events that are defined as suspected unexpected serious adverse 
reaction (SUSAR) (ie, reasonable possibility; see Section 7.1.4), Global Patient Safety & 
Pharmacovigilance may independently request that the treatment code be revealed (on a 
case-by-case basis) to comply with regulatory requirements. The report will be provided in an 
unblinded manner for regulatory submission. If this occurs, blinding will be maintained for the 
investigator and for other personnel involved in the conduct, analysis, and reporting of the data. 
3.8.3. 
Data Monitoring Committee 
This is not applicable. 
3.9. 
Drugs Used in the Study 
Additional details may also be found in the current version of the Investigator’s Brochure for 
TEV-48125.  
TEV-48125 will be provided as a sterile, unpreserved, colorless to slightly yellow, aqueous 
solution for injection, supplied in a 2.25-mL prefilled syringe for single-use administration, 
containing 150 mg/mL in 16±2.5 mM L-histidine, 0.2-mg/mL polysorbate 80, 84-mg/mL 
sucrose, and 0.136-mg/mL ethylenediaminetetraacetic acid (EDTA). 
TEV-48125 will be administered sc at a dose of 225 mg at visits 2 through 13. Each dose will be 
separated by approximately 4 weeks (28 days). A more detailed description of administration 
procedures is given in Section 5.1. 
This is an uncontrolled study with no other study drug.  

 
Long-Term Study–Chronic and Episodic Migraine 
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3.10. 
Drug Supply and Accountability 
3.10.1. 
Drug Storage and Security 
The study drug (TEV-48125) must be stored refrigerated at 2°C to 8°C (36°F to 46°F), protected 
from light; the site should have a process for monitoring the drug storage temperature. 
TEV-48125 supplies must be kept in a secure area (eg, locked refrigerator).  
3.10.2. 
Drug Accountability 
Each study drug shipment will include a packing slip listing the contents of the shipment, drug 
return instructions, and any applicable forms.  
Each investigator is responsible for ensuring that deliveries of study drug and other study 
materials from Teva are correctly received, recorded, handled, stored, accounted for, and used in 
accordance with this protocol. In addition, each investigator is responsible for ensuring that study 
drug and other material from Teva are correctly disposed of, safely and properly in accordance 
with local regulation.  
A record of study drug accountability (ie, study drug and other materials received, used, retained, 
returned, or destroyed) must be prepared and signed by the principal investigator or designee, 
with an account given for any discrepancies. 
3.11. 
Duration of Patient Participation and Justification 
This study will consist of a 28-day run-in period (only for patients not rolling over from the 
pivotal efficacy studies) and a 12-month treatment period. Patients will be followed for 
7.5 months (225 days) after administration of the final dose of study drug (ie, a 6.5-month 
follow-up period) for collection of pharmacokinetic, immunogenicity, and biomarker samples 
and inquiries about adverse events and concomitant medication use. It is considered that, with a 
half-life of around 45 days, there will be a complete washout of the drug from the circulating 
blood in 7.5 months (≥5 half-lives), allowing a more precise evaluation of ADA. 
Patients are expected to participate in this study for its entire duration, which is a minimum of 
18.5 months for patients rolling over from the pivotal efficacy studies or 19.5 months for patients 
not rolling over from the pivotal efficacy studies. In addition, patients rolling over from the 
pivotal efficacy studies for ADA evaluation only will participate in the current study for 
approximately 7.5 months. See Section 12.4 for the definition of the end of the study. 
3.12. 
Stopping Rules and Discontinuation Criteria 
There are no formal rules for early termination of this study. During the conduct of the study, 
serious adverse events will be reviewed (see Section 7.1.5) as they are reported from the 
investigational center to identify safety concerns. The study may be terminated by the sponsor at 
any time.  
A patient may discontinue participation in the study at any time for any reason (eg, lack of 
efficacy, consent withdrawn, and adverse event). The investigator and/or sponsor can withdraw a 
patient from the study at any time for any reason (eg, protocol violation or deviation as defined 
in Section 11.1.2, noncompliance, or adverse event). In addition, patients with abnormal hepatic 
laboratory values (eg, ALT, AST, ALP, gamma-glutamyl transpeptidase [GGT], total bilirubin, 

 
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54 
 
or international normalized ratio [INR]) may meet criteria for discontinuation from the study 
drug as summarized in Appendix E.  
3.13. 
Source Data Recorded on the Case Report Form 
All patient data must have supportive original source documentation in the medical records, or 
equivalent, before they are transcribed onto the CRF. Data may not be recorded directly onto the 
CRF and considered as source data unless the sponsor provides written instructions specifying 
which data are permitted to be recorded directly onto the CRF.  
Source data, including test results and/or assessments (eg, clinical laboratory, central ECG 
evaluation center, and electronic headache diary data) collected by other institutions outside of 
the study center, are sent to the investigational center where they are retained but not entered into 
the CRF unless otherwise noted in the protocol. These data may also be sent electronically to the 
sponsor (or organization performing data management) for direct entry into the clinical database 
(see Section 13.1). All data from other institutions will be available to the investigator. 
The CRFs are filed in the sponsor’s central file.  
3.14. 
Study Procedures 
Study procedures and assessments with their timing are summarized in Table 1 (patients rolling 
over from the pivotal efficacy studies), Table 2 (patients not rolling over from the pivotal 
efficacy studies), and Table 3 (patients rolling over from the pivotal efficacy studies for ADA 
assessment only). Detailed by-visit information is provided in the sections following the table. 
Detailed descriptions of each assessment are provided in Section 6 (efficacy assessments), 
Section 7 (safety assessments), and Section 8 (pharmacokinetic and other assessments).

 
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Table 1: 
Study Procedures and Assessments for Patients Rolling Over from the Pivotal Efficacy Studies 
Study period 
Pre-
treatment 
perioda 
Treatment period 
Follow-
up period 
Visit number 
V1 
V2b 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
Procedures and 
assessments (completed 
before dosing, when 
applicable, unless 
otherwise noted) 
Screening 
days  
-28 to -1 
Dose 1 
day 0 
(±5 
days) 
Dose 2 
day 28  
(±5 
days) 
Dose 3 
day 56 
(±5 
days) 
Dose 4 
day 84 
(±5 
days) 
Dose 5 
day 112 
(±5 
days) 
Dose 6 
day 140 
(±5 
days) 
Dose 7 
day 168 
(±5 
days) 
Dose 8 
day 196 
(±5 
days) 
Dose 9 
day 224 
(±5 
days) 
Dose 10 
day 252 
(±5 
days) 
Dose 11 
day 280 
(±5 
days) 
Dose 12 
day 308 
(±5 
days) 
EOT/early 
withdrawal 
day 336 (±5 
days) 
Final 
visit 
day 533 
(±15 
days) 
Informed consent 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion 
criteria 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomizationc 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Full physical 
examination, including 
weight 
 
Xd 
 
 
 
 
X 
X 
 
 
 
 
X 
X 
X 
12-lead ECGe 
 
Xd 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Vital signs measuremente 
 
Xd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Clinical laboratory testsf 
 
Xd 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Urine β-HCG testg 
 
Xd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse eventsh 
 
Xi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication 
inquiry 
 
Xj 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xk 
eC-SSRSl 
 
Xd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Provide electronic 
headache diary device 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
Complete electronic 
headache diary entriesm 
 
X 
 
 
X 
 
X 
X 
 
 
 
 
X 
X 
 
Review electronic 
headache diary 
 
 
X 
X 
X 
 
 
X 
 
 
 
 
 
X 
 
Return electronic 
headache diary device 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
X 
 

 
Long-Term Study–Chronic and Episodic Migraine 
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Study period 
Pre-
treatment 
perioda 
Treatment period 
Follow-
up period 
Visit number 
V1 
V2b 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
Procedures and 
assessments (completed 
before dosing, when 
applicable, unless 
otherwise noted) 
Screening 
days  
-28 to -1 
Dose 1 
day 0 
(±5 
days) 
Dose 2 
day 28  
(±5 
days) 
Dose 3 
day 56 
(±5 
days) 
Dose 4 
day 84 
(±5 
days) 
Dose 5 
day 112 
(±5 
days) 
Dose 6 
day 140 
(±5 
days) 
Dose 7 
day 168 
(±5 
days) 
Dose 8 
day 196 
(±5 
days) 
Dose 9 
day 224 
(±5 
days) 
Dose 10 
day 252 
(±5 
days) 
Dose 11 
day 280 
(±5 
days) 
Dose 12 
day 308 
(±5 
days) 
EOT/early 
withdrawal 
day 336 (±5 
days) 
Final 
visit 
day 533 
(±15 
days) 
Blood samples for 
plasma drug 
concentration 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Blood samples for serum 
ADA assessmentn 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
X 
X 
Blood sample for 
pharmacogenomic 
analysiso 
 
X 
Blood collection for 
serum, plasma, and RNA 
biomarker analysis 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
Urine collection for 
biomarker analysis 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
HIT-6p 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
MIDAS questionnaireq 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
PHQ-2/PHQ-9r 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
MSQOL questionnaire 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
EQ-5D-5L questionnaire 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
PGIC scale  
 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
WPAI questionnaire 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Administer study drug 
injection 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Injection site  
assessmentss 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
a The pretreatment period refers to the screening visit and 28-day run-in period of the pivotal efficacy studies (Studies TV48125-CNS-30049 and TV48125-CNS-30050).  

 
Long-Term Study–Chronic and Episodic Migraine 
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b Patients rolling over from the pivotal efficacy studies will begin study participation at visit 2. If visit 2 corresponds with EOT visit (visit 5) of the pivotal efficacy study, the EOT 
visit procedures/assessments for the pivotal efficacy study must be completed before the patient begins participation in this study, and the EOT procedures/assessments will not 
be repeated at visit 2. Refer to the protocols for Studies TV48125-CNS-30049 and TV48125-CNS-30050 for details regarding the EOT visit procedures/assessments. 
c Patients who received placebo in the pivotal efficacy studies will be randomized to receive 1 of 3 TEV-48125 dose regimens (a loading dose of TEV-48125 at 675 mg followed 
by monthly TEV-48125 at 225 mg [CM only], monthly TEV-48125 at 225 mg, or quarterly TEV-48125 at 675 mg).  
d Procedure/assessment will only be completed for patients who enter this study more than 30 days after completing visit 5 of the pivotal efficacy study. 
e Procedure/assessment will be performed before other assessments (eg, blood draws and administration of questionnaires). 
f Serum chemistry, hematology, coagulation, and urinalysis. 
g Women of childbearing potential only. 
h Inquiries about adverse events will be made at every visit. At visits 2 through 13, inquiries about adverse events will be made before and after study drug administration. 
Postdose inquiries will be made before the patient leaves the study center. 
i The predose adverse event inquiry will only be completed for patients who begin this study on a different day from the EOT visit of the pivotal efficacy study. 
j Procedure/assessment will only be completed for patients who begin this study on a different day from the EOT visit of the pivotal efficacy study. 
k As appropriate, patients should be treated with standard of care following completion of the EOT/early withdrawal visit. 
l The eC-SSRS Since Last Visit version will be completed. 
m Patients will complete electronic headache diary entries about the previous day daily (beginning on day 1) during the first 3 months, during the 4-week period after visit 7, and 
during the 4-week period after visit 13. 
n Blood samples for serum ADA assessment will also be collected upon observation of any severe hypersensitivity reaction (eg, anaphylaxis). 
o A single blood sample for pharmacogenomic analysis will be collected at visit 2 of the pivotal efficacy study or any visit thereafter from patients who consent to 
pharmacogenomic analyses, if the sample is not obtained during their participation in Studies TV48125-CNS-30049 or TV48125-CNS-30050. A separate informed consent form 
for pharmacogenomic sampling must be signed by the patient. 
p The HIT-6 will only be administered to patients with CM. 
q The MIDAS questionnaire will only be administered to patients with EM. 
r Patients 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. 
s Injection site assessments will be performed immediately and 1 hour after study drug administration. If a patient has severe injection site induration, erythema, and/or 
ecchymosis and/or grade 3 (severe) or grade 4 (worst possible) injection site pain at 1 hour after completion of study drug administration, the patient will be reassessed at 3 hours 
after study drug administration and hourly thereafter until the reaction/pain is of moderate or less severity. 
ADA=antidrug antibody; β-HCG=beta-human chorionic gonadotropin; ECG=electrocardiogram; eC-SSRS=electronic Columbia-Suicide Severity Rating Scale; 
EOT=end-of-treatment; EQ-5D-5L=EuroQol-5 Dimension, 5 response level version; FSH=follicle-stimulating hormone; HIT-6=6-item Headache Impact Test; MIDAS=Migraine 
Disability Assessment; MSQOL=Migraine-Specific Quality of Life; PGIC=Patient Global Impression of Change; PHQ-2=2-item Patient Health Questionnaire; PHQ-9=9-item 
Patient Health Questionnaire; V=visit; WPAI=Work Performance and Activity Impairment.  
  

 
Long-Term Study–Chronic and Episodic Migraine 
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Table 2: 
Study Procedures and Assessments for Patients Not Rolling Over from the Pivotal Efficacy Studies 
Study period 
Pre-
treatment 
perioda 
Treatment period 
Follow-up 
period 
Visit number 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
Procedures and 
assessments (completed 
before dosing, when 
applicable, unless 
otherwise noted) 
Screening 
days  
-28 to -1 
Dose 1 
day 0 
(+ 5 
days) 
Dose 2 
day 28  
(±5 
days) 
Dose 3 
day 56 
(±5 
days) 
Dose 4 
day 84 
(±5 
days) 
Dose 5 
day 112 
(±5 
days) 
Dose 6 
day 140 
(±5 
days) 
Dose 7 
day 168 
(±5 days) 
Dose 8 
day 
196 (±5 
days) 
Dose 9 
day 224 
(±5 
days) 
Dose 10 
day 252 
(±5 
days) 
Dose 11 
day 280 
(±5 
days) 
Dose 12 
day 308 
(±5 
days) 
EOT/early 
withdrawal 
day 336 
(±5 days) 
Final visit 
day 533 
(±15 days) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and psychiatric 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior medication history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Record demographic 
characteristics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion 
criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomizationb 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination, 
including weight/heightc 
X 
X 
X 
X 
X 
 
X 
X 
 
 
 
 
X 
X 
X 
12-lead ECGd,e 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Vital signs measurementd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Clinical laboratory testsf 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Serum β-HCG testg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine β-HCG testg 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
FSHh 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse eventse,i 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication 
inquirye 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xj 

 
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Study period 
Pre-
treatment 
perioda 
Treatment period 
Follow-up 
period 
Visit number 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
Procedures and 
assessments (completed 
before dosing, when 
applicable, unless 
otherwise noted) 
Screening 
days  
-28 to -1 
Dose 1 
day 0 
(+ 5 
days) 
Dose 2 
day 28  
(±5 
days) 
Dose 3 
day 56 
(±5 
days) 
Dose 4 
day 84 
(±5 
days) 
Dose 5 
day 112 
(±5 
days) 
Dose 6 
day 140 
(±5 
days) 
Dose 7 
day 168 
(±5 days) 
Dose 8 
day 
196 (±5 
days) 
Dose 9 
day 224 
(±5 
days) 
Dose 10 
day 252 
(±5 
days) 
Dose 11 
day 280 
(±5 
days) 
Dose 12 
day 308 
(±5 
days) 
EOT/early 
withdrawal 
day 336 
(±5 days) 
Final visit 
day 533 
(±15 days) 
eC-SSRSk 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Provide electronic 
headache diary devicel 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
Complete electronic 
headache diary entriesm 
X 
 
 
 
X 
 
X 
X 
 
 
 
 
X 
X 
 
Review electronic 
headache diary 
 
X 
X 
X 
X 
 
 
X 
 
 
 
 
 
X 
 
Return electronic 
headache diary device 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
X 
 
Blood samples for 
plasma drug 
concentratione 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Blood samples for serum 
ADA assessmentn 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
X 
X 
Blood sample for 
pharmacogenomic 
analysiso 
 
X 
Blood collection for 
serum, plasma, and RNA 
biomarker analysis 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
Urine collection for 
biomarker analysis 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
HIT-6p 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
MIDAS questionnaireq 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
PHQ-2/PHQ-9r 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 

 
Long-Term Study–Chronic and Episodic Migraine 
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Study period 
Pre-
treatment 
perioda 
Treatment period 
Follow-up 
period 
Visit number 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
Procedures and 
assessments (completed 
before dosing, when 
applicable, unless 
otherwise noted) 
Screening 
days  
-28 to -1 
Dose 1 
day 0 
(+ 5 
days) 
Dose 2 
day 28  
(±5 
days) 
Dose 3 
day 56 
(±5 
days) 
Dose 4 
day 84 
(±5 
days) 
Dose 5 
day 112 
(±5 
days) 
Dose 6 
day 140 
(±5 
days) 
Dose 7 
day 168 
(±5 days) 
Dose 8 
day 
196 (±5 
days) 
Dose 9 
day 224 
(±5 
days) 
Dose 10 
day 252 
(±5 
days) 
Dose 11 
day 280 
(±5 
days) 
Dose 12 
day 308 
(±5 
days) 
EOT/early 
withdrawal 
day 336 
(±5 days) 
Final visit 
day 533 
(±15 days) 
MSQOL questionnaire 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
EQ-5D-5L questionnaire 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
PGIC scale 
 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
WPAI questionnaire 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
Administer study drug 
injection 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Injection site  
assessmentss 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
a The pretreatment period includes the screening visit and the 28-day run-in period.  
b Eligible patients will be randomized to receive 1 of 3 TEV-48125 dose regimens (a loading dose of TEV-48125 at 675 mg followed by monthly TEV-48125 at 225 mg 
[CM only], monthly TEV-48125 at 225 mg, or quarterly TEV-48125 at 675 mg).  
c Height will only be obtained at screening. 
d Procedure/assessment will be performed before other assessments (eg, blood draws and administration of questionnaires). 
e Patients will return to the study center for up to 2 additional visits after any dose of study drug for blood sampling for plasma TEV-48125 concentration determination, triplicate 
12-lead ECGs, and inquiries about adverse events and concomitant medications. These visits should occur during the following time periods relative to any dose of study drug: 
3 to 10 days or 15 to 20 days after study drug administration. 
f Serum chemistry, hematology, coagulation, and urinalysis. 
g Women of childbearing potential only; a serum β-HCG test will be performed at screening, and urine β-HCG tests will be performed at subsequent visits. 
h Postmenopausal women only. 
i Inquiries about adverse events will be made at every visit. At visits 2 through 13, inquiries about adverse events will be made before and after study drug administration. 
Postdose inquiries will be made before the patient leaves the study center. 
j As appropriate, patients should be treated with standard of care following completion of the EOT/early withdrawal visit. 
k The eC-SSRS Baseline/Screening version will be completed at visit 2, and the eC-SSRS Since Last Visit version will be completed at all other visits. 
l Eligible patients will be given an electronic headache diary device and will be trained in its use and compliance requirements on the day of screening.  
m Patients will complete electronic headache diary entries about the previous day daily (beginning on day -27) during the first 4 months, during the 4-week period after visit 7, and 
during the 4-week period after visit 13.  
n Blood samples for serum ADA assessment will also be collected upon observation of any severe hypersensitivity reaction (eg, anaphylaxis). 
o A single blood sample for pharmacogenomic analysis will be collected at visit 2 or any other visit thereafter from patients who consent to pharmacogenomic analyses, if the 
sample is not obtained during their participation in Studies TV48125-CNS-30049 or TV48125-CNS-30050. A separate informed consent form for pharmacogenomic sampling 
must be signed by the patient. 

 
Long-Term Study–Chronic and Episodic Migraine 
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p The HIT-6 will only be administered to patients with CM. 
q The MIDAS questionnaire will only be administered to patients with EM. 
r Patients 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. 
s Injection site assessments will be performed immediately and 1 hour after study drug administration. If a patient has severe injection site induration, erythema, and/or 
ecchymosis and/or grade 3 (severe) or grade 4 (worst possible) injection site pain at 1 hour after completion of study drug administration, the patient will be reassessed at 3 hours 
after study drug administration and hourly thereafter until the reaction/pain is of moderate or less severity. 
ADA=antidrug antibody; β-HCG=beta-human chorionic gonadotropin; ECG=electrocardiogram; eC-SSRS=electronic Columbia Suicide Severity Rating Scale; EOT=end-of-
treatment; EQ-5D-5L=EuroQol-5 Dimension, 5 response level version; FSH=follicle-stimulating hormone; HIT-6=6-item Headache Impact Test; MIDAS=Migraine Disability 
Assessment; MSQOL=Migraine-Specific Quality of Life; PGIC=Patient Global Impression of Change; PHQ-2=2-item Patient Health Questionnaire; PHQ-9=9-item Patient Health 
Questionnaire; V=visit; WPAI=Work Performance and Activity Impairment. 
 

 
Long-Term Study–Chronic and Episodic Migraine 
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62 
Table 3: 
Study Procedures and Assessments for Patients Rolling Over from the 
Pivotal Efficacy Studies for Antidrug Antibody Assessment Only 
 
Enrollment visit 
Follow-up visit 
Visit number 
V2a 
V16 (ADA collection) 
Procedures and assessments 
Day 0 
Approximately 7.5 months 
(225±15 days) after the last dose 
of study drug during the pivotal 
efficacy study 
Informed consent 
X 
 
Adverse events 
X 
X 
Concomitant medication inquiry 
X 
X 
Blood sample for serum ADA 
assessment 
 
X 
a If visit 2 corresponds with EOT visit/early withdrawal visit of the pivotal efficacy study, the EOT visit 
procedures/assessments for the pivotal efficacy study must be completed before the patient begins participation in 
this study, and the EOT procedures/assessments will not be repeated at visit 2. 
ADA=antidrug antibody; EOT=end of treatment; V=visit.  
3.14.1. 
Procedures for Screening of Patients Not Rolling Over from the Pivotal Efficacy 
Studies (Visit 1 [Day -28]) 
Patients not rolling over from the pivotal efficacy studies will be screened approximately 28 days 
before the baseline visit. 
A signed and dated informed consent form will be obtained before screening procedures 
commence (see Section 12.1). Evaluations obtained as part of routine medical care and 
performed during the screening period may be used in place of the protocol-specific evaluations. 
In addition, disease-specific assessments performed within a specified time frame before 
informed consent may be used for the study. Patients will acknowledge and agree to the possible 
use of this information for the study by giving informed consent.  
After informed consent is obtained, patients who are screened will be assigned an 8-digit 
identification number such that all patients from each country are given consecutive 
identification numbers in successive order of inclusion. The first 2 digits of the screening number 
will be the number assigned to the country where the investigational center is located, the next 
3 digits will be the investigational center number, and the last 3 digits will be the patient number 
assigned at the investigator center (eg, the 3rd patient screened in the US [country 01] at 
center 101 would be given the number of 01101003). The screening number is the permanent 
number assigned to the patient for the duration of study. 
After confirmation of study eligibility, patients will be screen failed or randomized into the 
current study. For randomized patients, an enrollment number will be assigned consisting of the 
8-digit screening number for randomized patients and the last 2 digits of the assigned protocol 
(ie, 51 for Study TV48125-CNS-30051).  
A patient who is screened and does not meet study entry criteria will not be considered for 
screening again. 

 
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The following procedures will be performed at visit 1: 
• Obtain written informed consent before any other study-related procedures are 
performed. 
• Review inclusion/exclusion criteria.  
• Review medical and psychiatric history.  
• Review medication history.  
• Record demographic characteristics including race. 
• Perform vital signs measurements (includes systolic and diastolic blood pressure, 
pulse, body temperature, and respiratory rate). 
• Perform 12-lead ECG. 
• Perform physical examination, including weight and height. Body mass index will be 
calculated. 
• Perform clinical laboratory tests (serum chemistry, hematology, coagulation, and 
urinalysis). 
• Perform serum β-HCG test (women of childbearing potential only). 
• Perform FSH (postmenopausal women only). 
Patients who meet inclusion/exclusion criteria will be given an electronic headache diary device 
and instructed in its use and compliance requirements. 
3.14.2. 
Procedures Before Study Drug Treatment  
3.14.2.1. Patients Not Rolling Over from the Pivotal Efficacy Studies 
Patients not rolling over from the pivotal efficacy studies will complete a 28-day run-in period 
and baseline procedures before beginning study drug treatment. Additional details are presented 
in Section 3.14.2.1.1 and Section 3.14.2.1.2. 
3.14.2.1.1. 28-Day Run-In Period (Days -28 Through -1) 
Eligible patients not rolling over from the pivotal efficacy studies will complete electronic 
headache diary entries daily beginning on day -27. Patients will enter headache information 
(ie, occurrence of headache, duration of headache, maximum severity of headache, and acute 
migraine-specific medication use) about the previous day into the electronic headache diary 
device. Refer to Section 6.1 for additional details about the electronic headache diary. 

 
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3.14.2.1.2. Baseline (Visit 2 [Day 0 (+5 days)]) 
Patients not rolling over from the pivotal efficacy studies and who meet the inclusion/exclusion 
criteria at visit 1 will continue to visit 2, and baseline evaluations will be conducted. The 
following procedures will be performed at visit 2 for these patients before study drug 
administration: 
• Review study compliance. 
• Review electronic headache diary. 
• Review inclusion/exclusion criteria. 
• Perform physical examination (including weight). 
• Perform vital signs measurements (includes systolic and diastolic blood pressure, 
pulse, body temperature, and respiratory rate). 
• Perform 12-lead ECG. 
• Perform clinical laboratory tests (serum chemistry, hematology, coagulation, and 
urinalysis). 
• Inquire about adverse events. 
• Inquire about/review concomitant medications. 
• Complete the eC-SSRS Baseline/Screening version. 
• Perform urine β-HCG test (women of childbearing potential only). 
• Administer the HIT-6 (patients with CM only), MIDAS questionnaire (patients with 
EM only), MSQOL questionnaire, EQ-5D-5L questionnaire, WPAI questionnaire, 
and PHQ-2/PHQ-9. (Note: Patients 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.)  
• Obtain a 4-mL blood sample for plasma TEV-48125 concentration determination. 
• Obtain a 5-mL blood sample for serum ADA assessment. 
• Obtain a 5-mL urine sample for biomarker analysis. 
• Obtain an 18.5-mL blood sample (6 mL each for serum and plasma and 6.5 mL for 
ribonucleic acid [RNA]) for serum, plasma, and RNA biomarker analysis. 
In addition, a 6-mL blood sample for pharmacogenomics (deoxyribonucleic acid [DNA]) may be 
obtained from patients who consent to pharmacogenomics analysis. 
A patient who does not meet study entry criteria on the basis of results of baseline assessments 
and is not randomized in the study will not be considered for screening again. 
Patients who continue to meet the inclusion/exclusion criteria will be assigned a permanent 
unique randomization number generated by the IRT. This newly assigned number will be entered 
into the CRF.  

 
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3.14.2.2. Patients Rolling Over from the Pivotal Efficacy Studies (Visit 2 [Day 0]) 
After completing all EOT visit procedures for the pivotal efficacy studies, patients who provide 
informed consent and meet eligibility requirements will be enrolled into this long-term safety, 
tolerability, and efficacy study. These patients will retain their screening and enrollment numbers 
from the pivotal efficacy studies, and they will be assigned a new randomization number 
generated by the IRT. This newly assigned number will be entered into the CRF.  
Patients rolling over from the pivotal efficacy studies will begin this study at visit 2. If visit 2 
corresponds with the EOT visit (visit 5) of the pivotal efficacy study, then EOT visit 
procedures/assessments must be completed before the patient begins participation in this study. 
The EOT visit procedures/assessments are detailed in the protocols for 
Studies TV48125-CNS-30049 and TV48125-CNS-30050. 
The following procedures will be performed before study drug administration for patients who 
enroll in the current study on a different day from the EOT visit, but within 30 days: 
• Inquire about adverse events. 
• Inquire about/review concomitant medications. 
In addition, a single 6-mL blood sample for pharmacogenomics (DNA) may be obtained from 
patients who consent to pharmacogenomics analysis if the sample is not obtained during their 
participation in Studies TV48125-CNS-30049 or TV48125-CNS-30050. 
The following procedures will be performed before study drug administration for patients who 
complete the EOT visit of the pivotal efficacy study and enroll in the current study after more 
than 30 days: 
• Perform vital signs measurements (including systolic and diastolic blood pressure, 
pulse, body temperature, and respiratory rate). 
• Perform 12-lead ECG.  
• Perform physical examination, including weight. 
• Inquire about adverse events.  
• Inquire about/review concomitant medications. 
• Complete the eC-SSRS Since Last Visit version.  
• Perform clinical laboratory tests (serum chemistry, hematology, coagulation, and 
urinalysis).  
• Perform urine β-HCG test (women of childbearing potential only). 
In addition, a single 6-mL blood sample for pharmacogenomics (DNA) may be obtained from 
patients who consent to pharmacogenomics analysis if the sample is not obtained during their 
participation in Studies TV48125-CNS-30049 or TV48125-CNS-30050. 
All patients rolling over from the pivotal efficacy studies will be given an electronic headache 
diary device and instructed in its use and compliance requirements at visit 2.  

 
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3.14.2.3. Patients Rolling Over from the Pivotal Efficacy Studies for Antidrug Antibody 
Assessment Only (Visit 2 [Day 0]) 
Patients who do not complete the pivotal efficacy studies and those patients who complete the 
pivotal efficacy studies but do not wish to continue treatment during this long-term safety, 
tolerability, and efficacy study will be offered to attend a follow-up visit for ADA assessment. 
Patients who consent to the ADA assessment will retain their randomization and enrollment 
numbers from the pivotal efficacy studies.  
After consenting to participate in a follow-up visit for ADA assessment, the following 
procedures will be performed for patients who enroll in the current study on a different day from 
the EOT visit of the pivotal efficacy studies: 
• Inquire about adverse events. 
• Inquire about/review concomitant medications. 
3.14.3. 
Procedures During Study Drug Treatment 
Procedures during study drug treatment will be the same for patients rolling over from the 
pivotal efficacy studies and patients not rolling over from the pivotal efficacy studies. Patients 
rolling over from the pivotal efficacy studies for ADA assessment only will not receive study 
drug during the current study. 
3.14.3.1. Treatment Period (Days 0 Through 336 ± 5 Days [Visits 2 Through 14]) 
Patients will enter headache information (ie, occurrence of headache, duration of headache, 
maximum severity of headache, and acute migraine-specific medication use) about the previous 
day into the electronic headache diary device daily during the time periods specified in Table 1 
(patients rolling over from the pivotal efficacy studies) and Table 2 (patients not rolling over 
from the pivotal efficacy studies). Refer to Section 6.1 for additional details about the electronic 
headache diary device. 
3.14.3.1.1. Visit 2 (Day 0 [+5 days]/Dose 1) 
Patients will receive sc TEV-48125 at 675 or 225 mg according to their randomization after 
completing procedures/assessments described in Section 3.14.2.1.2 (patients not rolling over 
from the pivotal efficacy studies) or Section 3.14.2.2 (patients rolling over from the pivotal 
efficacy studies). The following procedures/assessments will be performed after dosing: 
• Perform local injection site assessment immediately and at 1 hour after completing 
study drug administration. Additional injection site assessments may be performed 
based on the severity of any observed injection site reaction. See Section 7.9 for 
additional details. 
• Inquire about postdose adverse events before the patient leaves the study center. 
3.14.3.1.2. Visit 3 (Day 28 ± 5 Days/Dose 2) 
The following procedures/assessments will be performed before study drug administration at 
visit 3: 

 
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• Review electronic headache diary. 
• Review study compliance. 
• Perform vital signs measurements (includes systolic and diastolic blood pressure, 
pulse, body temperature, and respiratory rate). 
• Perform physical examination (including weight) for patients not rolling over only. 
• Inquire about adverse events. 
• Inquire about/review concomitant medications. 
• Complete the eC-SSRS Since Last Visit version. 
• Perform urine β-HCG test (women of childbearing potential only). 
• Administer the PGIC scale.  
In addition, a single 6-mL blood sample for pharmacogenomics (DNA) may be obtained from 
patients who consent to pharmacogenomics analysis if the sample is not obtained at an earlier 
visit. 
Patients will receive sc TEV-48125 at 225 mg or placebo according to their randomization after 
completing predose procedures/assessments at each study visit. The following 
procedures/assessments will be performed after dosing: 
• Perform local injection site assessment immediately and at 1 hour after completing 
study drug administration. Additional injection site assessments may be performed 
based on the severity of any observed injection site reaction. See Section 7.9 for 
additional details. 
• Inquire about postdose adverse events before the patient leaves the study center. 
3.14.3.1.3. Visit 4 (Day 56 ± 5 Day/Dose 3) 
The following procedures/assessments will be performed before study drug administration at 
visit 4: 
• Review electronic headache diary. 
• Review study compliance. 
• Perform vital signs measurements (includes systolic and diastolic blood pressure, 
pulse, body temperature, and respiratory rate). 
• Perform physical examination (including weight) for patients not rolling over only. 
• Inquire about adverse events. 
• Inquire about/review concomitant medications. 
• Complete the eC-SSRS Since Last Visit version. 
• Perform clinical laboratory tests (serum chemistry, hematology, coagulation, and 
urinalysis). 
• Perform urine β-HCG test (women of childbearing potential only). 

 
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In addition, a single 6-mL blood sample for pharmacogenomics (DNA) may be obtained from 
patients who consent to pharmacogenomics analysis if the sample is not obtained at an earlier 
visit. 
Patients will receive sc TEV-48125 at 225 mg or placebo according to their randomization after 
completing predose procedures/assessments at each study visit. The following 
procedures/assessments will be performed after dosing: 
• Perform local injection site assessment immediately and at 1 hour after completing 
study drug administration. Additional injection site assessments may be performed 
based on the severity of any observed injection site reaction. See Section 7.9 for 
additional details. 
• Inquire about postdose adverse events before the patient leaves the study center. 
3.14.3.1.4. Visit 5 (Day 84/Dose 4) 
The following procedures/assessments will be performed before study drug administration at 
visit 5: 
• Review electronic headache diary. (Note: Patients will return the electronic headache 
diary device at this visit.) 
• Review study compliance. 
• Perform vital signs measurements (includes systolic and diastolic blood pressure, 
pulse, body temperature, and respiratory rate). 
• Perform physical examination (including weight) for patients not rolling over only. 
• Inquire about adverse events. 
• Inquire about/review concomitant medications. 
• Complete the eC-SSRS Since Last Visit version. 
• Perform urine β-HCG test (women of childbearing potential only). 
• Administer the PGIC scale. 
• Obtain a 4-mL blood sample for plasma TEV-48125 concentration determination. 
• Obtain a 5-mL blood sample for serum ADA assessment. 
In addition, a single 6-mL blood sample for pharmacogenomics (DNA) may be obtained from 
patients who consent to pharmacogenomics analysis if the sample is not obtained at an earlier 
visit. 
Patients will receive sc TEV-48125 at 675 or 225 mg according to their randomization after 
completing predose procedures/assessments at each study visit. Patients will receive a single sc 
dose of TEV-48125 at 225 mg after completing predose procedures/assessments at each study 
visit. The following procedures/assessments will be performed after dosing: 
• Perform local injection site assessment immediately and at 1 hour after completing 
study drug administration. Additional injection site assessments may be performed 

 
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based on the severity of any observed injection site reaction. See Section 7.9 for 
additional details. 
• Inquire about postdose adverse events before the patient leaves the study center. 
3.14.3.1.5. Visits 6, 10, and 12 (Days 112, 224, and 280 ± 5 Days, respectively/Doses 5, 9, and 
11, respectively)  
The following procedures/assessments will be performed before study drug administration at 
visits 6, 10, and 12: 
• Review study compliance. 
• Perform vital signs measurements (includes systolic and diastolic blood pressure, 
pulse, body temperature, and respiratory rate). 
• Inquire about adverse events. 
• Inquire about/review concomitant medications. 
• Complete the eC-SSRS Since Last Visit version. 
• Perform clinical laboratory tests (serum chemistry, hematology, coagulation, and 
urinalysis). 
• Perform urine β-HCG test (women of childbearing potential only). 
In addition, a single 6-mL blood sample for pharmacogenomics (DNA) may be obtained from 
patients who consent to pharmacogenomics analysis if the sample is not obtained at an earlier 
visit. 
Patients will receive sc TEV-48125 at 225 mg or placebo according to their randomization after 
completing predose procedures/assessments at each study visit. The following 
procedures/assessments will be performed after dosing: 
• Perform local injection site assessment immediately and at 1 hour after completing 
study drug administration. Additional injection site assessments may be performed 
based on the severity of any observed injection site reaction. See Section 7.9 for 
additional details. 
• Inquire about postdose adverse events before the patient leaves the study center. 
3.14.3.1.6. Visits 7 and 13 (Days 140 and 308 ± 5 Days, respectively/Doses 6 and 12, 
respectively) 
The following procedures/assessments will be performed before study drug administration at 
visits 7 and 13: 
• Provide electronic headache diary device. 
• Review study compliance. 
• Perform vital signs measurements (includes systolic and diastolic blood pressure, 
pulse, body temperature, and respiratory rate). 
• Perform full physical examination (including weight). 

 
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• Inquire about adverse events. 
• Inquire about/review concomitant medications. 
• Complete the eC-SSRS Since Last Visit version. 
• Perform urine β-HCG test (women of childbearing potential only). 
In addition, a single 6-mL blood sample for pharmacogenomics (DNA) may be obtained from 
patients who consent to pharmacogenomics analysis if the sample is not obtained at an earlier 
visit. 
Patients will receive sc TEV-48125 at 225 mg or placebo according to their randomization after 
completing predose procedures/assessments at each study visit. The following 
procedures/assessments will be performed after dosing: 
• Perform local injection site assessment immediately and at 1 hour after completing 
study drug administration. Additional injection site assessments may be performed 
based on the severity of any observed injection site reaction. See Section 7.9 for 
additional details. 
• Inquire about postdose adverse events before the patient leaves the study center. 
3.14.3.1.7. Visit 8 (Day 168 ± 5 Days/Dose 7) 
The following procedures/assessments will be performed before study drug administration at 
visit 8: 
• Review electronic headache diary. (Note: Patients will return the electronic headache 
diary device at this visit.) 
• Review study compliance. 
• Perform vital signs measurements (includes systolic and diastolic blood pressure, 
pulse, body temperature, and respiratory rate). 
• Perform full physical examination (including weight). 
• Inquire about adverse events. 
• Inquire about/review concomitant medications. 
• Complete the eC-SSRS Since Last Visit version. 
• Perform clinical laboratory tests (serum chemistry, hematology, coagulation, and 
urinalysis). 
• Perform urine β-HCG test (women of childbearing potential only). 
• Administer the HIT-6 (patients with CM only), MIDAS questionnaire (patients with 
EM only), PGIC scale, MSQOL questionnaire, EQ-5D-5L questionnaire, 
WPAI questionnaire, and PHQ-2/PHQ-9. (Note: Patients 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.) 
• Obtain a 4-mL blood sample for plasma TEV-48125 concentration determination. 

 
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• Obtain a 5-mL blood sample for serum ADA assessment. 
• Obtain a 5-mL urine sample for biomarker analysis. 
• Obtain an 18.5-mL blood sample (6 mL each for serum and plasma and 6.5 mL for 
RNA) for serum, plasma, and RNA biomarker analysis. 
In addition, a single 6-mL blood sample for pharmacogenomics (DNA) may be obtained from 
patients who consent to pharmacogenomics analysis if the sample is not obtained at an earlier 
visit. 
Patients will receive sc TEV-48125 at 675 or 225 mg according to their randomization after 
completing predose procedures/assessments at each study visit. The following 
procedures/assessments will be performed after dosing: 
• Perform local injection site assessment immediately and at 1 hour after completing 
study drug administration. Additional injection site assessments may be performed 
based on the severity of any observed injection site reaction. See Section 7.9 for 
additional details. 
• Inquire about postdose adverse events before the patient leaves the study center. 
3.14.3.1.8. Visit 9 (Day 196 ± 5 Days/Dose 8) 
The following procedures/assessments will be performed before study drug administration at 
visit 9: 
• Review study compliance. 
• Perform vital signs measurements (includes systolic and diastolic blood pressure, 
pulse, body temperature, and respiratory rate). 
• Inquire about adverse events. 
• Inquire about/review concomitant medications. 
• Complete the eC-SSRS Since Last Visit version. 
• Perform urine β-HCG test (women of childbearing potential only). 
In addition, a single 6-mL blood sample for pharmacogenomics (DNA) may be obtained from 
patients who consent to pharmacogenomics analysis if the sample is not obtained at an earlier 
visit. 
Patients will receive sc TEV-48125 at 225 mg or placebo according to their randomization after 
completing predose procedures/assessments at each study visit. The following 
procedures/assessments will be performed after dosing: 
• Perform local injection site assessment immediately and at 1 hour after completing 
study drug administration. Additional injection site assessments may be performed 
based on the severity of any observed injection site reaction. See Section 7.9 for 
additional details. 
• Inquire about postdose adverse events before the patient leaves the study center. 

 
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3.14.3.1.9. Visit 11 (Day 252 ± 5 Days /Dose 10) 
The following procedures/assessments will be performed before study drug administration at 
visit 11: 
• Review study compliance. 
• Perform vital signs measurements (includes systolic and diastolic blood pressure, 
pulse, body temperature, and respiratory rate). 
• Inquire about adverse events. 
• Inquire about/review concomitant medications. 
• Complete the eC-SSRS Since Last Visit version. 
• Perform urine β-HCG test (women of childbearing potential only). 
• Administer the PGIC scale. 
• Obtain a 4-mL blood sample for plasma TEV-48125 concentration determination. 
In addition, a single 6-mL blood sample for pharmacogenomics (DNA) may be obtained from 
patients who consent to pharmacogenomics analysis if the sample is not obtained at an earlier 
visit. 
Patients will receive sc TEV-48125 at 675 or 225 mg according to their randomization after 
completing predose procedures/assessments at each study visit. Patients will receive a single sc 
dose of TEV-48125 at 225 mg after completing predose procedures/assessments at each study 
visit. The following procedures/assessments will be performed after dosing: 
• Perform local injection site assessment immediately and at 1 hour after completing 
study drug administration. Additional injection site assessments may be performed 
based on the severity of any observed injection site reaction. See Section 7.9 for 
additional details. 
• Inquire about postdose adverse events before the patient leaves the study center. 
3.14.3.1.10. 
Additional Visit(s) for Pharmacokinetic Sampling 
Patients not rolling over from the pivotal efficacy studies will return to the study center for up to 
2 additional visits at 3 to 10 days or 15 to 20 days after administration of any dose of study drug, 
and the following procedures/assessments will be performed: 
• Inquire about adverse events. 
• Inquire about/review concomitant medications. 
• Perform triplicate 12-lead ECGs.  
• Obtain a 4-mL blood sample for plasma TEV-48125 concentration determination. 

 
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3.14.3.1.11. 
End-of-Treatment Visit (Visit 14 [Day 336 ± 5 Days]) 
The following procedures/assessments will be performed at the EOT visit (visit 14): 
• Review headache diary. (Note: Patients will return the electronic headache diary 
device at this visit.) 
• Review study compliance. 
• Perform vital signs measurements (includes systolic and diastolic blood pressure, 
pulse, body temperature, and respiratory rate). 
• Perform 12-lead ECG. 
• Perform physical examination (including weight). 
• Inquire about adverse events. 
• Inquire about/review concomitant medications. 
• Complete the eC-SSRS Since Last Visit version. 
• Perform clinical laboratory tests (serum chemistry, hematology, coagulation, and 
urinalysis). 
• Perform urine β-HCG test (women of childbearing potential only). 
• Administer the HIT-6 (patients with CM only), MIDAS questionnaire (patients with 
EM only), PGIC scale, MSQOL questionnaire, EQ-5D-5L questionnaire, 
WPAI questionnaire, and PHQ-2/PHQ-9. (Note: Patients 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.) 
• Obtain a 4-mL blood sample for plasma TEV-48125 concentration determination. 
• Obtain a 5-mL blood sample for serum ADA assessment. 
• Obtain a 5-mL urine sample for biomarker analysis. 
• Obtain an 18.5-mL blood sample (6 mL each for serum and plasma and 6.5 mL for 
RNA) for serum, plasma, and RNA biomarker analysis. 
In addition, a single 6-mL blood sample for pharmacogenomics (DNA) may be obtained from 
patients who consent to pharmacogenomics analysis if the sample is not obtained at an earlier 
visit. 
After completing the EOT visit, patients may be treated with standard-of-care migraine 
treatment, as appropriate.  

 
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3.14.4. 
Procedures After Study Drug Treatment 
3.14.4.1. Patients Rolling Over from the Pivotal Efficacy Studies and New Patients (Final 
Visit [Visit 15 (Day 533)]) 
Procedures after study drug treatment will be the same for patients rolling over from the pivotal 
efficacy studies who receive study drug during the current study and patients not rolling over 
from the pivotal efficacy studies.  
Patients who participate in the study in compliance with the protocol for the entire treatment 
period (ie, from visit 2 through visit 14) will be considered to have completed the study. Patients 
may be treated with standard of care following completion of visit 14. 
Patients who complete the treatment period will have a follow-up visit approximately 7.5 months 
(225 days [the approximate equivalent of 5 half-lives]) after administration of the final dose of 
study drug. The following procedures/assessments will be performed at this visit: 
• Inquire about adverse events. 
• Inquire about/review concomitant medications. 
• Perform physical examination (including weight). 
• Complete the eC-SSRS Since Last Visit version. 
• Obtain a 4-mL blood sample for plasma TEV-48125 concentration determination. 
• Obtain a 5-mL blood sample for serum ADA assessment. 
• Obtain a 5-mL urine sample for biomarker analysis. 
• Obtain an 18.5-mL blood sample (6 mL each for serum and plasma and 6.5 mL for 
RNA) for serum, plasma, and RNA biomarker analysis. 
In addition, a single 6-mL blood sample for pharmacogenomics (DNA) may be obtained from 
patients who consent to pharmacogenomics analysis if the sample is not obtained at an earlier 
visit. 
Patients who discontinue treatment prematurely must be encouraged to continue to attend the 
regular scheduled visits, and complete the prescribed safety and efficacy evaluations through the 
EOT visit and the follow-up visit, if at all possible. 
Patients who both discontinue treatment and also withdraw from the study should have EOT 
(early withdrawal) visit procedures/assessments (see Table 1 and Table 2) performed on the last 
day the patient receives the study drug, or as soon as possible thereafter. The patient should also 
return for the follow-up visit approximately 7.5 months after the last dose of study drug if at all 
possible. 
Procedures for patients who withdraw prematurely from the study are described in Section 4.4. 
As appropriate, patients should be treated with standard of care following termination of the 
study. 
Patients with ongoing adverse events or clinically significant abnormal laboratory test results (as 
interpreted by the investigator) will be monitored as described in Section 7.1.2. 

 
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See Section 12.4 for the definition of the end of the study. 
3.14.4.2. Patients Rolling Over from the Pivotal Efficacy Studies for Antidrug Antibody 
Assessment Only (Visit 16 [Antidrug Antibody Collection])  
Patients rolling over from the pivotal efficacy studies for ADA assessment only may agree to 
attend a follow-up visit during this study approximately 7.5 months (225±15 days [the 
approximate equivalent of 5 half-lives]) after administration of the final dose of study drug. The 
following procedures/assessments will be performed at this visit: 
• Inquire about adverse events. 
• Inquire about/review concomitant medications. 
• Obtain a 5-mL blood sample for serum ADA assessment. 
3.14.5. 
Unscheduled Visits 
An unscheduled visit may be performed at any time during the study at the patient’s request or as 
deemed necessary by the investigator. The date and reason for the unscheduled visit will be 
recorded on the CRF as well as any other data obtained (eg, adverse events, concomitant 
medications and treatments, and results from procedures or tests). 
Procedures performed during unscheduled visits include the following: 
• Review study compliance. 
• Perform vital signs measurements (including systolic and diastolic blood pressure, 
pulse, body temperature, and respiratory rate). 
• Inquire about adverse events. 
• Inquire about/review concomitant medications. 
Other procedures may be performed at the discretion of the investigator. 

 
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4. 
SELECTION AND WITHDRAWAL OF PATIENTS 
Prospective waivers (exceptions) from study eligibility criteria to allow patients to enter a study 
are not granted by Teva (see Section 11.1.2). 
4.1. 
Patient Inclusion Criteria 
4.1.1. 
Patients Rolling Over from the Pivotal Efficacy Studies 
Patients may be included in this study only if they meet all of the following criteria: 
a. Patient signs and dates the informed consent document. 
b. Patients must have completed the pivotal efficacy study without major protocol 
violations. 
c. Patients may continue with a stable dose/regimen of the preventive medication they 
were taking during the pivotal efficacy studies. 
d. Patient must be willing and able to comply with study restrictions, to remain at the 
clinic for the required duration during the study period, and to return to the clinic for 
the follow-up evaluation as specified in this protocol. 
4.1.2. 
Patients Not Rolling Over from the Pivotal Efficacy Studies 
Patients may be included in this study only if they meet all of the following criteria: 
a. Males or females aged 18 to 70 years, inclusive, with migraine onset at ≤50 years of 
age. 
b. Patient signs and dates the informed consent document. 
c. Patient has history of migraine (according to ICHD-3 criteria [Classification 
Committee of the IHS, 2013]) or clinical judgment suggests a migraine diagnosis (not 
better accounted for by another ICHD-3 diagnosis) for ≥12 months prior to screening. 
d. Patient fulfills the following criteria for EM or CM with prospectively collected 
baseline information during the 28-day run-in period: 
− Patients with EM: 
○ headache occurring on ≥4 and ≤14 days  
○ on ≥4 days, fulfilling any of the following: 
 ICHD-3 diagnostic criteria C and D for 1.1 Migraine without aura 
(Appendix D) 
 ICHD-3 criteria B and C for 1.2 Migraine with aura (Appendix D) 
 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. 

 
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− Patients with CM: 
○ Headache occurring on ≥15 days 
○ on ≥8 days, fulfilling any of the following: 
 ICHD-3 diagnostic criteria C and D for 1.1 Migraine without aura 
(Appendix D) 
 ICHD-3 criteria B and C for 1.2 Migraine with aura (Appendix D) 
 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. 
e. Not using preventive medications (presented in Appendix B) (ie, at least 5 half-lives 
have passed since last use) or using no more than 1 preventive medication (presented 
in Appendix A) 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 
beginning the 28-day run-in period.  
f. Body mass index of 17.5 to 37.5 kg/m2 and a total body weight between 45 and 
120 kg, inclusive 
g. All patients must be of nonchildbearing potential, defined as: 
− women surgically sterile by documented complete hysterectomy, bilateral 
oophorectomy, or bitubal ligations or confirmed to be postmenopausal (at least 
1 year since last menses and follicle-stimulating hormone above 35 U/L) 
− men surgically sterile by documented vasectomy 
or 
if of childbearing potential, patients must meet any of the following criteria: 
− Patients must simultaneously use 2 forms of highly effective contraception 
methods (defined in Section 5.2) with their partners during the entire study period 
and for 7.5 months after the last dose of study drug. 
− Sexual abstinence is only considered a highly effective method if defined as 
refraining from heterosexual intercourse in the defined period. The reliability of 
sexual abstinence needs to be evaluated in relation to the duration of the clinical 
study and the preferred and usual lifestyle of the subject. Periodic abstinence (eg, 
calendar, ovulation, symptothermal, post-ovulation methods), declaration of 
abstinence for the duration of a study, and withdrawal are not acceptable methods 
of contraception. 
h. Female patients of childbearing potential must have a negative serum β-HCG 
pregnancy test at screening (confirmed by urine dipstick β-HCG pregnancy test at 
baseline). 

 
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i. The patient demonstrated compliance with the electronic headache diary during the 
run-in period by entry of headache data on a minimum of 24 out of 28 days 
(~85% diary compliance) 
j. The patient is in good health as determined by a medical and psychiatric history, 
medical examination, 12-lead ECG, serum chemistry, hematology, coagulation, 
and urinalysis.  
k. The patient must be willing and able to comply with study restrictions, to remain at 
the clinic for the required duration during the study period, and to return to the 
clinic for the follow up evaluation as specified in this protocol. 
Patients Rolling Over from the Pivotal Efficacy Studies for ADA Assessment Only: Patients may 
be included in this study if they sign and date the informed consent document. 
4.2. 
Patient Exclusion Criteria 
4.2.1. 
Patients Rolling Over from the Pivotal Efficacy Studies 
Patients will be excluded from participating in this study if they meet any of the following 
criteria:  
a. Any finding that, in the judgment of the investigator, is clinically significantly 
abnormal, including hematology values, serum chemistry, coagulation tests, or 
urinalysis (abnormal tests may be repeated for confirmation) 
b. Pregnant or nursing females 
c. Any finding in the baseline 12-lead ECG considered clinically significant in the 
judgment of the investigator 
d. Compliance with daily diary entry lower than 75% at the last month of the 
double-blind treatment period of the pivotal efficacy study 
4.2.2. 
Patients Not Rolling Over from the Pivotal Efficacy Studies 
Patients will be excluded from participating in this study if they meet any of the following 
criteria:  
a. Clinically significant hematological, cardiac, renal, endocrine, pulmonary, 
gastrointestinal, genitourinary, neurologic, hepatic, or ocular disease, at the discretion 
of the investigator 
b. 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 
c. History of clinically significant cardiovascular disease or vascular ischemia (such as 
myocardial, neurological [eg, cerebral ischemia], 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 
d. Known infection or history of human immunodeficiency virus, tuberculosis, or 
chronic hepatitis B or C infection 

 
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e. Past or current history of cancer in the past 5 years, except for appropriately treated 
nonmelanoma skin carcinoma  
f. Pregnant or nursing females 
g. History of hypersensitivity reactions to injected proteins, including monoclonal 
antibodies 
h. Participation in a clinical study of a new chemical entity or a prescription medicine 
within 2 months before study drug administration or 5 half-lives, whichever is longer 
i. Any finding in the baseline 12 lead ECG considered clinically significant in the 
judgment of the investigator 
j. Any finding that, in the judgment of the investigator, is a clinically significant 
abnormality, including serum chemistry, hematology, coagulation, and urinalysis test 
values (abnormal tests may be repeated for confirmation) 
k. Hepatic enzymes (ALT, AST, and ALP) >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 
l. Serum creatinine >1.5 × the ULN, clinically significant proteinuria, or evidence of 
renal disease at screening 
m. History of alcohol or drug abuse during the past 2 years, or alcohol or drug 
dependence during the past 5 years 
n. The patient cannot participate or successfully complete the study, in the opinion of 
their healthcare provider or the investigator, for any of the following reasons: 
− mentally or legally incapacitated or unable to give consent for any reason 
− in custody due to an administrative or a legal decision, under guardianship, or 
institutionalized 
− unable to be contacted in case of emergency 
− has any other condition, which, in the opinion of the investigator, makes the 
patient inappropriate for inclusion in the study 
o. Patient is a study center or sponsor employee who is directly involved in the study or 
the relative of such an employee 
Patients Rolling Over from the Pivotal Efficacy Studies for ADA Assessment Only: Not 
applicable. 
4.3. 
Justification for Key Inclusion and Exclusion Criteria 
The inclusion and exclusion criteria select for patients who meet ICHD-3 criteria for CM and 
EM (Classification Committee of the IHS, 2013). Because headache consortium guidelines 
recommend preventive therapies for patients with CM and patients with EM occurring on more 
than 4 days per month due to the frequency of headaches and high degree of disability, patients 
will be allowed to remain on stable doses of no more than 2 (patients not rolling over from the 
pivotal efficacy studies) or 1 (patients rolling over from the pivotal studies) concomitant 

 
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preventive medication with at least moderate efficacy (Silberstein et al 2012) for the duration of 
the study. If discontinuation of preventive medication is clinically indicated by the investigator 
(eg, due to no further need or safety concerns), the medications may be stopped, and the reason 
must be recorded. 
4.4. 
Withdrawal Criteria and Procedures 
In accordance with the Declaration of Helsinki (in accordance with the applicable country’s 
acceptance), each patient is free to withdraw from the study at any time. The investigator also 
has the right to withdraw a patient from the study in the event of intercurrent illness, adverse 
events, pregnancy (see Section 7.2), or other reasons concerning the health or well-being of the 
patient, or in the event of lack of cooperation. In addition, a patient may be withdrawn from the 
study as described in Sections 3.12, 3.14.4, 5.4, and 7.1.7.  
Should a patient decide to withdraw after administration of study drug, or should the investigator 
decide to withdraw the patient, all efforts will be made to complete and report all observations up 
to the time of withdrawal. A complete final evaluation at the time of the patient’s withdrawal 
should be made and an explanation given as to why the patient is withdrawing or being 
withdrawn from the study. 
The reason for and date of withdrawal from study drug treatment and the reason for and date of 
withdrawal from the study must be recorded on the source documentation and transcribed onto 
the CRF. If a patient withdraws consent, every attempt will be made to determine the reason. If 
the reason for withdrawal is an adverse event or a potentially clinically significant abnormal 
laboratory test result, monitoring will be continued at the discretion of the investigator (eg, until 
the event has resolved or stabilized, until the patient is referred to the care of a healthcare 
professional, or until a determination of a cause unrelated to the study drug or study procedure is 
made). The specific event or test result must be recorded on the source documentation and 
transcribed onto the CRF.  
All protocol-specified procedures/assessments should be performed at the early withdrawal visit 
(see EOT/early withdrawal visit in Table 1 and Table 2). Patients who withdraw from the study 
will be asked to return to the clinical site for a follow-up visit approximately 7.5 months after 
their last dose of study drug. Immunogenicity, pharmacokinetic, and safety 
procedures/assessments will be performed at this visit (see Table 1 and Table 2). 
A patient should only be designated as lost to follow up if the site is unable to establish contact 
with the patient after 3 documented attempts via 2 different methods (phone, text, e-mail, 
certified letter, etc.). 

 
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5. 
TREATMENT OF PATIENTS 
5.1. 
Drugs Administered During the Study  
Patients rolling over from the pivotal efficacy studies who were randomized to the active 
treatment groups and will continue receiving study drug in the current study will continue 
receiving the same treatment (ie, monthly TEV-48125 at 225 mg or quarterly TEV-48125 at 
675 mg) throughout this long-term safety, tolerability, and efficacy study. Patients rolling over 
from the pivotal efficacy studies who received placebo and will continue receiving study drug in 
the current study and patients not rolling over will be randomly assigned in a 1:1 ratio using IRT 
as follows: 
• Patients with CM will receive sc TEV-48125 at 675 mg (loading dose) followed by 
11 monthly sc doses of TEV-48125 at 225 mg or sc TEV-48125 at 675 mg once 
every 3 months for 12 months for a total of 4 doses. 
• Patients with EM will receive monthly sc TEV-48125 at 225 mg for 12 months or sc 
TEV-48125 at 675 mg once every 3 months for 12 months for a total of 4 doses 
Study drug will be administered by qualified study personnel as sc injections approximately 
every 4 weeks (28 days). The 4-week period will be determined relative to the planned dosing 
day provided the patient returns to the study center within the tolerance window (±5 days). If the 
patient returns to the study center more than 5 days late, then the 4-week period will be 
determined from the actual dosing day rather than the planned dosing day. 
In order to maintain the study blind, all patients will receive 3 injections at visits 2, 5, 8, and 11 
and 1 injection at all other visits as detailed in Table 4. 
Table 4: 
Study Drug Administration by Treatment Group and Visit 
Treatment group in this 
study 
Visit 2 
Visits 5, 8, and 11 
Visits 3, 4, 6, 7, 9, 10, 
12, and 13 
Loading dose of TEV-48125 at 
675 mg followed by monthly 
TEV-48125 at 225 mg 
3 active injections 
(225 mg/1.5 mL) 
1 active injection 
(225 mg/1.5 mL) and two 
1.5-mL placebo 
injections 
1 active injection 
(225 mg/1.5 mL) 
Monthly TEV-48125 at 
225 mg 
1 active injection 
(225 mg/1.5 mL) and 
two 1.5-mL placebo 
injections 
1 active injection 
(225 mg/1.5 mL) and 
two 1.5-mL placebo 
injections 
1 active injection 
(225 mg/1.5 mL) 
Quarterly TEV-48125 at 
675 mg 
3 active injections 
(225 mg/1.5 mL) 
3 active injections 
(225 mg/1.5 mL) 
one 1.5-mL placebo 
injection 
Individual visit kits containing 1 prefilled syringe with a staked 27 G ½” needle will be provided. 
At the time of each study visit, the IRT will be queried, and site personnel will retrieve and 
administer 1.5 mL from each syringe contained in the appropriately numbered kit(s). Kit 
numbers will be entered into the CRF. 

 
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The recommended sc injection sites follow the National Institutes of Health Patient Education 
Guidelines of June 2012, which are available in Appendix C of this document and at the 
following website: http://www.cc.nih.gov/ccc/patient_education/pepubs/subq.pdf. The suggested 
sites of injection are back of upper arms, lower abdomen/belly/waistline, and front of thighs. At 
each visit, the injections should be given in a different location (eg, not in precisely the same 
place), and study staff member(s) responsible for administration of injections should inspect 
previous injection sites to ensure that they are free of bruising and tenderness and that proper 
rotation of sites is performed.  
Study drug should be removed from the refrigerator and allowed to equilibrate at room 
temperature for 15 to 30 minutes before study drug administration.  
A 1.5-mL volume from each syringe in each visit’s kit(s) must be injected sc for dosing to be 
considered complete. The total number of sc injections and their locations will be recorded for 
each dosing visit. 
5.2. 
Restrictions 
Medications prohibited before and/or during the study are described in Section 5.3 and in the 
exclusion criteria (Section 4.2). Restrictions in regard to pregnancy and required laboratory 
values are provided in the inclusion and exclusion criteria (Section 4.1 and Section 4.2, 
respectively). Restrictions in regard to sexual activity are detailed in the inclusion and exclusion 
criteria (Section 4.1 and Section 4.2, respectively), and highly effective contraception methods 
are reviewed below. 
Highly effective contraception methods include the following hormonal and other methods of 
birth control: 
• combined (estrogen and gestagen) oral contraceptives, hormone implants, hormone 
rings, contraceptive patch, and hormone injectables initiated at least 7 days before 
study drug administration 
• intrauterine device in place for a period of at least 2 months before study drug 
administration 
• barrier methods of contraception: condoms with spermicide for males, diaphragm 
with spermicide for females, and portio cap with spermicide for females 
• vasectomy for male partners of female patients 
There were no additional restrictions in this study. 
In addition, male patients may not donate sperm for the duration of the study and for 7.5 months 
after discontinuation of study drug. 
5.3. 
Prior and Concomitant Therapy or Medication 
Any prior or concomitant therapy, medication, or procedure that a patient has had within 
6 months before study drug administration and up to the end of the study period will be recorded 
on the CRF. In addition, migraine preventive medication that a patient took within 2 years before 
study drug administration will be recorded. Generic or trade name, indication, and dosage will be 

 
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recorded. The sponsor will encode all therapy and medication according to the World Health 
Organization drug dictionary. 
Patients will be allowed to remain on stable doses of up to 1 (patients rolling over from the 
pivotal efficacy studies) or 2 (patients not rolling over from the pivotal efficacy studies) 
concomitant preventive migraine medication for the duration of the study provided the 
medication has at least moderate evidence of efficacy as defined by guidelines (Silberstein et al 
2012) and presented in Appendix A. Patients on preventive medication must be on a stable dose 
for at least 2 months of consecutive use prior to study entry. Alternatively, patients must have 
discontinued the preventive medication at least 5 half-lives prior to screening. If discontinuation 
of preventive medication is clinically indicated by the investigator (eg, due to no further need or 
safety concerns), the medications may be stopped, and the reason must be recorded. For all 
patients not remaining on preventive migraine medications, disallowed mediations are presented 
in Appendix B. 
Patients will be allowed to use acute medication to treat acute migraine attacks, as needed. 
All concomitant medications taken during the study, including over-the-counter medications, 
vitamins, or herbal or nutritional supplements, must be recorded with indication, daily dose, and 
start and stop dates of administration. All patients will be questioned about concomitant 
medication use at each visit. 
5.4. 
Procedures for Monitoring Patient Compliance 
The investigator will be responsible for monitoring patient compliance. If the investigator or the 
sponsor determines that the patient is not in compliance with the study protocol, the investigator 
and the sponsor should determine whether the patient should be withdrawn. The IEC/IRB should 
be notified. 
5.5. 
Total Blood Volume 
The total volume of blood to be collected during this study for each patient rolling over from the 
pivotal efficacy studies is approximately 164.5 mL, as detailed in Table 5. 
Table 5: 
Blood Volumes for Patients Rolling Over from the Pivotal Efficacy Studies 
Type of samples 
Volume per sample (mL) 
Number of samples 
Volume 
Serum chemistry  
6 
Up to 7a 
42 
Hematology 
3 
Up to 7a 
21 
Pharmacokinetic 
4 
5 
20 
ADA 
5 
4 
20 
Biomarkerb 
18.5 
3 
55.5 
Pharmacogenomicc 
6 
1 
6 
Total 
-- 
27 
164.5 
a All patients will have blood samples for clinical laboratory tests collected at visits 4, 6, 8, 10, 12, and 14. Patients who enroll in 
this study more than 30 days after completing the EOT visit of the pivotal efficacy studies will have additional blood samples 
collected for clinical laboratory tests at visit 2. 
b For each 18.5-mL sample, individual volumes will be 6 mL each for serum and plasma and 6.5 mL for RNA. 
c A pharmacogenomic sample will be collected from patients who consent to pharmacogenomic analysis, if a sample is not 
obtained during the pivotal efficacy study. 
ADA=antidrug antibody; EOT=end-of-treatment; RNA=ribonucleic acid. 

 
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The total volume of blood to be collected for each patient who does not rollover from the pivotal 
efficacy studies is approximately 212 mL, as detailed in Table 6.  
Table 6: 
Blood Volumes for Patients Not Rolling Over from the Pivotal Efficacy 
Studies 
Type of samples 
Volume per sample (mL) 
Number of samples 
Volume 
Serum chemistry and 
pregnancya 
6 
8 
48 
Hematology 
3 
8 
24 
FSHb 
3 
1 
3 
Pharmacokinetic 
4 
Up to 8c 
32 
ADA 
5 
5 
25 
Biomarkerd 
18.5 
4 
74 
Pharmacogenomice 
6 
1 
6 
Total 
-- 
35 
212 
a Women of childbearing potential only. 
b Postmenopausal women only. 
c Blood samples for TEV-48125 concentration determination will be collected at visits 2, 5, 8, 11, 14, and 15. In addition, 
patients will return to the study center for at least 1 and up to 2 additional visits after any dose of study drug for blood sampling 
for plasma TEV-48125 concentration. These visits should occur during the following time periods relative to any dose of study 
drug: 3 to 10 days or 15 to 20 days after study drug administration. 
d For each 18.5-mL sample, individual volumes will be 6 mL each for serum and plasma and 6.5 mL for RNA. 
e Collected from patients who consent to pharmacogenomic analysis. 
ADA=antidrug antibody; FSH=follicle-stimulating hormone; RNA=ribonucleic acid. 
The total blood volume collected during the current study for patients rolling over from the 
pivotal efficacy studies for ADA assessment only will be approximately 5 mL. 

 
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6. 
ASSESSMENT OF EFFICACY 
6.1. 
Primary Efficacy Measure and Justification  
There is no primary efficacy measure. 
6.2. 
Electronic Headache Diary 
Exploratory efficacy endpoints will be derived from headache variables collected during the time 
period specified in Table 1 (patients rolling over from the pivotal efficacy studies) and Table 2 
(patients not rolling over from the pivotal efficacy studies) using an electronic headache diary 
device. Eligible patients will receive comprehensive training from site personnel in the use of the 
electronic headache diary device. Site personnel will also instruct patients on the requirement for 
timely and daily completion of the electronic diary. 
On each day, the patient will be asked to record diary data for the previous 24-hour period. 
Patients may be asked about their performance at work, school, and when doing household 
chores (ie, functional assessments). Patients who report headache on the previous day will 
answer questions about the headache (ie, the number of hours with headache, presence of 
associated symptoms, and use of acute migraine medications). Additional details regarding the 
questions patients will answer can be found in the electronic headache diary training manual. 
If a patient fails to log in and complete the diary for the preceding day, the patient will be 
prompted to enter the missed day’s information the next time he/she accesses the electronic diary 
provided no more than 48 hours have elapsed since completion of that day. If more than 48 hours 
have elapsed since completion of a diary day, the patient will not be allowed to enter diary 
information for that day, and it will be considered a missed day. 
Rating of headache severity and duration of headache for each day will be completed in the 
electronic diary. 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, the headache severity will be subjectively rated by the patient as follows: 
• mild headache 
• moderate headache 
• severe headache 
Patients will also record whether photophobia, phonophobia, nausea, and vomiting are present, 
and they will record any migraine medications (name of drug, number of tablets/capsules, and 
the dose in milligrams per tablet/capsule) taken on each day. 
6.3. 
Six-Item Headache Impact Test 
The HIT-6 was developed by Kosinski et al (2003) as a short form for reliably assessing the 
adverse headache impact in clinical practice and clinical research settings. The questionnaire 
measures the adverse impact of headache on social functioning, role functioning, vitality, 
cognitive functioning, and psychological distress. It also assesses headache severity. The HIT-6 

 
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has been shown to be a reliable and valid tool for assessment of headache impact in patients with 
CM (Yang et al 2011). 
Patients with CM will complete the HIT-6 at time points specified in Table 1 (patients rolling 
over from the pivotal efficacy studies) and Table 2 (patients not rolling over from the pivotal 
efficacy studies). 
6.4. 
Migraine Disability Assessment Questionnaire 
The MIDAS questionnaire is a 5-item instrument developed to assess headache-related disability 
based on lost days of activity in 3 domains (work, household work, and nonwork) over the 
previous 3 months. The total of the scores of the first 5 questions is used for grading of disability, 
with scores of 0 to 5, 6 to 10, 11 to 20, and ≥21 interpreted as disability grades 1 (little or no 
disability), 2 (mild disability), 3 (moderate disability), and 4 (severe disability), respectively. It 
has been shown to be reliable and valid for migraine, with substantially higher scores in migraine 
cases than non-migraine cases (Stewart et al 1999a, Stewart et al 1999b). 
Patients with EM will complete the MIDAS questionnaire at time points specified in Table 1 
(patients rolling over from the pivotal efficacy studies) and Table 2 (patients not rolling over 
from the pivotal efficacy studies). 
6.5. 
Two-Item Patient Health Questionnaire/9-Item Patient Health 
Questionnaire 
The PHQ is a 9-item questionnaire with each item corresponding to 1 criterion of the Diagnostic 
and Statistical Manual for Mental Disorders 4th 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 (Spitzer et al 1999). 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. The PHQ-2 and the PHQ-9 
are well-validated measures for detecting and monitoring depression, anxiety, and somatization 
(Kroenke et al 2010). 
Patients will complete the PHQ-2 at time points specified in Table 1 (patients rolling over from 
the pivotal efficacy studies) and Table 2 (patients not rolling over from the pivotal efficacy 
studies). If the PHQ-2 is positive (ie, a score ≥3), patients will complete questions 3 through 9 
[unique questions] of the PHQ-9. 
6.6. 
Migraine-Specific Quality of Life Questionnaire 
The MSQOL, version 2.1, is a 14-item questionnaire to assess the impact of migraine and 
migraine treatment on a patient’s quality of life during the previous 4 weeks, which has been 
shown to be a reliable and valid tool for use in CM and EM (Bagley et al 2012). 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. 

 
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Patients will complete the MSQOL at time points specified in Table 1 (patients rolling over from 
the pivotal efficacy studies) and Table 2 (patients not rolling over from the pivotal efficacy 
studies). 
6.7. 
EuroQol-5 Dimension Questionnaire 
The EQ-5D-5L is a standardized questionnaire that assesses overall state of health. The 
EQ-5D-5L consist of 2 parts. In Part 1, patients rate their health state in 5 domains: mobility, 
self-care, usual activities, pain/discomfort, and mood, 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, patients 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. 
Patients will complete the EQ-5D-5L at the time points specified in Table 1 (patients rolling over 
from the pivotal efficacy studies) and Table 2 (patients not rolling over from the pivotal efficacy 
studies). 
6.8. 
Patient Global Impression of Change Scale 
The PGIC scale is a validated generic tool for assessment of overall change in the severity of 
illness following treatment. Patients 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 study on a 7-point scale where 1=no change (or condition 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.  
Patients will complete the PGIC scale at time points specified in Table 1 (patients rolling over 
from the pivotal efficacy studies) and Table 2 (patients not rolling over from the pivotal efficacy 
studies). 
6.9. 
Work Productivity and Activity Impairment Questionnaire 
The generic version of the WPAI questionnaire measures the overall effect of health on 
productivity at work and daily activities. The specific health problems version of the WPAI 
questionnaire allows investigators to attribute productivity and activity impairment issues to 
specific 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, 1 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) (Reilly et al 1993).  

 
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Patients will complete the WPAI questionnaire at time points specified in Table 1 (patients 
rolling over from the pivotal efficacy studies) and Table 2 (patients not rolling over from the 
pivotal efficacy studies). 

 
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7. 
ASSESSMENT OF SAFETY  
In this study, safety will be assessed by qualified study personnel by evaluating the following: 
reported adverse events, clinical laboratory test results, vital signs measurements, 12-lead ECG 
findings, physical examination findings (including body weight measurements), eC-SSRS scores, 
local injection site assessments, and concomitant medication usage. 
7.1. 
Adverse Events  
7.1.1. 
Definition of an Adverse Event 
An adverse event is any untoward medical occurrence in a patient administered a pharmaceutical 
product, regardless of whether it has a causal relationship with this treatment.  
In this study, any adverse event occurring after the clinical study patient has signed the informed 
consent form for this study should be recorded and reported as an adverse event. 
An adverse event can, therefore, be any unfavorable and unintended physical sign, symptom, or 
laboratory parameter that develops or worsens in severity during the course of this study, or 
significant worsening of the disease under study or of any concurrent disease, whether or not 
considered related to the study drug. A new condition or the worsening of a pre-existing 
condition will be considered an adverse event. Stable chronic conditions (such as arthritis) that 
are present before study entry and do not worsen during this study will not be considered adverse 
events.  
Accordingly, an adverse event can include any of the following: 
• intercurrent illnesses 
• physical injuries 
• events possibly related to concomitant medication 
• significant worsening (change in nature, severity, or frequency) of the disease under 
study or other pre-existing conditions (Note: A condition recorded as pre-existing that 
is intermittently symptomatic [eg, headache] and that occurs during this study should 
be recorded as an adverse event.) 
• drug interactions 
• events occurring during diagnostic procedures or during any follow-up period of this 
study 
• laboratory or diagnostic test abnormalities that result in the withdrawal of the patient 
from the study, are associated with clinical signs and symptoms or a serious adverse 
event, or require medical treatment or further diagnostic work-up, or are considered 
by the investigator to be clinically significant (Note: Abnormal laboratory test results 
at the screening visit that preclude a patient from entering the study or receiving study 
drug are not considered adverse events.)  
• all events of possible drug-induced liver injury with hyperbilirubinemia (defined as 
AST or ALT ≥3 × the ULN, plus either total bilirubin ≥2 × the ULN or INR >1.5) or 

 
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Hy’s Law events require immediate study treatment cessation and reporting as a 
serious adverse event. Refer to Appendix E for guidance regarding monitoring 
patients with elevated liver function tests. 
Migraine exacerbations, including acute headache, requiring headache medications will be 
collected as part of the efficacy assessment in this study. Migraine exacerbations (including acute 
headache) should be recorded as an adverse event only if the presentation and/or outcome is 
more severe than would typically be expected from the normal course of the disease in a 
particular patient or if they are severe enough to require hospitalization of the patient, in which 
case they are recorded as serious adverse events. 
7.1.2. 
Recording and Reporting Adverse Events 
For adverse event recording, the study period is defined for each patient as the time period from 
signature of the informed consent form for this study through the follow-up visit (approximately 
7.5 months after the final dose of study drug). Adverse events will be collected at each visit via 
adverse event inquiry. 
All adverse events that occur during the defined study period must be recorded on the source 
documentation and transcribed onto the CRF, regardless of the severity of the event or judged 
relationship to the study drug. For serious adverse events, the serious adverse event form must 
also be completed and the serious adverse event must be reported immediately (see 
Section 7.1.5.3.1). The investigator does not need to actively monitor patients for adverse events 
once the study has ended. Serious adverse events occurring to a patient after the defined study 
period should be reported to the sponsor if the investigator becomes aware of them, following the 
procedures described in Section 7.1.5.3.1.  
At each contact with the patient, the investigator or designee must question the patient about 
adverse events by asking an open-ended question such as, “Have you had any unusual symptoms 
or medical problems since the last visit? If yes, please describe.” All reported or observed signs 
and symptoms will be recorded individually, except when considered manifestations of a 
medical condition or disease state. A precise diagnosis will be recorded whenever possible. 
When such a diagnosis is made, all related signs, symptoms, and any test findings will be 
recorded collectively as a single diagnosis on the CRF and, if it is a serious adverse event, also 
on the serious adverse event form. 
The clinical course of each adverse event will be monitored at suitable intervals until it resolves, 
stabilizes, or returns to baseline, or until the patient is referred for continued care to a another 
health care professional, or until a determination of a cause unrelated to the study drug or study 
procedure is made. 
The onset and end dates, duration (in case of adverse event duration of less than 24 hours), action 
taken regarding study drug, treatment administered, and outcome for each adverse event must be 
recorded on the source documentation and transcribed onto the CRF.  
The relationship of each adverse event to study drug and study procedures, and the severity and 
seriousness of each adverse event, as judged by the investigator, must be recorded as described 
below. 

 
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7.1.3. 
Severity of an Adverse Event 
The severity of each adverse event must be recorded as 1 of the choices on the following scale: 
Mild:  
No limitation of usual activities 
Moderate:  Some limitation of usual activities 
Severe:  
Inability to carry out usual activities 
7.1.4. 
Relationship of an Adverse Event to the Study Drug 
The relationship of an adverse event to the study drug is characterized as follows: 
Term 
Definition 
Clarification 
No reasonable 
possibility 
(not related) 
 
This category applies to adverse 
events that, after careful 
consideration, are clearly due to 
extraneous causes (disease, 
environment, etc) or to adverse 
events that, after careful medical 
consideration at the time they are 
evaluated, are judged to be unrelated 
to the study drug. 
The relationship of an adverse event may be considered 
“no reasonable possibility” if it is clearly due to 
extraneous causes or if at least 2 of the following apply: 
• 
It does not follow a reasonable temporal sequence 
from the administration of the study drug. 
• 
It could readily have been produced by the patient’s 
clinical state, environmental, or toxic factors, or other 
modes of therapy administered to the patient. 
• 
It does not follow a known pattern of response to the 
study drug.  
• 
It does not reappear or worsen when the study drug is 
re-administered.  
Reasonable 
possibility 
(related) 
 
This category applies to adverse 
events for which, after careful 
medical consideration at the time 
they are evaluated, a connection with 
the study drug administration cannot 
be ruled out with certainty. 
The relationship of an adverse event may be considered 
“reasonable possibility” if at least 2 of the following 
apply: 
• 
It follows a reasonable temporal sequence from 
administration of the study drug. 
• 
It cannot be reasonably explained by the known 
characteristics of the patient’s clinical state, 
environmental or toxic factors or other modes of 
therapy administered to the patient. 
• 
It disappears or decreases on cessation or reduction in 
dose. There are important exceptions when an 
adverse event does not disappear upon 
discontinuation of the study drug, yet a drug 
relationship clearly exists. 
• 
It follows a known pattern of response to the study 
drug. 

 
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7.1.5. 
Serious Adverse Events 
7.1.5.1. 
Definition of a Serious Adverse Event 
A serious adverse event is an adverse event occurring at any dose that results in any of the 
following outcomes or actions: 
• death 
• a life-threatening adverse event (ie, the patient was at immediate risk of death from 
the event as it occurred); does not include an event that, had it occurred in a more 
severe form, might have caused death 
• inpatient hospitalization or prolongation of existing hospitalization, which means that 
hospital inpatient admission and/or prolongation of hospital stay were required for 
treatment of an adverse event, or that they occurred as a consequence of the event. 
Hospitalizations scheduled prior to study entry will not be considered serious adverse 
events, unless there was worsening of the pre-existing condition during the patient’s 
participation in this study.  
• persistent or significant disability or incapacity (refers to a substantial disruption of 
one’s ability to conduct normal life functions) 
• a congenital anomaly/birth defect 
• an important medical event that may not result in death, be life-threatening, or require 
hospitalization, but may jeopardize the patient and may require medical intervention 
to prevent one of the outcomes listed in this definition. Examples of such events are 
intensive treatment in an emergency room or at home for allergic bronchospasm, 
blood dyscrasias or convulsions that do not result in hospitalization, or the 
development of drug dependency or drug abuse. Note: Any suspected transmission of 
an infectious agent via a medicinal product is considered an important medical event. 
An adverse event that does not meet any of the criteria for seriousness listed above will be 
regarded as a nonserious adverse event. 
7.1.5.2. 
Expectedness 
A serious adverse event that is not included in the Adverse Reaction section of the relevant 
reference safety information by its specificity, severity, outcome, or frequency is considered an 
unexpected adverse event. The reference safety information for this study is the Investigator’s 
Brochure. 
The sponsor’s Pharmacovigilance Department will determine the expectedness for all serious 
adverse events. 
For the purpose of SUSAR reporting, the version of the reference safety information document at 
the moment of the occurrence of the SUSAR applies. 

 
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7.1.5.3. 
Reporting a Serious Adverse Event 
7.1.5.3.1. Investigator Responsibility 
To satisfy regulatory requirements, all serious adverse events (as described in Section 7.1.5.1) 
that occur during the defined study period (including the protocol-defined follow-up period, 
described in Section 7.1.2), regardless of judged relationship to treatment with the study drug, 
must be reported to the sponsor by the investigator. The event must be reported within 24 hours 
of when the investigator learns about it. Completing the serious adverse event form and reporting 
the event must not be delayed, even if not all the information is available. The investigator does 
not need to actively monitor patients for adverse events once this study has ended. Serious 
adverse events occurring in a patient after the defined study period should be reported to the 
sponsor if the investigator becomes aware of them. 
The serious adverse event form should be sent to the local safety officer (LSO) or other 
designated personnel (a contract research organization [CRO] in a country without a sponsor 
LSO; contact information is in the Clinical Study Personnel Contact Information section); the 
LSO will forward the report to the sponsor’s Global Patient Safety & Pharmacovigilance 
Department. 
The following information should be provided to record the event accurately and completely: 
• study number 
• investigator and investigational center identification 
• patient number 
• onset date and detailed description of adverse event 
• investigator’s assessment of the relationship of the adverse event to the study drug 
(no reasonable possibility, reasonable possibility) 
Additional information may include the following: 
• age and sex of patient 
• date of 1st dose of study drug 
• date and amount of last administered dose of study drug 
• action taken 
• outcome, if known 
• severity 
• explanation of assessment of relatedness 
• concomitant therapy (including doses, routes, and regimens) and treatment of the 
event 
• pertinent laboratory or other diagnostic test data  
• medical history 
• results of dechallenge/rechallenge, if known 

 
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• for an adverse event resulting in death:  
− cause of death (whether or not the death is related to study drug) 
− autopsy findings (if available) 
Each report of a serious adverse event will be reviewed and evaluated by the investigator and the 
sponsor to assess the nature of the event and the relationship of the event to the study drug, study 
procedures, and underlying disease.  
Additional information (follow-up) about any serious adverse event unavailable at the initial 
reporting should be forwarded by the investigational center within 24 hours of when it becomes 
known to the same address as the initial report.  
For all countries, the sponsor’s Global Patient Safety & Pharmacovigilance Department will 
distribute the Council for International Organizations of Medical Sciences form/extensible 
markup language file to the LSO and/or CRO for local submission to the regulatory authorities, 
IEC/IRBs, and investigators, according to regulations. The investigator is responsible for 
ensuring that the IRB/IEC is also informed of the event, in accordance with local regulations.  
Blinding will be maintained for the people who are involved directly in the study. Therefore, in 
case of a SUSAR, only the LSO and/or CRO personnel involved with safety regulatory 
submissions will receive the unblinded report for regulatory submission; the others will receive a 
blinded report.  
Note: Although pregnancy is not a serious adverse event, the process for reporting a pregnancy is 
the same as that for reporting a serious adverse event, but using the pregnancy form (see 
Section 7.2).  
7.1.5.3.2. Sponsor Responsibility 
If a serious unexpected adverse event is believed to be related to the study drug or study 
procedures, the sponsor will take appropriate steps to notify all investigators participating in 
sponsored clinical studies of TEV-48125 and the appropriate regulatory authorities (and 
IEC/IRB, if appropriate).  
In addition to notifying the investigators and regulatory authorities (and IEC/IRB, if appropriate), 
other measures may be required, including the following:  
• altering existing research by modifying the protocol 
• discontinuing or suspending the study 
• altering the process of informed consent by modifying the existing consent form and 
informing current study participants of new findings 
• modifying listings of expected toxicities to include adverse events newly identified as 
related to TEV-48125 
7.1.6. 
Protocol-Defined Adverse Events of Special Interest 
The following are considered protocol-defined adverse events to be sent to the sponsor’s Global 
Patient Safety and Pharmacovigilance Department for evaluation: ophthalmic adverse events of 
at least moderate severity, events of possible drug-induced liver injury (AST or ALT ≥3 × the 

 
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ULN, total bilirubin ≥2 × the ULN or INR >1.5), Hy’s Law events, or events of suspected 
anaphylaxis and severe hypersensitivity reactions. Severe hypersensitivity reactions will be 
monitored using the diagnostic criteria for anaphylaxis as outlined by the 2006 Joint National 
Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network Second 
Symposium on Anaphylaxis (Sampson et al, 2006 [also see Appendix F]). 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. 
The process for reporting a protocol-defined adverse event is the same as that for reporting a 
serious adverse event (see Section 7.1.5.3). Protocol-defined adverse events for reporting to 
Pharmacovigilance Department can be either serious or nonserious according to the criteria 
outlined in Section 7.1.5.1. 
7.1.7. 
Withdrawal Due to an Adverse Event 
Any patient who experiences an adverse event may be withdrawn from the study or from study 
drug at any time at the discretion of the investigator. If a patient is withdrawn because of an 
adverse event, both the adverse events page and termination page of the CRF will be completed 
at that time.  
The patient will be monitored at the discretion of the investigator (eg, until the event has 
resolved or stabilized, until the patient is referred to the care of a health care professional, or 
until a determination of a cause unrelated to the study drug or study procedure is made). The 
investigator must inform the clinical project physician/clinical leader as soon as possible of all 
patients who are being considered for withdrawal due to adverse events. Additional reports must 
be provided when requested. 
If a patient is withdrawn from the study or study drug for multiple reasons that include adverse 
events, the termination page of the CRF should indicate that the withdrawal was related to an 
adverse event. An exception to this requirement will be the occurrence of an adverse event that, 
in the opinion of the investigator, is not severe enough to warrant discontinuation but that 
requires the use of a prohibited medication, thereby requiring discontinuation of the patient. In 
such a case, the reason for discontinuation would be need to take a prohibited medication, not the 
adverse event. 
7.1.8. 
Overdose of Study Drug  
Any dose of study drug (whether the investigational product or placebo), whether taken 
intentionally or unintentionally, in excess of that prescribed must be immediately reported to the 
sponsor. When the identification of the study drug must be known, the investigator must follow 
the procedures outlined in Section 3.8.  
7.1.9. 
Protocol Deviations Because of an Adverse Event 
If a patient experiences an adverse event or medical emergency, departures from the protocol 
may be allowed on a case-by-case basis. After stabilization and/or treatment has been 
administered to ensure patient safety, the investigator or other physician in attendance must 
contact the individual identified in the Clinical Study Personnel Contact Information section of 
this protocol as soon as possible to discuss the situation. The investigator, in consultation with 
the sponsor, will decide whether the patient should continue to participate in the study. 

 
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7.2. 
Pregnancy 
All pregnancies of women participating in the study that occur during the study, or within 
7.5 months after the last administration of TEV-48125, are to be reported immediately to the 
individual identified in the clinical study personnel contact information section of this protocol, 
and the investigator must provide the LSO and/or CRO with the pregnancy form. The process for 
reporting a pregnancy is the same as that for reporting a serious adverse event (see 
Section 7.1.5.3).  
Any female patient becoming pregnant during the study will discontinue treatment. All patients 
who become pregnant will be monitored for the outcome of the pregnancy (including 
spontaneous or voluntary termination). If the pregnancy continues to term, the outcome (health 
of the infant up to 8 weeks of age), including details of birth and presence or absence of any birth 
defect, congenital abnormalities, or maternal and newborn complications, will be reported to the 
sponsor. Any complication of pregnancy during the study and any complication of pregnancy 
that the investigator becomes aware of after termination from the study will be reported as an 
adverse event or serious adverse event, as appropriate. 
If the pregnancy does not continue to term, 1 of the following actions will be taken: 
• For a spontaneous abortion, report as a serious adverse event. 
• For an elective abortion due to developmental anomalies, report as a serious adverse 
event. 
• For an elective abortion not due to developmental anomalies, report on the pregnancy 
form; do not report as an adverse event. 
For pregnancies of partners of men participating in the study, the Teva Pharmacovigilance 
Department will determine the procedure to appropriately follow up after notification as 
described above. All partners who become pregnant and provide appropriate consent to the Teva 
Pharmacovigilance Department will be monitored to the completion or termination of the 
pregnancy. 
7.3. 
Clinical Laboratory Tests 
All clinical laboratory test results outside of the reference range will be interpreted by the 
investigator as belonging to 1 of the following categories: 
• abnormal but not a clinically significant worsening from baseline  
• abnormal and a clinically significant worsening from baseline  
A laboratory test result that has significantly worsened (according to medical judgment) from the 
baseline result will be recorded on the source documentation, transcribed onto the CRF as an 
adverse event, and monitored as described in Section 7.1.2. An adverse event includes a 
laboratory or diagnostic test abnormality (once confirmed by repeat testing) that results in the 
withdrawal of the patient from the study, the temporary or permanent cessation of treatment with 
study drug, or medical treatment or further diagnostic work-up. 
In addition, potentially clinically significant values will be predefined by the sponsor for selected 
laboratory parameters and will be detailed in the statistical analysis plan.  

 
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Clinical laboratory tests (serum chemistry, hematology, coagulation, and urinalysis) will be 
performed at the time points detailed in Table 1 (patients rolling over from the pivotal efficacy 
studies) and Table 2 (patients not rolling over from the pivotal efficacy studies). Clinical 
laboratory tests will be performed using the central laboratory. Specific laboratory tests to be 
performed are listed below. 
7.3.1. 
Serum Chemistry 
The following serum chemistry tests will be performed: 
• calcium 
• phosphorus 
• sodium 
• potassium 
• chloride 
• carbon dioxide 
• magnesium 
• glucose 
• blood urea nitrogen 
• creatinine 
• ALT 
• AST 
• total bilirubin 
• direct bilirubin 
• indirect bilirubin (calculated) 
• lactate dehydrogenase  
• GGT 
• ALP 
• albumin 
• creatine phosphokinase 
• total protein 
7.3.2. 
Hematology 
The following hematology tests will be performed: 
• hemoglobin 
• hematocrit 

 
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• red blood cell (RBC) count  
• RBC indices 
− mean corpuscular volume 
− mean corpuscular hemoglobin concentration 
− RBC distribution width 
• platelet count 
• white blood cell (WBC) count and differential count (absolute values and 
percentages) 
− neutrophils 
− lymphocytes 
− eosinophils 
− monocytes 
− basophils 
7.3.3. 
Coagulation 
The following coagulation tests will be performed:  
• prothrombin time 
• partial thromboplastin time 
• INR 
7.3.4. 
Urinalysis 
Urinalysis will include testing for the following: 
• color and appearance 
• specific gravity 
• pH 
• blood (hemoglobin) 
• glucose 
• albumin 
• protein 
• ketones 
• leukocyte esterase 
• nitrite 
• direct bilirubin  

 
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• microscopic 
− bacteria 
− RBCs 
− WBCs 
− casts 
− crystal 
7.3.5. 
Other Clinical Laboratory Tests 
7.3.5.1. 
Human Chorionic Gonadotropin Tests 
At screening (visit 1), women of childbearing potential who are not rolling over from the pivotal 
efficacy studies will have a serum β-HCG test. Urine β-HCG tests will be performed for women 
of childbearing potential at all other time points specified in Table 1 (patients rolling over from 
the pivotal efficacy studies) and Table 2 (patients not rolling over from the pivotal efficacy 
studies). Any patient who becomes pregnant during the study will be withdrawn. Procedures for 
reporting the pregnancy are provided in Section 7.2.  
7.3.5.2. 
Follicle-Stimulating Hormone Tests 
Postmenopausal women not rolling over from the pivotal efficacy studies will have an FSH test 
at screening (visit 1). 
7.4. 
Vital Signs 
Vital signs (pulse, systolic and diastolic blood pressure, body temperature, and respiratory rate) 
will be measured before other assessments (eg, blood draws and administration of 
questionnaires) at the time points detailed in Table 1 (patients rolling over from the pivotal 
efficacy studies) and Table 2 (patients not rolling over from the pivotal efficacy studies). 
Before pulse and blood pressure are measured, the patient must be in a supine or 
semi-erect/seated 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 patient. For any abnormal vital sign 
finding, the measurement should be repeated as soon as possible. Any vital sign value that is 
judged by the investigator as a clinically significant change (worsening) from a baseline value 
will be considered an adverse event, recorded on the source documentation and transcribed onto 
the CRF, and monitored as described in Section 7.1.2. 
In addition, potentially clinically significant values may be predefined by the sponsor for 
selected vital signs (see Section 9.7.2) and, if so, will be documented in the statistical analysis 
plan or other relevant documents (eg, medical monitoring plan). 
7.5. 
Electrocardiography 
A 12-lead ECG will be conducted before other assessments (eg, blood draws and administration 
of questionnaires) at the time points detailed in Table 1 (patients rolling over from the pivotal 

 
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efficacy studies) and Table 2 (patients not rolling over from the pivotal efficacy studies). The 
ECGs should be performed after the patient has been supine for at least 5 minutes.  
The ECGs performed during the additional visits for pharmacokinetic sampling (patients not 
rolling over from the pivotal efficacy studies only) will be performed in triplicate.  
A qualified physician at a central diagnostic center will be responsible for interpreting the ECG. 
ECGs should be performed and transmitted according to the central ECG reading instructions 
provided in the ECG user manual. ECG equipment will be provided to all clinical sites. 
Although the ECG interpretation will be performed centrally, the clinical evaluation remains 
under the Investigator’s responsibility. 
The ECG will be evaluated by the Investigator at the time of recording (signed and dated), and 
the printout should be kept in the source documentation file. When potentially clinically 
significant findings are detected by the Investigator, a cardiologist should be consulted for a 
definitive interpretation. All communications and diagnoses should be filed in the source 
documentation file. The Investigator’s interpretation will be recorded in the CRF regardless of 
the central reading interpretation. Any abnormal findings assessed by the Investigator as 
clinically significant should be recorded in the relevant CRF modules (eg, adverse event, medical 
history). 
Objective alerts are predefined as described in the central ECG reading manual. In these cases, 
the site and the sponsor will be informed immediately. 
Any unscheduled ECGs must also be submitted for central ECG reading. 
Any ECG finding that is judged by the investigator as a potentially clinically significant change 
(worsening) compared with a baseline value will be considered an adverse event, recorded on the 
source documentation and transcribed onto the CRF, and monitored as described in 
Section 7.1.2. 
7.6. 
Physical Examinations 
Physical examinations, including height (to be obtained at the screening visit only) and weight 
will be performed at the time points detailed in Table 1 (patients rolling over from the pivotal 
efficacy studies) and Table 2 (patients not rolling over from the pivotal efficacy studies).  
A complete physical examination will include the following organ systems: general appearance; 
head, eyes, ears, nose, and throat; chest and lung; heart; abdomen; musculoskeletal; skin; lymph 
nodes; and neurological. Any physical examination finding that is judged by the investigator as a 
potentially clinically significant change (worsening) compared with a baseline value will be 
considered an adverse event, recorded on the CRF, and monitored as described in Section 7.1.2.  
7.7. 
Electronic Columbia-Suicide Severity Rating Scale 
The eC-SSRS will be used to assess the patient’s suicidal ideation (severity and intensity) and 
behavior (Posner et al 2011). The eC-SSRS Baseline/Screening version will be completed by the 
patient at visit 2 for patients not rolling over from the pivotal efficacy studies, and the eC-SSRS 
Since Last Visit version will be completed at all other time points, as described in Table 1 

 
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(patients rolling over from the pivotal efficacy studies) and Table 2 (patients not rolling over 
from the pivotal efficacy studies)  
Any positive findings on the eC-SSRS Since Last Visit version requires evaluation by a 
physician or doctoral-level psychologist. 
7.8. 
Concomitant Therapy or Medication 
Concomitant therapy or medication usage will be monitored throughout the study. Details of 
prohibited medications are found in Section 5.3.  
7.9. 
Immunogenicity 
Blood samples for serum ADA assessment will be collected at visits 5, 8, 14 (EOT/early 
withdrawal visit), and 15 (final visit) for patients rolling over from the pivotal efficacy studies 
and at those time points as well as visit 2 for patients not rolling over from the pivotal efficacy 
studies. Blood samples for ADA assessment will also be collected upon observation of any 
severe hypersensitivity reaction (eg, anaphylaxis). See Appendix F for the clinical criteria for 
diagnosing anaphylaxis. Bioanalytical personnel should be made aware of any anaphylaxis 
occurrence as soon as possible in case an anti-TEV-48125 immunoglobulin E assay is required. 
For patients rolling over from the pivotal efficacy studies for ADA assessment only, blood 
samples for serum ADA assessment will be collected at visit 16 (follow-up visit). 
7.10. 
Injection Site Assessments 
Injection site assessments will be performed immediately and 1 hour after administration of each 
dose of study drug (see Table 1 [patients rolling over from the pivotal efficacy studies] and 
Table 2 [patients not rolling over from the pivotal efficacy studies]). The injection site(s) will be 
assessed for erythema, induration, ecchymosis, and pain, and severity will be graded according 
to the following criteria: 
• Injection-site erythema, injection-site induration, and injection-site ecchymosis will 
be graded according to measurements: absent, 5 mm 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 measured as summarized in Table 7. 

 
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Table 7: 
Severity of Pain Scale for Injection Site Assessments 
Grade 
Assessment 
0 
No pain 
1 
Mild 
2 
Moderate 
3 
Severe 
4 
Worst possible 
If a patient has severe injection site induration, erythema, and/or ecchymosis and/or grade 3 
(severe) or grade 4 (worst possible) injection site pain at 1 hour after completion of study drug 
administration, the patient will be reassessed at 3 hours after study drug administration and 
hourly thereafter until the reaction/pain is of moderate or less severity. 
Appropriate treatment may be provided if necessary, in which case it must be recorded as 
concomitant medication. 
Injection site reactions will also be recorded as adverse events as described in Section 7.1. 
7.11. 
Methods and Timing of Assessing, Recording, and Analyzing Safety 
Data 
All adverse events will be reviewed on a periodic basis by the clinical project physician/medical 
monitor according to the safety monitoring plan (eg, scheduled safety reviews for TEV-48125) 
as interim/preliminary safety databases become available. Safety data will additionally be 
evaluated periodically and ad hoc (if necessary) in the Product Safety Group. 
Methods and timing of assessing safety data are discussed in Section 3.14. Procedures for 
recording safety data are discussed in Section 13.1, and methods of safety analyses are discussed 
in Section 9.7.2.  

 
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8. 
ASSESSMENT OF PHARMACOKINETICS/IMMUNOGENICITY/ 
BIOMARKERS 
8.1. 
Pharmacokinetic Variables 
Sampling for pharmacokinetics will be sparse. Thus, the TEV-48125 pharmacokinetic samples 
will be analyzed using a population pharmacokinetic approach and will be reported separately to 
the clinical study report.  
Samples from all patients will be analyzed for TEV-48125 using an appropriate validated 
method.  
8.1.1. 
Specimen Sampling and Handling 
Blood samples (4 mL) will be collected via venipuncture or indwelling catheter at the time points 
detailed in Table 1 (patients rolling over from the pivotal efficacy studies) and Table 2 (patients 
not rolling over from the pivotal efficacy studies) for plasma concentration measurements of 
TEV-48125.  
The dates and times of study drug administration and the date and time of each pharmacokinetic 
sample will be recorded on the source documentation and transcribed onto the CRF.  
For plasma collection, samples will be collected into dipotassium EDTA collection tubes, 
inverted slowly 6 to 8 times to mix the contents, and placed on water/ice (~4°C). Blood samples 
will be centrifuged (1500g, ~10 minutes, 2°C to 6°C) between 5 minutes and 1 hour after 
sampling. If a refrigerated centrifuge is not available, samples should be chilled before 
centrifugation. Other measures should be taken as appropriate to prevent samples from heating 
significantly during centrifugation. Separated plasma will be transferred in approximately equal 
portions into 2 labeled, 2-mL polypropylene tubes (sets A and B). 
Labels for samples should include study number, patient number, period, nominal collection 
time, set (A or B), and indication that they are pharmacokinetic samples. Samples will be stored 
at a temperature within the range of -70°C ±20°C in an upright position until they are shipped to 
the central laboratory. 
8.1.2. 
Shipment and Analysis of Samples 
Plasma samples for all patients will be shipped frozen on dry ice from the investigational center 
to the central laboratory, where they will be stored until shipment to the sponsor or its designee 
for analysis. 
• Set A samples will be transported (frozen) with a temperature data logger, by 
next-day courier, to the central laboratory.  
• Set B samples will either be sent to the same laboratory as that for set A on a 
subsequent day, by next-day courier, or be retained at the investigational center until 
the study is completed and the clinical study report has been issued (unless shipment 
to another facility is requested by the sponsor).  

 
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Samples will be analyzed using a validated method. Timing of the initiation of sample analysis 
will be determined by the Teva Pharmaceuticals bioanalytical representative responsible for the 
bioanalysis. Refer to the laboratory manual for additional details. 
8.2. 
Immunogenicity Testing 
Samples from all patients will be analyzed for ADA using an appropriate validated method.  
8.2.1. 
Blood Sampling and Handling 
Blood samples (5 mL) will be collected via venipuncture or indwelling catheter at the time points 
detailed in Table 1 (patients rolling over from the pivotal efficacy studies), Table 2 (patients not 
rolling over from the pivotal efficacy studies), and Table 3 (patients rolling over from the pivotal 
efficacy studies for ADA assessment only) for immunogenicity testing.  
For serum collection, samples will be collected into Vacutainer tubes containing no 
anticoagulant, and allowed to set at room temperature less than 30 minutes to allow for serum 
separation to occur. Samples will then be centrifuged (1500g, approximately 10 minutes, 2°C to 
6°C). If a refrigerated centrifuge is not available, samples should be chilled before centrifugation. 
Other measures should be taken as appropriate to prevent samples from heating significantly 
during centrifugation. Separated serum will be transferred in approximately equal portions into 
2 labeled, 2-mL polypropylene tubes (sets A and B). 
Sample labels should include study number, patient number, period, nominal collection time, set 
(A or B), and indication that they are ADA samples. Serum samples will be stored at a 
temperature within the range of -70°C ± 20°C in an upright position until they are shipped to the 
central laboratory. 
8.2.2. 
Shipment and Analysis of Samples 
Serum samples for all patients will be shipped frozen on dry ice from the investigational center 
to the central laboratory, where they will be stored until shipment to the sponsor or its designee 
for analysis.  
• Set A samples will be transported (frozen) with a temperature data logger, by 
next-day courier, to the central laboratory.  
• Set B samples will either be sent to the same laboratory as that for set A on a 
subsequent day, by next-day courier, or be retained at the investigational center until 
the study is completed and the clinical study report has been issued (unless shipment 
to another facility is requested by the sponsor).  
Samples will be analyzed using an appropriate validated method. Timing of the initiation of 
sample analysis will be determined by the Teva Pharmaceuticals department representative 
responsible for the bioanalysis. Refer to the laboratory manual for additional details. 
8.3. 
Assessment of Exploratory Biomarkers 
Biomarkers are defined as biological substances that monitor physiological effects, assess drug 
activity, and predict clinical outcome, safety, and response to therapy.  

 
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Calcitonin gene-related peptide-containing nerve fibers are prevalent in bone tissue and have 
been hypothesized to be important in the regulation of bone metabolism, response to bone injury, 
and the perception of bone pain. In vitro, CGRP is anabolic to osteoblasts and can inhibit 
maturation to osteoclasts. Preclinical studies suggest that CGRP antagonism may have benefit in 
osteoarthritis (Benschop et al 2014) and bone-related pain. In the current study, exploratory 
analysis may be conducted on blood (serum, plasma, and RNA) and urine biomarkers of 
extracellular matrix turnover, bone formation, and bone resorption.  
In preclinical models, CGRP can promote angiogenesis in ischemia, capsaicin-induced synovitis, 
and neovascularization of tumors. Exploratory analysis will be conducted on 
endothelial/angiogenic markers to determine if TEV-48125 alters angiogenic markers. 
Calcitonin gene-related peptide is known to act directly on macrophage and dendritic cells by 
inhibiting them from producing inflammatory cytokines and presenting antigens to T cells. It has 
been hypothesized that CGRP may act as a regulator of the innate immune response. Exploratory 
analysis will be conducted on inflammatory endpoints in blood to examine effects of TEV-48125 
in patients with migraine. 
Based on the known biology of CGRP’s mechanism of action, biomarker assessment will 
potentially include markers of bone remodeling, inflammation, and angiogenesis. Multiplex 
immunoassay panels will be applied to measure changes in urine, serum, plasma, and RNA 
biomarkers. 
The planned biomarker analysis will be detailed in a separate document, which may be updated 
at a later stage before the analysis to allow updating with new scientific information.  
8.3.1. 
Pharmacogenomic Assessment 
A single blood sample (6 mL) for pharmacogenomic analysis will be collected from each patient 
who provides consent for pharmacogenomic testing; this sample may be collected during the 
pivotal efficacy studies (for patients rolling over from Studies TV48125-CNS-30049 and 
TV48125-CNS-30050) or during the current the study. Pharmacogenomic assessment potentially 
includes the association analysis of both known and unknown DNA and RNA genetic variations. 
In the current study, known CGRP and migraine-associated genes will be examined to determine 
their association with clinical treatment responses to study drug 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). The current list of genes with 
polymorphisms associated with either CGRP target engagement or migraine mechanism of 
action includes CALCA, CALCB, CALCRL, CRCP, RAMP, PRDM16, AJAP1, TSPAN2, 
MEF2D, TRPM8, TGFBR2, PHACTR1, FHL5, C7orf10, MMP16, ASTN2, LRP1, APOA1BP, 
TBC1D7, FUT9, STAT6, ATP5B, and MTHFR (Anttila et al 2013). The final list of genes that 
may be investigated may be edited at a later time before the analysis to allow updating with new 
scientific information. Genetic analysis could also include sequencing of the whole genome 
and/or RNA transcripts, if required.  
Pharmacogenomic assessment will be performed based on study results. Samples will be used for 
investigations related to headache, indications where CGRP pathways are implicated, and 
indications that may be associated with the risk of headache or those that are common 

 
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comorbidities associated with headache and/or response to study drug or related investigational 
drugs. 
8.3.2. 
Specimen Sampling and Handling 
Blood samples (a total of 18.5 mL; 6 mL each for plasma and serum and 6.5 mL for RNA 
[PAXgene]) will be collected via venipuncture or indwelling catheter at the time points detailed 
in Table 1 (patients rolling over from the pivotal efficacy studies) and Table 2 (patients not 
rolling over from the pivotal efficacy studies) for serum, plasma, and RNA biomarker measures. 
Urine will be collected in parallel with blood collection. In addition, a 6-mL whole blood sample 
will be collected at baseline for DNA. Details for processing and handling of each type of 
biomarker sample will be outlined in the laboratory manual.  
All blood and urine tubes will be labeled with the patient coded number. Following DNA 
extraction from pharmacogenomic sample, the sample will be labeled with a new code 
(ie, double coding), so that genetic data will not be recorded having a patient number.  
Samples will be stored for a period of up to 15 years from the last patient last visit in the main 
study and then destroyed. 
8.3.3. 
Shipment and Analysis of Samples 
Biomarker samples for serum, plasma, RNA, and urine will be stored at –70°C and sent to the 
central laboratory on dry ice, per instructions in the laboratory manual. Sample labels should 
include study number, patient randomization number, visit code, collection date and time, and 
indication that they are biomarker samples. Shipments should be made as specified in laboratory 
manual. An electronic file containing sample demographics will be e-mailed to the respective 
biomarker laboratory and the sponsor’s biomarker representative for each shipment. 
Following DNA extractions of whole blood, the samples will be stored at –70°C and labeled 
with a new code (ie, double coding), so that genomic data will not be recorded with a patient 
number. Data will be kept confidential and stored separately. 
The biomarker sample analyses will be performed if and when required. Since new techniques 
continue to be developed, the method and laboratory that will be recommended for the future 
biomarker analysis cannot be anticipated. 
8.4. 
Methods and Timing of Assessing, Recording, and Analyzing Clinical 
Pharmacology Data 
Methods and timing of assessing clinical pharmacology data are discussed in Section 3.14. 
Procedures for recording clinical pharmacology data are discussed in Section 13.1, and methods 
of analyses are discussed in Section 9.5.4.  

 
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9. 
STATISTICS 
This is an approximately 19-month, multicenter, randomized, double-blind, parallel-group study 
to evaluate the long-term safety, tolerability, and efficacy of sc TEV-48125 in adult patients with 
migraine. 
9.1. 
Sample Size and Power Considerations 
There are no statistical considerations for this sample size. A total of 1842 patients (867 patients 
from Study TV48125-CNS-30049, 675 patients from Study TV48125-30050, and approximately 
300 patients who did not participate in the pivotal efficacy studies) are planned for enrollment, 
and a 30% drop-out rate is anticipated. 
9.2. 
Analysis Sets  
9.2.1. 
Intent-to-Treat Analysis Set 
The intent-to-treat (ITT) analysis set will include all patients who are randomized in this study 
for long-term safety evaluation, regardless if they receive study treatment or not. In this 
population, treatment will be assigned based on the treatment to which patients are randomized, 
regardless of which treatment they actually received. 
9.2.2. 
Safety Analysis Set 
The safety analysis set will include all patients who receive at least 1 dose of TEV-48125. In this 
population, treatment will be assigned based upon the treatment patients actually receive, 
regardless of the treatment to which they are randomized. 
9.2.3. 
Full Analysis Set  
The full analysis set (FAS) will include all patients in the safety analysis set and have at least 
1 postbaseline efficacy assessment. 
9.2.4. 
Antidrug Antibody Only Analysis Set 
The ADA only analysis set will include all patients rolling over from the pivotal efficacy studies 
for ADA assessment only. 
9.3. 
Data Handling Conventions 
Missing diary data will be handled in the same way as in the double-blind pivotal efficacy 
studies. The details will be provided in the statistical analysis plan. 
9.4. 
Study Population 
The ITT analysis set (see Section 9.2.1) will be used for all study population summaries unless 
otherwise noted. Summaries will be presented overall, by indication, and by treatment group. 

 
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9.4.1. 
Patient Disposition 
Data from patients screened, patients screened but not randomized and reason not randomized, 
patients who are randomized (ie, in the ITT set), patients randomized but not treated, patients in 
the safety, and FAS analysis sets, patients who complete the study, and patients who withdraw 
from the study will be summarized using descriptive statistics. Data from patients who withdraw 
from the study will also be summarized by reason for withdrawal using descriptive statistics. 
9.4.2. 
Demographic and Baseline Characteristics  
Patient demographic and baseline characteristics, including medical history, prior medications, 
and 12-lead ECG findings, will be summarized using descriptive statistics. For continuous 
variables, descriptive statistics (number [n], mean, standard deviation [SD], median, minimum, 
and maximum) will be provided. For categorical variables, patient counts and percentages will 
be provided. Categories for missing data will be presented if necessary. 
9.5. 
Efficacy Analysis  
Individuals with CM often complain of continuous levels of very low severity headache, which 
is typically not modified during the earlier stages of treatment. Accordingly, and following the 
Classification Committee of the IHS guidelines (Silberstein et al 2008), headache days of at least 
moderate severity for both CM and EM patients will be defined for the purpose of this study as a 
calendar day (0:00 to 23:59) when the patient reports: 
• a day with headache pain that lasts ≥4 hours with a peak severity of at least moderate 
severity  
or 
• a day when the patient used an acute migraine-specific medication (triptans or ergots) 
to treat a headache of any severity or duration 
Migraine day is endorsed based on the same criteria as described in the pivotal studies. For CM 
patients, a migraine day is endorsed when at least 1 of the following situations occur: 
• a calendar day (0:00 to 23:59) demonstrating ≥4 consecutive hours of a headache 
meeting criteria for migraine with or without aura 
• a calendar day (0:00 to 23:59) demonstrating ≥4 consecutive hours of a headache 
meeting criteria for probable migraine, a migraine subtype where only 1 migraine 
criterion is missing 
• a calendar day (0:00 to 23:59) demonstrating a headache of any duration that was 
treated with migraine-specific medications (triptans and ergot compounds) 
For EM patients, a migraine day is endorsed when at least 1 of the following situations occur:  
• a calendar day (0:00 to 23:59) demonstrating ≥2 consecutive hours of a headache 
meeting criteria for migraine with or without aura 
• a calendar day (0:00 to 23:59) demonstrating ≥2 consecutive hours of a headache 
meeting criteria for probable migraine, a migraine subtype where only 1 migraine 
criterion is missing 

 
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• a calendar day (0:00 to 23:59) demonstrating a headache of any duration that was 
treated with migraine-specific medications (triptans and ergot compounds) 
9.5.1. 
Primary Endpoint  
The primary endpoints for this study are safety-related and are presented in Section 9.7. 
9.5.2. 
Secondary Endpoints 
There are no secondary endpoints for this study. 
9.5.3. 
Exploratory Endpoints 
Exploratory efficacy endpoints are as follows: 
• mean change from baseline (28-day run-in period) in the number of migraine days 
during the 4-week periods after visits 4, 7, and 13 
• mean change from baseline (28-day run-in period) in the number of headache days of 
at least moderate severity during the 4-week periods after visits 4, 7, and 13 
• mean change from baseline (28-day run-in period) in the number of migraine days 
during the 4-week periods after visits 4, 7, and 13 in patients not receiving 
concomitant migraine preventive medications at baseline 
• mean change from baseline (28-day run-in period) in the number of headache days of 
at least moderate severity during the 4-week periods after visits 4, 7, and 13 in 
patients not receiving concomitant migraine preventive medications at baseline 
• mean change from baseline (28-day run-in period) in the number of migraine days 
during the 4-week period after the 1st dose of study drug for new patients and 
placebo-treated rollover patients 
• mean change from baseline (28-day run-in period) in the number of headache days of 
at least moderate severity during the 4-week period after the 1st dose of study drug for 
new patients and placebo-treated rollover patients 
• mean change from baseline (28-day run-in period) in the number of headache days of 
any severity during the 4-week periods after visits 4, 7, and 13 
• mean change from baseline (28-day run-in period) in the number of days of use of 
any acute headache medications during the 4-week periods after visits 4, 7, and 13 
• proportion of patients reaching at least 50%, 75%, and total (100%) reduction in the 
number of headache days of at least moderate severity during the 4-week periods 
after visits 4, 7, and 13 
• proportion of patients reaching at least 50% and 75% reduction in the number of 
headache days of at least moderate severity during the 4-week periods after visit 4 
who sustain the same level of response during the 4-week periods after visits 7 and 13 
• proportion of patients reaching at least 50%, 75%, and total (100%) reduction in the 
number of migraine days during the 4-week periods after visits 4, 7, and 13 

 
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• proportion of patients reaching at least 50% and 75% reduction in the number of 
migraine days during the 4-week periods after visit 4 who sustain the same level of 
response during the 4-week periods after visits 7 and 13 
• proportion of patients discontinuing concomitant preventive medications during the 
treatment period  
• mean change from baseline (day 0) in disability score in patients with CM, as 
measured by the HIT-6, at visits 8 and 14  
• mean change from baseline (day 0) in disability score in patients with EM, as 
measured by the MIDAS questionnaire, at visits 8 and 14 
• mean change from baseline (day 0) in quality of life, as measured by the MSQOL 
questionnaire, at visits 8 and 14 
• mean change from baseline (day 0) in patient health status, as measured by the 
EQ-5D-5L questionnaire, at visits 8 and 14 
• assessment of patient satisfaction, as measured by the PGIC scale at visits 3, 5, 8, 11, 
and 14 
• mean change from baseline (day 0) in patient depression status, as measured by the 
PHQ-2 and PHQ-9, at visits 8 and 14  
• mean change from baseline (day 0) in patient work productivity and activity 
impairment, as measured by the WPAI questionnaire, at visits 8 and 14 
9.5.4. 
Planned Method of Analysis 
The FAS (see Section 9.2.3) will be used for all efficacy analyses. Summaries will be presented 
by indication and treatment group for new patients and rollover patients separately, unless 
otherwise specified. 
9.5.4.1. 
Primary Efficacy Analysis 
Not applicable.  
9.5.4.2. 
Sensitivity Analysis 
No sensitivity analyses are planned for this study.  
9.5.4.3. 
Secondary Efficacy Analysis 
Not applicable. 
9.5.4.4. 
Exploratory Efficacy Analysis 
All efficacy variables will be summarized descriptively. For continuous variables, descriptive 
statistics (n, mean, SD, standard error of mean, median, minimum, and maximum) will be 
provided for actual values and changes from baseline to each visit. For categorical variables, 
frequency and percentage will be provided. For rollover patients, their baseline is defined as the 
baseline in the pivotal efficacy studies.  

 
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9.6. 
Multiple Comparisons and Multiplicity 
No inferential analysis will be performed in this study. 
9.7. 
Safety and Tolerability Endpoints and Analysis 
Safety and tolerability analyses will be performed on the safety analysis set. Summaries will be 
presented overall, by indication and by treatment group. 
9.7.1. 
Safety and Tolerability Endpoints 
The safety and tolerability endpoints for this study are as follows: 
• occurrence of adverse events throughout the study 
• changes from baseline in clinical laboratory (serum chemistry, hematology, 
coagulation, and urinalysis) test results 
• abnormal standard 12-lead ECG findings 
• changes from baseline in vital signs (pulse, systolic and diastolic blood pressure, body 
temperature, and respiratory rate) measurements  
• abnormal physical examination findings  
• abnormal local injection site tolerability findings (ie, erythema, induration, and 
ecchymosis) and occurrence of injection site pain  
• suicidal ideation and behavior as suggested by the eC-SSRS 
Safety and tolerability measures and time points are provided in Table 1 (patients rolling over 
from the pivotal efficacy studies), Table 2 (patients not rolling over from the pivotal efficacy 
studies), and Table 3 (patients rolling over from the pivotal efficacy studies for ADA assessment 
only). 
9.7.2. 
Safety and Tolerability Analysis 
All adverse events will be coded using the Medical Dictionary for Regulatory Activities. Each 
patient will be counted only once in each preferred term or system organ class category for the 
analyses of safety. Summaries will be presented for all adverse events (overall and by severity), 
adverse events determined by the investigator to be related to study treatment (ie, reasonable 
possibility; see Section 7.1.4) (defined as related or with missing relationship) (overall and by 
severity), serious adverse events, and adverse events causing withdrawal from the study. Patient 
listings of serious adverse events and adverse events leading to withdrawal will be presented. 
Injection site erythema, induration, ecchymosis, and pain will be assessed, and severity will be 
graded as described in Section 7.9, and findings will be listed and summarized. 
Changes in laboratory and vital signs measurement data will be summarized descriptively. All 
values will be compared with prespecified boundaries to identify potentially clinically significant 
changes or values, and such values will be listed. 

 
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The use of concomitant medications will be summarized by therapeutic class using descriptive 
statistics. Concomitant medications will include all medications taken while the patient is treated 
with study drug. 
Safety data will be summarized descriptively overall, by diagnosis, and by treatment group. For 
continuous variables, descriptive statistics (n, mean, SD, median, minimum, and maximum) will 
be provided for actual values and changes from baseline to each time point. For categorical 
variables, patient counts and percentages will be provided. Descriptive summaries of serious 
adverse events, patient withdrawals due to adverse events, and potentially clinically significant 
abnormal values (clinical laboratory or vital signs) based on predefined criteria will also be 
provided. 
If any patient dies during the study, a listing of deaths will be provided and all relevant 
information will be discussed in the patient narrative included in the clinical study report.  
9.8. 
Pharmacokinetic Analysis 
Pharmacokinetic plasma concentration results (TEV-48125) will be tabulated descriptively at 
each planned sampling time point by indication and treatment group. 
9.9. 
Biomarker Analysis 
Biomarker analysis will include logistic regression, receiver operating characteristic curves, and 
summary statistics. Results will be reported separately.  
9.10. 
Pharmacokinetic/Pharmacodynamic Analysis 
The pharmacokinetic/pharmacodynamic relationship will be estimated by compartmental 
techniques. The pharmacokinetic parameters will be based on TEV-48125 measurements. The 
pharmacodynamic measures will be the efficacy responses.  
The pharmacokinetic/pharmacodynamic relationship will be estimated using the most 
appropriate model after comparing different candidate models for their quality of fit. Covariates 
that may affect the pharmacokinetic/pharmacodynamic relationship will be tested for inclusion in 
the model. This analysis will be reported separately. 
9.11. 
Immunogenicity Analysis 
Summary of immunogenicity results will be provided, and the incidence of immunogenicity will 
be calculated. The impact of immunogenicity on the pharmacokinetic profile, drug efficacy, and 
clinical safety will be evaluated. This impact analysis will be reported separately. 
9.12. 
Planned Interim Analysis 
No interim analysis is planned for this study. After database lock in the pivotal study, safety 
and/or efficacy summaries will be generated based on interim data cut to be included in the 
Biologics License Application submission. 

 
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9.13. 
Reporting Deviations from the Statistical Plan 
Deviations from the statistical plan, along with the reasons for the deviations, will be described 
in protocol amendments, the statistical analysis plan, the clinical study report, or any 
combination of these, as appropriate, and in accordance with applicable local and regional 
requirements and regulations. 

 
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10. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
The medical experts, study monitors, auditors, IEC/IRB, and health authority inspectors (or their 
agents) will be given direct access to source data and documentation (eg, medical charts/records, 
laboratory test results, printouts, and videotapes) for source data verification, provided that 
patient confidentiality is maintained in accordance with local requirements. 
The investigator must maintain the original records (ie, source documents) of each patient’s data 
at all times. Examples of source documents are hospital records, office visit records, examining 
physician’s finding or notes, consultant’s written opinion or notes, laboratory reports, drug 
inventory, study drug label records, diary data, protocol-required worksheets, and CRFs that are 
used as the source (see Section 3.13). 
The investigator will maintain a confidential patient identification list that allows the 
unambiguous identification of each patient. All study-related documents must be kept until 
notification by the sponsor.  

 
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11. 
QUALITY CONTROL AND QUALITY ASSURANCE 
11.1. 
Protocol Amendments and Protocol Deviations and Violations 
11.1.1. 
Protocol Amendments 
No changes from the final approved (signed) protocol will be initiated without the prior written 
approval or favorable opinion of a written amendment by the IEC/IRB and national and local 
competent authorities, as applicable, except when necessary to address immediate safety 
concerns to the patients, or when the change involves only nonsubstantial logistics or 
administration. The principal investigator at each investigational center, the coordinating 
investigator (if applicable), and the sponsor will sign the protocol amendment.  
11.1.2. 
Protocol Violations 
Any deviation from the protocol that affects, to a significant degree, (a) the safety, physical, or 
mental integrity of the subjects of the study and/or (b) the scientific value of the study will be 
considered a protocol violation. Protocol violations may include nonadherence on the part of the 
patient, the investigator, or the sponsor to protocol-specific inclusion and exclusion criteria, 
primary objective variable criteria, or GCP guidelines; noncompliance to study drug 
administration; and use of prohibited medications. Protocol violations will be identified and 
recorded by investigational center personnel in the CRF. All protocol violations will be reported 
to the responsible IEC/IRB, as required. 
When a protocol violation is reported, the sponsor will determine whether to discontinue the 
patient from the study or permit the patient to continue in the study, with documented approval 
from the medical expert. The decision will be based on ensuring the safety of the patient and 
preserving the integrity of the study.  
Changes in the inclusion and exclusion criteria of the protocol are not prospectively granted by 
the sponsor. If investigational center personnel learn that a patient who did not meet protocol 
inclusion and exclusion criteria was entered in a study, they must immediately inform the 
sponsor of the protocol violation. If such patient has already completed the study or has 
withdrawn early, no action will be taken but the violation will be recorded. 
11.2. 
Information to Study Personnel 
The investigator is responsible for giving information about the study to all staff members 
involved in the study or in any element of patient management, both before starting the study and 
during the course of the study (eg, when new staff members become involved). The investigator 
must assure that all study staff members are qualified by education, experience, and training to 
perform their specific responsibilities. These study staff members must be listed on the 
investigational center authorization form, which includes a clear description of each staff 
member’s responsibilities. This list must be updated throughout the study, as necessary. 
The study monitor is responsible for explaining the protocol to all study staff, including the 
investigator, and for ensuring that they comply with the protocol. Additional information will be 

 
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made available during the study when new staff members become involved in the study and as 
otherwise agreed upon with either the investigator or the study monitor. 
11.3. 
Study Monitoring 
To ensure compliance with GCP guidelines, the study monitor or representative is responsible 
for ensuring that patients have signed the informed consent form and the study is conducted 
according to applicable standard operating procedures (SOPs), the protocol, and other written 
instructions and regulatory guidelines. 
The study monitor is the primary association between the sponsor and the investigator. The main 
responsibilities of the study monitor(s) are to visit the investigator before, during, and after the 
study to ensure adherence to the protocol, that all data are correctly and completely recorded and 
reported, and that informed consent is obtained and recorded for all patients before they 
participate in the study and when changes to the consent form are warranted, in accordance with 
IEC/IRB approvals. 
The study monitor(s) will contact the investigator and visit the investigational center at regular 
intervals throughout the study. The study monitor will be permitted to check and verify the 
various records (CRFs and other pertinent source data records, including specific electronic 
source documentation [see Section 3.13]) relating to the study to verify adherence to the protocol 
and to ensure the completeness, consistency, and accuracy of the data being recorded. If 
electronic CRFs are used for the study, the study monitor will indicate verification by 
electronically applying source document verification flags to the CRF and will ensure that all 
required electronic signatures are being implemented accordingly. 
As part of the supervision of study progress, other sponsor personnel may, on request, 
accompany the study monitor on visits to the investigational center. The investigator and 
assisting staff must agree to cooperate with the study monitor to resolve any problems, errors, or 
possible misunderstandings concerning the findings detected in the course of these monitoring 
visits and/or provided in follow-up written communication. 
11.4. 
Clinical Product Complaints 
A clinical product complaint is defined as a problem or potential problem with the physical 
quality or characteristics of clinical drug supplies and/or clinical device supplies used in a 
clinical research study sponsored by Teva. Examples of a product complaint include, but are not 
limited to, the following:  
• suspected contamination 
• questionable stability (eg, color change, flaking, crumbling, etc) 
• defective components 
• missing or extra units (eg, primary container is received at the site with more or less 
than the designated number of units inside) 
• incorrect packaging or incorrect or missing labeling/labels 
• unexpected or unanticipated taste or odor (or both) 

 
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• device not working correctly or appears defective in some manner 
Each investigational center will be responsible for reporting a possible clinical product complaint 
by completing the Product Complaint Form provided by Teva and emailing it to 
 within 48 hours of becoming aware of the issue. 
For complaints involving a device or other retrievable item, it is required that the device (or 
item) be sent back to the sponsor for investigative testing whenever possible. For complaints 
involving a drug product, all relevant samples (eg, the remainder of the patient’s drug supply) 
should be sent back to the sponsor for investigative testing whenever possible.  
11.4.1. 
Product Complaint Information Needed from the Investigational Center 
In the event that the Product Complaint Form cannot be completed, the investigator will obtain 
the following information, as available: 
• investigational center number and principal investigator name 
• name, phone number, and address of the source of the complaint  
• clinical protocol number 
• patient identifier (patient study number) and corresponding visit numbers, if 
applicable 
• patient number, bottle, and kit numbers (if applicable)  
• product available for return (yes, no) 
• product was taken or used according to protocol (yes, no) 
• description or nature of complaint 
• associated serious adverse event (yes, no) 
• clinical supplies unblinded (yes, no) 
• date and name of person receiving the complaint  
Note: Reporting a complaint must not be delayed because not all the required information can be 
immediately obtained. Known information must be immediately reported. The sponsor will 
collaborate with the investigator to obtain any outstanding information. 
11.4.2. 
Handling the Study Drug at the Investigational Center 
The investigator is responsible for retaining the product in question in a location separate from 
the investigator’s clinical study supplies. The sponsor may request that the investigator return the 
product for further evaluation and/or analysis. If this is necessary, the clinical study monitor or 
designee will provide the information needed for returning the study drug. 
If it is determined that the investigational center must return all of the study drug, the sponsor 
will provide the information needed to handle the return. 
The integrity of the randomization code and corresponding blinded clinical supplies will be 
maintained whenever possible. A serious adverse event or the potential for a product quality 

 
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problem existing beyond the scope of the complaint may be a reason to unblind the clinical 
supplies for an affected patient. 
11.4.3. 
Adverse Events or Serious Adverse Events Associated with a Product Complaint 
If there is an adverse event or serious adverse event, the protocol should be followed. 
11.4.4. 
Documenting a Product Complaint 
The investigator will record a description of the product complaint in the source documentation 
as well as any actions taken to resolve the complaint and to preserve the safety of the patient. 
Once the complaint has been investigated by the sponsor and the investigator, if necessary, an 
event closure letter may be sent to the investigational center where the complaint originated or to 
all investigational centers using the product. 
11.5. 
Audit and Inspection 
The sponsor may audit the investigational center to evaluate study conduct and compliance with 
protocols, SOPs, GCPs, and applicable regulatory requirements. The sponsor’s Global Clinical 
Quality Assurance department, independent of the Global Clinical Development department, is 
responsible for determining the need for (and timing of) an investigational center audit. 
The investigator must accept that regulatory authorities, and sponsor representatives may 
conduct inspections to verify compliance with GCP guidelines. 

 
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12. 
ETHICS 
Details of compliance with regulatory guidances and applicable laws are provided in Section 1.6. 
12.1. 
Informed Consent 
The investigator, or a qualified person designated by the investigator, should fully inform the 
patient of all pertinent aspects of the study, including the written information approved by the 
IEC/IRB. All written and/or oral information about the study will be provided in a language as 
nontechnical as practical and understood by the patient. The patient should be given ample time 
and opportunity to inquire about details of the study and to decide whether or not to participate in 
the study. The above should be detailed in the source documentation. 
Written informed consent will be obtained from each patient before any study-specific 
procedures or assessments are done and after the aims, methods, anticipated benefits, and 
potential hazards are explained, according to the IEC/IRB requirements. The patient’s 
willingness to participate in the study will be documented in a consent form, which will be 
signed and personally dated by the patient and by the person who conducted the informed 
consent discussion. The investigator will keep the original consent forms, and copies will be 
given to the patients. It will also be explained to the patients that the patient is free to refuse entry 
into the study and free to withdraw from the study at any time without prejudice to future 
treatment. 
Patients will be asked to sign a separate informed consent form if they agree to provide blood 
samples for pharmacogenomic assessment.  
12.2. 
Health Authorities and Independent Ethics Committees/Institutional 
Review Boards 
Before this study starts, the protocol will be submitted to the national/local health authorities and 
to each IEC/IRB for review. As required, the study will not start at a given investigational center 
before the IEC/IRB and health authority (where applicable) for the center to give written 
approval or a favorable opinion. 
12.3. 
Confidentiality Regarding Study Patients 
The investigator must ensure that the privacy of the patients, including their identity and all 
personal medical information, will be maintained at all times. In CRFs and other documents or 
image material submitted to the sponsor, patients will be identified not by their names, but by an 
identification code (ie, identification number). 
Personal medical information may be reviewed for the purpose of patient safety and/or verifying 
data in the source and transcribed onto the CRF. This review may be conducted by the study 
monitor, properly authorized persons on behalf of the sponsor, the quality assurance unit, and/or 
regulatory authorities. Personal medical information will always be treated as confidential. 

 
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12.4. 
Declaration of the End of the Clinical Study 
The end of the study is defined as the date the last patient attends the follow-up visit (visit 15) 
that will be performed approximately 7.5 months after the last dose of study drug. For clinical 
investigational centers located in the EU, a declaration of the end of the clinical study will be 
made according to the procedures outlined in Directive 2001/20/ED, Article 10(c); for other 
countries, local regulations will be followed. 
12.5. 
Registration of the Clinical Study 
In compliance with local regulations and in accordance with Teva standard procedures, this 
clinical study may be registered on clinical studies registry websites. 

 
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13. 
DATA HANDLING, DATA QUALITY CONTROL, AND RECORD 
KEEPING 
13.1. 
Data Collection 
Data will be collected using CRFs that are specifically designed for this study. The data collected 
on the CRFs will be captured in a clinical data management system (CDMS) that meets the 
technical requirements described in 21CFR Part 11. The CDMS will be fully validated to ensure 
that it meets the scientific, regulatory, and logistical requirements of the study before it is used to 
capture data from this study. Before using the CDMS, all users will receive training on the 
system and study-specific training. After they are trained, users will be provided with individual 
system access rights. 
Data will be collected at the investigational center by appropriately designated and trained 
personnel, and CRFs must be completed for each patient who provided informed consent. Patient 
identity should not be discernible from the data provided on the CRF. Data will be verified using 
the data source by the study monitor, and reviewed for consistency by Data Management using 
both automated logical checks and manual review. All data collected will be approved by the 
investigator at the investigational center. This approval acknowledges the investigator’s review 
and acceptance of the data as being complete and accurate.  
If data are processed from other sources (eg, central laboratory, bioanalytical laboratory, central 
image center, electronic diary data, or ePRO Tablet), the results will be sent to the investigational 
center, where they will be retained but not entered into the CRF, unless otherwise specified in the 
protocol. These data may also be sent electronically to the sponsor (or organization performing 
data management) for direct entry into the clinical database. Laboratory test results will not be 
entered into the CRF, unless otherwise noted in the protocol. All data from other sources will be 
available to the investigators. 
For patients who enter a study but do not meet entry criteria, at a minimum, data for screen 
failure reason, demography, and adverse events from the time of informed consent will be 
entered into the CRF. 
13.2. 
Data Quality Control  
Data Management is responsible for the accuracy, quality, completeness, and internal 
consistency of the data from this study. Data handling, including data quality control (QC), will 
comply with international regulatory guidelines, including ICH GCP guidelines. Data 
management and control processes specific to this study, along with all steps and actions taken 
regarding data management and data QC, will be described in a data management plan. 
Case report forms received will be processed and reviewed for completeness, consistency, and 
the presence of mandatory values. Applicable terms will be coded according to the coding 
conventions for this study. Logical checks will be implemented to ensure data quality and 
accuracy. Any necessary changes will be made in the clinical database, and data review and 
validation procedures will be repeated as needed. Data from external sources will be compared 
with the information available in the CDMS. Discrepancies found will be queried. 

 
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Data corrections in the CDMS will be made using the CDMS update function. The system 
requires a reason for each change and keeps a complete audit trail of the data values, dates and 
times of modifications, and authorized electronic approvals of the changes. 
At the conclusion of the study, the CDMS and all other study data will be locked to further 
additions or corrections. Locking the study data represents the acknowledgement that all data 
have been captured and confirmed as accurate. 
13.3. 
Archiving of Case Report Forms and Source Documents  
13.3.1. 
Sponsor Responsibilities 
The sponsor will have final responsibility for the processing and QC of the data. Data 
management oversight will be carried out as described in the sponsor’s SOPs for clinical studies. 
Day-to-day data management tasks for this study are delegated to a CRO, and these functions 
may be carried out as described in the SOPs for clinical studies at that organization. These SOPs 
will be reviewed by the sponsor before the start of data management activities. The original 
CRFs will be archived by the sponsor. Center-specific CRFs will be provided to the respective 
investigational centers for archiving.  
13.3.2. 
Investigator Responsibilities 
The investigator must maintain all written and electronic records, accounts, notes, reports, and 
data related to the study and any additional records required to be maintained under country, 
state/province, or other local laws, including, but not limited to, the following:  
• full case histories 
• signed informed consent forms 
• patient identification lists 
• CRFs for each patient on a per-visit basis  
• data results from other sources (eg, central laboratory, bioanalytical laboratory, 
central image center, and electronic diary data) 
• safety reports 
• financial disclosure reports/forms 
• reports of receipt, use, and disposition of the study drug 
• copies of all correspondence with sponsor, the IRB/IEC, and any regulatory authority 
The investigator will retain all records related to the study until the CRO or sponsor sends 
written notification that records may be destroyed. If, after 10 years from study completion, or 
earlier (in the case of the investigative center closing or going out of business), the investigator 
reasonably determines that study record retention has become unduly burdensome, and sponsor 
has not provided written notification of destruction, then the investigator may submit a written 
request to sponsor at least sixty 60 days before any planned disposition of study records. Upon 
receipt of such request, the sponsor may make arrangements for appropriate archival or 

 
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disposition, including requiring that the investigator deliver such records to the sponsor. The 
investigator shall notify the sponsor of any accidental loss or destruction of study records.  

 
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14. 
FINANCING AND INSURANCE 
A separate clinical study agreement, including a study budget, will be entered into between each 
principal investigator and the sponsor (or the CRO designated by the sponsor) before the study 
drug is delivered. 
This clinical study is insured in accordance with the corresponding local legal provisions. The 
policy coverage is subject to the full policy terms, conditions, extensions, and exclusions. 
Excluded from the insurance cover are inter alia, damages to health, and worsening of previous 
existing disease that would have occurred or continued if the patient had not taken part in the 
clinical study. 
The policy of Clinical Trials Insurance will be provided to the investigational centers by the 
sponsor. 
For covered clinical studies (see 21CFR54), the investigator will provide the sponsor with 
financial information required to complete Form FDA 3454. Each investigator will notify the 
sponsor of any relevant changes during the conduct of the study and for 1 year after the study has 
been completed. 

 
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15. 
REPORTING AND PUBLICATION OF RESULTS 
The sponsor is responsible for ensuring that the public has access to the appropriate information 
about the study by conforming to local and regional requirements and regulations for registration 
and posting of results.  
The sponsor is responsible for the preparation of a clinical study report, in cooperation with the 
coordinating investigator. The final report is signed by the sponsor and, if applicable, by the 
coordinating investigator. 
When the sponsor generates reports from the data collected in this study for presentation to 
regulatory authorities, drafts may be circulated to the coordinating investigator for comments and 
suggestions. An endorsement of the final report will be sought from the coordinating 
investigator. 
All unpublished information given to the investigator by the sponsor shall not be published or 
disclosed to a third party without the prior written consent of the sponsor. The primary 
publication from this study will report the results of the study in accordance with the current 
“Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly Work in 
Medical Journals” (www.ICMJE.org). Publication of the results will occur in a timely manner 
according to applicable regulations.  
Authorship will be based on meeting all of the following 4 criteria: 
• substantial contributions to the conception or design of the work or the acquisition, 
analysis, or interpretation of data for the work 
• drafting the work or revising it critically for important intellectual content 
• final approval of the version to be published 
• 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 
The publications committee established by the sponsor will oversee this process. Additional 
publications may follow. Policies regarding the publication of the study results are defined in the 
financial agreement.  
No patent applications based on the results of the study may be made by the investigator nor may 
assistance be given to any third party to make such an application without the written 
authorization of the sponsor. 

 
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16. 
REFERENCES 
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meta-analysis identifies new susceptibility loci for migraine. Nat Genet 2013;45(8):912-7. 
Armour KL, Clark MR, Hadley AG, Williamson LM. Recombinant human IgG molecules 
lacking Fcgamma receptor I binding and monocyte triggering activities. Eur J Immunol 
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Ashina M, Bendtsen L, Jensen R, Schifter S, Jansen-Olesen I, Olesen J. Plasma levels of 
calcitonin gene-related peptide in chronic tension-type headache. Neurology 2000;55(9):1335–
40. 
Bagley CL, Rendas-Baum R, Maglinte GA, Yan M, Varon SF, Lee J, et al. Validating Migraine-
specific Quality of Life questionnaire v 2.1 in episodic and chronic migraine. Headache 
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Benschop RJ, Collins EC, Darling RJ, Allan BW, Leung D, Conner EM, et al. Development of a 
novel antibody to cGRP for the treatment of osteoarthritis-related pain. Osteoarthritis Cartilage 
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Bigal ME, Lipton RB. Clinical course in migraine: conceptualizing migraine transformation. 
Neurology 2008;71(11):848-55. 
Bigal ME, Serrano D, Buse D, Scher A, Stewart WF, Lipton RB. Acute migraine medications 
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migraine prevention: a randomized controlled trial. JAMA 2004;291(8):965-73. 
Edvinsson L, Goadsby PJ. Extracerebral manifestations in migraine. A peptidergic involvement? 
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Eftekhari S, Edvinsson L. Possible sites of action of the new calcitonin gene-related peptide 
receptor antagonists. Ther Adv Neurol Disord 2010;3(6):369–78. 
Goadsby PJ, Edvinsson L, Ekman R. Vasoactive peptide release in the extracerebral circulation 
of humans during migraine headache. Ann Neurol 1990:28(2):183–7. 
Goadsby PJ, Hargreaves R. Refractory migraine and chronic migraine: pathophysiological 
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Goadsby PJ, Lipton RB, Ferrari MD. Migraine--current understanding and treatment. N Engl J 
Med 2002;346(4):257–70. 
Hansen JM, Hauge AW, Olesen J, Ashina M. Calcitonin gene-related peptide triggers 
migraine-like attacks in patients with migraine with aura. Cephalalgia 2010;30(10):1179–86. 
Hewitt DJ, Aurora SK, Dodick DW, Goadsby PJ, Ge YJ, Bachman R, et al. Randomized 
controlled trial of the CGRP receptor antagonist MK-3207 in the acute treatment of migraine. 
Cephalalgia 2011;31(6):712–22. 

 
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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. 
Ho TW, Ferrari MD, Dodick DW, Galet V, Kost J, Fan X, et al. Efficacy and tolerability of 
MK-0974 (telcagepant), a new oral antagonist of calcitonin gene-related peptide receptor, 
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Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical Journals. Available 
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Classification Committee of the International Headache Society. The International Classification 
of Headache Disorders, 3rd edition (beta version). Cephalalgia 2013;33(9):629-808. 
Klapper J. Divalproex sodium in migraine prophylaxis: a dose-controlled study. Cephalalgia 
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short-form survey for measuring headache impact: the HIT-6. Qual Life Res 2003;12(8):963-74. 
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anxiety, and depressive symptom scales: a systematic review. Gen Hosp Psychiatry 
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Lipton RB, Bigal ME, Diamond M, Freitag F, Reed ML, Stewart WF. Migraine prevalence, 
disease burden, and the need for preventive therapy. Neurology 2007;68(5):343–9. 
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optimal treatment and prevention. Headache 2015;55(S2):103-22. 
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peptide receptor antagonist BIBN 4096 BS for the acute treatment of migraine. N Engl J Med 
2004;350(11):1104–10. 
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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. 
Sampson HA, Munoz-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 
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Clin Immunol 2006 Feb;117(2):391-7. 
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(1-2):81–9. 

 
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Shamliyan TA, Kane RL, Taylor FR. Migraine in adults: Preventative pharmacologic treatments. 
Comparative effectiveness review No. 103. (Prepared by the University of Minnesota Evidence 
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EHC068-EF. Rockville, MD: Agency for Healthcare Research and Quality: April 2013. 
www.effectivehealthcare.ahrq.gov/final.cfm. 
Silberstein SD, Neto W, Schmitt J, Jacobs D; for the MIGR-001 Study Group. Topiramate in 
migraine prevention; results of a large controlled trial. Arch Neurol 2004;61:490-5. 
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. 
Silberstein S, Holland S, Freitag F, Dodick DW, Argoff C, Ashma E. Evidence-based guideline 
update: pharmacologic treatment of episodic migraine prevention in adults. Neurology 
2012;78:1337-45. 
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MD: the PHQ primary care study. Primary care evaluation of metal disorders. Patient health 
questionnaire. JAMA 1999;282(18):1737-44. 
Stewart WF, Lipton RB, Kolodner K, Liberman J, Sawyer J. Reliability of the migraine 
disability assessment score in a population-based sample of headache sufferers. Cephalalgia 
1999a Mar;19(2):74,107-14. 
Stewart WF, Lipton RB, Whyte J, Dowson A, Kolodner K, Liberman JN, et al. An international 
study to assess reliability of the Migraine Disability Assessment (MIDAS) score. Neurology 
1999b;53(5):988-94. 
Yang M, Rendas-Baum R, Varon SF, Kosinsky M. Validation of the Headache Impact Test 
(HIT-6) across episodic and chronic migraine. Cephalalgia 2011;31(3):357-67. 
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. 

 
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17. 
SUMMARY OF CHANGES TO PROTOCOL 
17.1. 
Amendment 01 Dated 30 March 2016 
The primary reasons for this amendment are as follows:  
• To incorporate required revisions based on health authority input from the European 
Medicines Agency, FDA, and Pharmaceuticals and Medical Devices Agency 
• To provide clarifying language for the inclusion and exclusion criteria 
• To clarify allowed and disallowed preventive medications 
• To revise protocol-defined adverse events of special interest and to add clinical 
criteria for diagnosing anaphylaxis 
• To update and/or clarify versions of certain exploratory endpoints, including the 
EQ-5D (now -5L) and PGIC, respectively 
This revision is considered to be substantial by the sponsor’s Authorized Representative. Other 
nonsubstantial revisions have been made to the protocol (and protocol synopsis, as appropriate). 
These changes are unlikely to affect to a significant degree the safety or rights (physical or 
mental integrity) of the patients in the clinical study or the scientific value of the clinical study. 
Where indicated, Table 1 (Study Procedures and Assessments for Patients Rolling Over from the 
Pivotal Efficacy Studies) and Table 2 (Study Procedures and Assessments for Patients Not 
Rolling Over from the Pivotal Efficacy Studies) have been revised to reflect changes described 
below.

 
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Table 8: 
Changes to the Protocol  
Original text with changes shown 
New wording 
Reason/Justification for 
change 
Page Headers 
Uncontrolled Study—Chronic and Episodic Migraine 
Study TV48125 CNS 30051 Long-Term Study–Chronic 
and Episodic Migraine 
Long-Term Study–Chronic and Episodic 
Migraine 
Headers revised for clarity 
TITLE PAGE (Other section affected by this change: Clinical Study Personnel Contact Information) 
Monitors 
NCGS, Inc. 
65 Society Street288 Meeting Street 
Suite 400 
Charleston, South Carolina 29401 
United States 
Monitors 
NCGS, Inc. 
288 Meeting Street 
Suite 400 
Charleston, South Carolina 29401 
United States 
Update was made to the address 
of the monitors. 
Authorized Representative 
Teva Branded Pharmaceutical Products R&D, Inc. 
Teva Branded Pharmaceutical Products R&D, Inc. 
Authorized Representative 
Teva Branded Pharmaceutical Products R&D, 
Inc. 
This reflects a change in 
responsibilities at Teva, Inc. 
Sponsor’s Medical Expert 
Teva Pharmaceuticals 
Sponsor’s Medical Expert 
Teva Pharmaceuticals 
This reflects a change in 
responsibilities at Teva, Inc. and 
a minor correction to the 
department name.  

 
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Minor change was made in the 
representative’s title and 
department name. 
© 20152016 Teva Branded Pharmaceutical Products R&D, 
Inc. All rights reserved. 
© 2016 Teva Branded Pharmaceutical 
Products R&D, Inc. All rights reserved. 
Administrative change. 
Amendment history was added. 
Administrative change. 
Signature pages were updated according to the most recent template. 
Administrative change. 
CLINICAL LABORATORY AND OTHER DEPARTMENTS AND INSTITUTIONS 
Bioanalytical Pharmacokinetics Evaluation  
Teva Branded Pharmaceuticals R&D, Inc. 
 
Bioanalytical Immunogenicity Evaluation  
Teva Branded Pharmaceuticals R&D, Inc. 
 
Biomarker Evaluation 
Teva Branded Pharmaceuticals R&D, Inc. 
Bioanalytical Pharmacokinetics Evaluation 
Teva Branded Pharmaceuticals R&D, Inc. 
 
Bioanalytical Immunogenicity Evaluation  
 
 Teva Branded 
Pharmaceuticals R&D, Inc. 
 
Biomarker Evaluation 
Teva Branded Pharmaceuticals R&D, Inc. 
This change was made to update 
the personnel responsible for the 
applicable evaluations and their 
titles, as applicable 
Pharmacogenomic and Biomarker Sample Storage 
BioStorage Technologies, Inc.  
2910 Fortune Circle West, Suite E  
Pharmacogenomic and Biomarker Storage 
BioStorage Technologies, Inc.  
2910 Fortune Circle West, Suite E  
Available vendor information 
was added. 

 
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Indianapolis, IN 46241 USA 
 
BioStorage Technologies, GmbH  
Im Leuschnerpark 1b  
64347 Griesheim, Germany 
Indianapolis, IN 46241 USA 
 
BioStorage Technologies, GmbH  
Im Leuschnerpark 1b  
64347 Griesheim, Germany 
CLINICAL STUDY PROTOCOL SYNOPSIS  
Rate Method of Blinding and Randomization 
The sponsor, investigators, study staff (except for staff 
involved in bioanalytical analyses), and patients will be 
blinded to treatment assignment. The Sponsor will be 
unblinded when the pivotal efficacy studies have been 
unblinded. A computer-generated master randomization list 
will be provided to drug packaging facilities. 
The sponsor, investigators, study staff (except 
for staff involved in bioanalytical analyses), 
and patients will be blinded to treatment 
assignment. A computer-generated master 
randomization list will be provided to drug 
packaging facilities. 
The sentence was included in 
error. 
Study Drug Dose, Mode of Administration, and Administration Rate 
Prefilled syringes (active or placebo) will be contained in 
uniquely numbered kits and stored (refrigerated at 2°C to 
8°C) on site. Active syringes will contain 150 mg/mL of 
TEV-48125, and placebo syringes will contain the same 
vehicle and excipients as those for active injections. Each kit 
will contain 1 prefilled syringe. All study drugs will be 
administered by a qualified clinic staff member separate from 
the staff member(s) responsible for collecting safety and 
efficacy information from the patients.  
Prefilled syringes (active or placebo) will be 
contained in uniquely numbered kits and 
stored (refrigerated at 2°C to 8°C) on site. 
Active syringes will contain 150 mg/mL of 
TEV-48125, and placebo syringes will contain 
the same vehicle and excipients as those for 
active injections. Each kit will contain 1 
prefilled syringe. 
The requirement for 
administration of study drugs by 
a qualified clinic staff member 
separate from the staff 
member(s) responsible for 
collecting safety and efficacy 
information from the patients 
was removed.  

 
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1 
BACKGROUND INFORMATION 
1.1 Introduction (Other sections affected by this change: Section 16) 
However, approximately 3% to 6% of individuals with EM 
evolve, in any given year, to a significantly more disabling 
condition called chronic migraine (CM) (Bigal et al 2008, 
Lipton et al 2007, Scher et al 2003). Individuals with CM 
present with headaches of any severity on 15 or more days per 
month and have full-blown migraine on at least 8 days per 
month (Classification Committee of the IHS, 2013). A 
sizable proportion of individuals with CM experiences daily 
headaches and, therefore, faces considerable disability (Bigal 
and Lipton 2008). 
[…] 
Calcitonin gene-related peptide (CGRP) is a well-studied 
neuropeptide found at the centers of the migraine processes, 
both centrally and peripherally (Eftekhari and Edvinsson 
2010, Olesen 2011). 
However, approximately 3% of individuals 
with EM evolve, in any given year, to a 
significantly more disabling condition called 
chronic migraine (CM) (Bigal et al 2008, 
Lipton et al 2007, Scher et al 2003). 
Individuals with CM present with headaches 
of any severity on 15 or more days per month 
and have full-blown migraine on at least 8 
days per month (Classification Committee of 
the IHS, 2013). A sizable proportion of 
individuals with CM experiences daily 
headaches and, therefore, faces considerable 
disability (Bigal and Lipton 2008). 
[…] 
Calcitonin gene-related peptide (CGRP) is a 
well-studied neuropeptide found at the centers 
of the migraine processes, both centrally and 
peripherally (Eftekhari and Edvinsson 2010). 
Update/correction of 
information and associated 
literature on evolution of EM to 
CM was made. 
 
Revision of other select 
literature cited was made here 
and throughout the document. 
Although there are more than 40 medications within these 
classes of drugs that are used with varying response rates to 
prevent migraine, only 5 marketed drugs are approved by 
the Food and Drug Administration (FDA) in the United 
States (US) for the preventive treatment of migraine; 4 of 
them are approved for the prophylaxis of migraine: 
propranolol, timolol maleate, divalproex sodium, and 
topiramate. The clinical trials (Brandes et al 2004, 
Klapper 1997, Mathew et al 1995, Nadelmann et al 1986, 
Silberstein et al 2004) that supported registration of these 
drugs for this indication were conducted before the 
establishment of CM as a single entity and generally 
included patients with headaches on less than 15 days per 
month. 4 (propranolol [Inderal®, Akrimax Pharmaceuticals], 
Although there are more than 40 medications 
within these classes of drugs that are used 
with varying response rates to prevent 
migraine, only 5 marketed drugs are approved 
by the Food and Drug Administration (FDA) 
in the United States (US) for the preventive 
treatment of migraine; 4 of them are approved 
for the prophylaxis of migraine: propranolol, 
timolol maleate, divalproex sodium, and 
topiramate. The clinical studies (Brandes et al 
2004, Klapper 1997, Mathew et al 1995, 
Nadelmann et al 1986, Silberstein et al 2004) 
that supported registration of these drugs for 
this indication were conducted before the 
Update/correction was made 
regarding approved drugs for 
preventive treatment of migraine 
and associated literature. 

 
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timolol [Blocadren®, Merck & Co, Inc.], divalproex sodium 
[Depakote®, AbbVie, Inc.], and topiramate [Topamax®, 
Jannsen]) are approved by the United States Food and Drug 
Administration (FDA) for the prevention or prophylaxis of 
EM and only 1 (onabotulinumtoxinA [Botox®, Allergan, 
Inc.]) is approved for the prevention of CM Only 
1 medication, onabotulinumtoxinA, is approved for 
prophylaxis of CM (Lipton and Silberstein 2015). Notably, 
despite evidence suggesting that inhibition of CGRP is 
effective as a preventive migraine treatment, no available 
treatment directly targets CGRP. 
establishment of CM as a single entity and 
generally included patients with headaches on 
less than 15 days per month. Only 
1 medication, onabotulinumtoxinA, is 
approved for prophylaxis of CM (Lipton and 
Silberstein 2015). 
1.3.1 
Nonclinical Studies 
The inflammation was consideredsuspected to be the result of 
immune complex formation/deposition from the monkeys’ 
immunogenic response to the drug (TEV-48125) and was not 
considered to be clinically relevant. In the pivotal 6-month 
chronic toxicity study in monkeys following once-weekly sc 
dosing at dosage levels of up to 300 mg/kg/week, achieving 
high exposure throughout the study, no microscopic 
findings 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.  
[…] 
Additionally, pivotal reproductive and developmental toxicity 
studies in animalsrabbits and rats with TEV-48125 were 
conducted. The in life portion was and completed, and 
evaluation is ongoing. 
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 pivotal 6-month chronic 
toxicity study in monkeys following once-
weekly sc dosing at dosage levels of up to 
300 mg/kg/week, achieving high exposure 
throughout the study, no microscopic findings 
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.  
[…] 
Additionally, pivotal reproductive and 
Text was updated with the latest 
relevant information available 
from the nonclinical studies. 

 
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developmental toxicity studies in rabbits and 
rats with TEV-48125 were conducted and 
completed. 
1.8 Location and Timing of Study (Other sections affected by this change: Synopsis) 
This study is planned to be conducted… at approximately 
130140 centers. 
This study is planned to be conducted… at 
approximately 140 centers. 
The number of study centers 
was expanded. 
2 
PURPOSE OF THE STUDY AND STUDY OBJECTIVES 
2.2.3 
Exploratory Objectives (Other sections affected by this change: Synopsis and Sections 2.3.3 and 9.5.3) 
• 
to evaluate the efficacy of sc TEV-48125 in patients with 
migraine, as assessed by the reduction in the number of 
headache days of at least moderate severity 
• 
to evaluate the efficacy of sc TEV-48125 in patients 
with migraine, as assessed by the reduction in the 
number of migraine days in patients not receiving 
concomitant migraine preventive medications at 
baseline 
• 
to evaluate the efficacy of sc TEV-48125 in patients 
with migraine, as assessed by the reduction in the 
number of headache days of at least moderate severity 
in patients not receiving concomitant migraine 
preventive medications at baseline 
• 
to evaluate the efficacy of sc TEV-48125 in patients 
with migraine, as assessed by the reduction in the 
number of migraine days for new patients and 
placebo-treated rollover patients 
• 
to evaluate the efficacy of sc TEV-48125 in patients 
with migraine, as assessed by the reduction in the 
number of headache days of at least moderate severity 
for new patients and placebo-treated rollover patients 
• 
[…] 
• 
to evaluate the incidenceimmunogenicity of TEV-48125 
and the impact of ADAs on clinical outcome in patients 
• to evaluate the efficacy of sc TEV-48125 
in patients with migraine, as assessed by 
the reduction in the number of headache 
days of at least moderate severity 
• to evaluate the efficacy of sc TEV-48125 
in patients with migraine, as assessed by 
the reduction in the number of migraine 
days in patients not receiving 
concomitant migraine preventive 
medications at baseline 
• to evaluate the efficacy of sc TEV-48125 
in patients with migraine, as assessed by 
the reduction in the number of headache 
days of at least moderate severity in 
patients not receiving concomitant 
migraine preventive medications at 
baseline 
• to evaluate the efficacy of sc TEV-48125 
in patients with migraine, as assessed by 
the reduction in the number of migraine 
days for new patients and placebo-treated 
rollover patients 
• to evaluate the efficacy of sc TEV-48125 
in patients with migraine, as assessed by 
Four exploratory objectives 
were added for improved 
alignment across migraine 
studies and in line with the 
several added endpoints 
(below). 
 
Exploratory objectives were 
revised for clarity and 
correctness. 
 
Several minor editorial changes 
were made 

 
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exposed to TEV-48125 
• 
[…] 
• 
to explore the relationship between genetic 
polymorphisms within the CGRP receptor-ligand 
complex (eg, CALCA, CALCB, CALCRL, CRCP, and 
RAMP) and migraine-associated genes (eg, PRDM16, 
AJAP1, TSPAN2, MEF2D, TRPM8, TGFBR2, 
PHACTR1, FHL5, C7orf10, MMP16, ASTN2, LRP1, 
APOA1BP, TBC1D7, FUT9, STAT6, ATP5B, and 
MTHFR) and mode-of-action-related pathways versus 
hypertension, migraine severity, and safety and efficacy 
responses 
 
the reduction in the number of headache 
days of at least moderate severity for new 
patients and placebo-treated rollover 
patients 
• […] 
• to evaluate the immunogenicity of 
TEV-48125 and the impact of ADAs on 
clinical outcome in patients exposed to 
TEV-48125 
• […] 
• to explore the relationship between 
genetic polymorphisms within the CGRP 
receptor-ligand complex (eg, CALCA, 
CALCB, CALCRL, CRCP, and RAMP) 
and migraine-associated genes (eg, 
PRDM16, AJAP1, TSPAN2, MEF2D, 
TRPM8, TGFBR2, PHACTR1, FHL5, 
C7orf10, MMP16, ASTN2, LRP1, 
APOA1BP, TBC1D7, FUT9, STAT6, 
ATP5B, and MTHFR) and mode-of-
action-related pathways versus 
hypertension, migraine severity, and 
safety and efficacy responses 

 
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2.3.3 
Exploratory Efficacy Endpoints (Other sections affected by this change: Synopsis and Sections 2.2.3 and 9.5.3) 
• 
mean change from baseline (28-day run-in period) in the 
number of migraine days during the 4-week periods after 
visits 4, 7, and 13 
• 
mean change from baseline (28 day run in period) in the 
monthly average number of migraine days during the 
long term safety study  
• 
mean change from baseline (28-day run-in period) in 
the number of headache days of at least moderate 
severity during the 4-week periods after visits 4, 7, and 
13 
• 
mean change from baseline (28-day run-in period) in 
the number of migraine days during the 4-week 
periods after visits 4, 7, and 13 in patients not 
receiving concomitant migraine preventive 
medications at baseline 
• 
mean change from baseline (28-day run-in period) in 
the number of headache days of at least moderate 
severity during the 4-week periods after visits 4, 7, and 
13 in patients not receiving concomitant migraine 
preventive medications at baseline 
• 
mean change from baseline (28-day run-in period) in 
the number of migraine days during the 4-week period 
after the 1st dose of study drug for new patients and 
placebo-treated rollover patients 
• 
mean change from baseline (28-day run-in period) in 
the number of headache days of at least moderate 
severity during the 4-week period after the 1st dose of 
study drug for new patients and placebo-treated 
• 
mean change from baseline (28-day run-in 
period) in the number of migraine days 
during the 4-week periods after visits 4, 7, 
and 13 
• 
mean change from baseline (28-day run-in 
period) in the number of headache days of 
at least moderate severity during the 4-
week periods after visits 4, 7, and 13 
• 
mean change from baseline (28-day run-in 
period) in the number of migraine days 
during the 4-week periods after visits 4, 7, 
and 13 in patients not receiving 
concomitant migraine preventive 
medications at baseline 
• 
mean change from baseline (28-day run-in 
period) in the number of headache days of 
at least moderate severity during the 4-
week periods after visits 4, 7, and 13 in 
patients not receiving concomitant 
migraine preventive medications at 
baseline 
• 
mean change from baseline (28-day run-in 
period) in the number of migraine days 
during the 4-week period after the 1st dose 
of study drug for new patients and 
placebo-treated rollover patients 
• 
mean change from baseline (28-day run-in 
period) in the number of headache days of 
at least moderate severity during the 4-
Several endpoints and/or time 
points were added for improved 
alignment across migraine 
studies.  
 
Several endpoints were deleted 
to preserve focus on key items. 
 
Several minor editorial changes 
were made. 
 

 
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rollover patients 
• 
mean change from baseline (28-day run-in period) in the 
number of headache days of any severity during the 4-
week periods after visits 4, 7, and 13 
• 
mean change from baseline (28-day run-in period) in the 
number of days of use of any acute headache medications 
during the 4-week periods after visits 4, 7, and 13 
• 
mean change from baseline (28 day run in period) in the 
monthly average number of days of use of any acute 
headache medications during the long term safety study 
• 
proportion of patients reaching at least 50%, 75%, 
and total (100%) reduction in the number of headache 
days of at least moderate severity during the 4-week 
periods after visits 4, 7, and 13 
• 
proportion of patients reaching at least 50% and 75% 
reduction in the number of headache days of at least 
moderate severity during the 4-week periods after visit 
4 who sustain the same level of response during the 4-
week periods after visits 7 and 13 
• 
proportion of patients reaching at least 50%, 75%, 
and total (100%) reduction in the number of migraine 
days during the 4-week periods after visits 4, 7, and 13 
• 
proportion of patients reaching at least 50% and 75% 
reduction in the number of migraine days during the 
4-week periods after visit 4 who sustain the same level 
of response during the 4-week periods after visits 7 
and 13 
• 
proportion of patients discontinuing concomitant 
preventive medications during the 4 week periods after 
week period after the 1st dose of study 
drug for new patients and placebo-treated 
rollover patients 
• 
mean change from baseline (28-day run-in 
period) in the number of headache days of 
any severity during the 4-week periods 
after visits 4, 7, and 13 
• 
mean change from baseline (28-day run-in 
period) in the number of days of use of 
any acute headache medications during the 
4-week periods after visits 4, 7, and 13 
• 
proportion of patients reaching at least 
50%, 75%, and total (100%) reduction in 
the number of headache days of at least 
moderate severity during the 4-week 
periods after visits 4, 7, and 13 
• 
proportion of patients reaching at least 
50% and 75% reduction in the number of 
headache days of at least moderate 
severity during the 4-week periods after 
visit 4 who sustain the same level of 
response during the 4-week periods after 
visits 7 and 13 
• 
proportion of patients reaching at least 
50%, 75%, and total (100%) reduction in 
the number of migraine days during the 4-
week periods after visits 4, 7, and 13 
• 
proportion of patients reaching at least 
50% and 75% reduction in the number of 
migraine days during the 4-week periods 

 
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visits 7 and 13treatment period  
• 
mean change from baseline (day 0) in disability score in 
patients with CM, as measured by the 6-item Headache 
Impact Test (HIT-6), at 4 weeks after visits 7 8 and 1314  
• 
mean change from baseline (day 0) in disability score in 
patients with EM, as measured by the Migraine Disability 
Assessment (MIDAS) questionnaire, at 4 weeks after 
visits 78 and 13 14 
• 
mean change from baseline (day 0) in quality of life, as 
measured by the Migraine-Specific Quality of Life 
(MSQOL) questionnaire, at 4 weeks after visits 78 
and 1314 
• 
mean change from baseline (day 0) in patient health 
status, as measured by the EuroQol-5 Dimension, 5 
response level version (EQ-5D-5L) questionnaire, at 4 
weeks after visits 78 and 13 14 
• 
assessment of patient satisfaction, as measured by the 
Patient Global Impression of Change (PGIC) scale at 
visits 3, 5, 8, 11, and 14 
• 
mean change from baseline (day 0) in patient depression 
status, as measured by the 2-item Patient Health 
Questionnaire (PHQ-2) and 9-item Patient Health 
Questionnaire (PHQ-9), at visits 8 and 14  
• 
mean change from baseline (day 0) in patient work 
productivity and activity impairment, as measured by the 
Work Productivity and Activity Impairment (WPAI) 
questionnaire, at visits 8 and 14 
after visit 4 who sustain the same level of 
response during the 4-week periods after 
visits 7 and 13 
• 
proportion of patients discontinuing 
concomitant preventive medications 
during the treatment period  
• 
mean change from baseline (day 0) in 
disability score in patients with CM, as 
measured by the 6-item Headache Impact 
Test (HIT-6), at visits 8 and 14  
• 
mean change from baseline (day 0) in 
disability score in patients with EM, as 
measured by the Migraine Disability 
Assessment (MIDAS) questionnaire, at 
visits 8 and 14 
• 
mean change from baseline (day 0) in 
quality of life, as measured by the 
Migraine Specific Quality of Life 
(MSQOL) questionnaire, at visits 8 and 14 
• 
mean change from baseline (day 0) in 
patient health status, as measured by the 
EuroQol-5 Dimension, 5 response level 
version (EQ-5D-5L) questionnaire, at 
visits 8 and 14 
• 
assessment of patient satisfaction, as 
measured by the Patient Global 
Impression of Change (PGIC) scale at 
visits 3, 5, 8, 11, and 14 
• 
mean change from baseline (day 0) in 
patient depression status, as measured by 

 
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the 2-item Patient Health Questionnaire 
(PHQ-2) and 9-item Patient Health 
Questionnaire (PHQ-9), at visits 8 and 14  
• 
mean change from baseline (day 0) in 
patient work productivity and activity 
impairment, as measured by the Work 
Productivity and Activity Impairment 
(WPAI) questionnaire, at visits 8 and 14 
2.3.3 
Exploratory Efficacy Endpoints (Other sections affected by this change: Synopsis, List of Abbreviations, and Sections 3.1, 3.6, 3.14 
[Tables 1 and 2], 3.14.2.1.2, 3.14.3.1.7, 3.14.3.1.11, 6.7, and 9.5.3) 
• 
mean change from baseline (day 0) in patient health 
status, as measured by the EuroQol-5 Dimension, 5 
response level version (EQ-5D-5L) questionnaire, at 4 
weeks after visits 78 and 1314 
• 
mean change from baseline (day 0) in 
patient health status, as measured by the 
EuroQol-5 Dimension, 5 response level 
version (EQ-5D-5L) questionnaire, at 
visits 8 and 14 
This change reflects the update 
to the 5-level version instead of 
the 3-level version of the EQ-5D 
(5 responses). 
2.3.5.2 Immunogenicity Endpoints (Other sections affected by this change: Synopsis) 
The immunogenicity endpoint is the incidence and 
immunogenicity of TEV-48125 and the impact of ADAs on 
clinical outcome after monthly sc doses of TEV 48125 and at 
7.5 months after stopping treatment. 
The immunogenicity endpoint is the 
immunogenicity of TEV-48125 and the 
impact of ADAs on clinical outcome after sc 
doses of TEV-48125 and at 7.5 months after 
stopping treatment. 
Updated the endpoint; the 
specification of “monthly” was 
considered to be unnecessary. 

 
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141 
 
3.1 General Design and Study Schema (Other sections affected by this change: Synopsis and Sections 3.1, 3.11, 3.14 [Tables 1 and 2], and 
3.14.3.1) 
…the study will consist of a 12-month double blind treatment 
period… 
 
…the study will consist of a 12-month 
treatment period… 
 
The text was updated to reflect 
that the study may be unblinded 
prior to 12 months of treatment 
due to unblinding of the pivotal 
studies. 
3.1 General Design and Study Schema (Other sections affected by this change: Synopsis and Sections 3.14.2.2, 3.14.2.3, and 5.1) 
Female and male patients 18 to 70 years of age, inclusive, 
with CM and EM who complete the pivotal efficacy studies 
(Studies TV48125-CNS-30049 and TV48125-CNS-30050) 
and approximately 300 patients (approximately half of whom 
have a diagnosis of CM and half of whom have a diagnosis of 
EM) who have not participated in the pivotal efficacy studies 
may enter this long-term safety, tolerability, and efficacy 
study if they meet the inclusion/exclusion criteria and provide 
informed consent. In addition, patients who do not complete 
the pivotal efficacy studies and those patients who complete 
the pivotal efficacy studies but do not wish to continue 
treatment during this long-term safety, tolerability, and 
efficacy study may attend a follow-up visit during this study 
for the purpose of ADA assessment approximately 7.5 months 
after their last dose of study drug.  
Female and male patients 18 to 70 years of 
age, inclusive, with CM and EM who 
complete the pivotal efficacy studies 
(Studies TV48125-CNS-30049 and TV48125-
CNS-30050) and approximately 300 patients 
(approximately half of whom have a diagnosis 
of CM and half of whom have a diagnosis of 
EM) who have not participated in the pivotal 
efficacy studies may enter this long-term 
safety, tolerability, and efficacy study if they 
meet the inclusion/exclusion criteria and 
provide informed consent. In addition, 
patients who do not complete the pivotal 
efficacy studies and those patients who 
complete the pivotal efficacy studies but do 
not wish to continue treatment during this 
long-term safety, tolerability, and efficacy 
study may attend a follow-up visit during this 
study for the purpose of ADA assessment 
approximately 7.5 months after their last dose 
of study drug.  
“Tolerability” was added to the 
description of the study 
throughout the document for 
consistency. 
3.1 General Design and Study Schema (Other sections affected by this change: Sections 3.14.2.1.2 and 9.4.1) 
New patients (not rolling over from the pivotal efficacy 
studies) using up to 2 preventive medications at the time of 
study enrollmentthe screening visit will be allowed to remain 
New patients (not rolling over from the 
pivotal efficacy studies) using up to 2 
preventive medications at the time of the 
An error was corrected. In this 
study, enrollment is considered 
to occur at the time of 

 
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on the medications… 
screening visit will be allowed to remain on 
the medications… 
randomization rather than at 
screening. 
3.4 Safety and Tolerability Measures and Time Points (Other sections affected by this change: Synopsis) 
vital signs measurements (systolic and diastolic blood 
pressure, pulse, oral temperature, and respiratory rate) 
vital signs measurements (systolic and 
diastolic blood pressure, pulse, temperature, 
and respiratory rate) 
“Oral” was removed to allow 
temperature to be measured 
using other methods (eg, under 
arm). 
3.5.3 
Biomarker Measures and Time Points (Other sections affected by this change: Synopsis) 
A blood sample for pharmacogenomic analysis will be 
collected from patients who consent to pharmacogenomic 
analysis and who have not already had a sample collected 
during the pivotal efficacy studies at the baseline visit or 
any visit thereafter. 
A blood sample for pharmacogenomic 
analysis will be collected from patients who 
consent to pharmacogenomic analysis and 
who have not already had a sample collected 
during the pivotal efficacy studies at the 
baseline visit or any visit thereafter. 
Clarification was made to 
indicate that no patients should 
have more than 1 
pharmacogenomic sample 
collected. 
3.7 Randomization and Blinding (Other sections affected by this change: Synopsis) 
Patients will be stratified by gender, country, and baseline 
preventive medication use at baseline (yes, no). 
Patients will be stratified by gender, country, 
and baseline preventive medication use (yes, 
no). 
Language was aligned with the 
pivotal efficacy studies. 
3.8.1 
Randomization 
Patient randomization codes will be maintained in a secure 
location within Teva Global Biometrics or in a secure location 
with the vendor contracted to create the listClinical Supply 
Chain. 
Patient randomization codes will be 
maintained in a secure location within Teva 
Clinical Supply Chain. 
Randomization security 
procedures were updated. 
3.8.2 
Blinding/Unblinding 
Pharmacokinetic data may be assessed during the study. For 
patients who have pharmacokinetic sample bioanalysis and/or 
data analysis conducted, the individuals responsible for 
sample bioanalysis and other responsible personnel will know 
who received each TEV 48125 dose regimen. Personnel 
responsible for bioanalysis will be provided with the 
randomization code in order to facilitate the analysis. 
Pharmacokinetic data may be assessed during 
the study. Personnel responsible for 
bioanalysis will be provided with the 
randomization code in order to facilitate the 
analysis. However, the personnel responsible 
for bioanalysis will not have access to clinical 
safety and efficacy data and will provide 
The blinding criteria and 
procedures with respect to 
pharmacokinetic data were 
updated.  

 
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However, the personnel responsible for bioanalysis and 
pharmacokinetic data analysis will not have access to clinical 
safety and efficacy data and will provide concentration data to 
other personnel in a manner that will not identify individual 
patients (ie, a dummy patient identifier will be linked to an 
individual patient’s concentration data).  
concentration data to other personnel in a 
manner that will not identify individual 
patients (ie, a dummy patient identifier will be 
linked to an individual patient’s concentration 
data). 
3.11 
Duration of Patient Participation and Justification 
It is considered that, with a half-life of around 45 days, there 
will be a complete washout of the antibody drug from the 
circulating blood in 7.5 months (≥5 half-lives), allowing a 
more precise evaluation of ADA. 
It is considered that, with a half-life of around 
45 days, there will be a complete washout of 
the drug from the circulating blood in 7.5 
months (≥5 half-lives), allowing a more 
precise evaluation of ADA. 
An error was corrected. 
3.14 
Study Procedures, Tables 1 and 2 (Related to the change in Section 7.1.6 described below) 
Blood samples for serum ADA concentrationassessmentn 
 
n 
Blood samples for serum ADA assessment will also be 
collected upon observation of any severe hypersensitivity 
reaction (eg, anaphylaxis). 
 
Blood samples for serum ADA assessmentn 
 
n 
Blood samples for serum ADA 
assessment will also be collected upon 
observation of any severe hypersensitivity 
reaction (eg, anaphylaxis). 
These additional blood sample 
collections are related to the 
designation of anaphylaxis and 
severe hypersensitivity reactions 
as adverse events of special 
interest in this amendment. 
 
“Concentration” and “assay” 
were changed to “assessment” 
throughout the document for 
consistency of verbiage. 
3.14 
Study Procedures, Tables 1 and 2 
X (A single blood sample for pharmacogenomic analysis will 
be collected at visit 2 or any visit thereafter from patients who 
consent to this procedure. A separate informed consent form 
for pharmacogenomic sampling must be signed by the 
patient.) 
Blood sample for pharmacogenomic analysiso  
o 
A single blood sample for pharmacogenomic analysis 
Blood sample for pharmacogenomic analysiso  
 
o 
A single blood sample for 
pharmacogenomic analysis will be collected at 
visit 2 or any visit thereafter from patients 
who consent to this procedure, if the sample is 
not obtained during their participation in 
Details of this sampling were 
moved to a footnote and revised 
to emphasize that a separate ICF 
is required. It was emphasized 
that a sample should only be 
collected in this study if the 
sample was not obtained during 

 
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will be collected at visit 2 or any visit thereafter from 
patients who consent to this procedure, if the sample is not 
obtained during their participation in Studies 
TV48125-CNS-30049 or TV48125-CNS-30050. A separate 
informed consent form for pharmacogenomic sampling 
must be signed by the patient. 
Studies TV48125-CNS-30049 or TV48125-
CNS-30050. A separate informed consent 
form for pharmacogenomic sampling must be 
signed by the patient. 
the pivotal study. 
3.14 
Study Procedures, Table 1 
d 
Procedure/assessment will only be completed for patients 
who enter this study more than 30 days after completing visit 
5 of the pivotal efficacy study. 
d 
Procedure/assessment will only be 
completed for patients who enter this study 
more than 30 days after completing visit 5 of 
the pivotal efficacy study. 
Clarification was added. 
3.14 
Study Procedures, Table 2 (Other sections affected by this change: Table 6) 
e Patients will return to the study center for up to 2 additional 
visits at 3 to 10 days or 15 to 20 days after any dose of study 
drug for blood sampling for plasma TEV-48125 
concentration determination, triplicate 12-lead ECGs, and 
inquiries about adverse events and concomitant medications. 
These visits should occur during the following time 
periods relative to any dose of study drug: 3 to 10 days 
or 15 to 20 days after study drug administration. 
e 
Patients will return to the study center for 
up to 2 additional visits after any dose of 
study drug for blood sampling for plasma 
TEV-48125 concentration determination, 
triplicate 12-lead ECGs, and inquiries about 
adverse events and concomitant medications. 
These visits should occur during the following 
time periods relative to any dose of study 
drug: 3 to 10 days or 15 to 20 days after study 
drug administration. 
Editorial change was made. 
3.14.1 Procedures for Screening of Patients Not Rolling Over from the Pivotal Efficacy Studies (Visit 1 [Day –28]) 
The first 2 digits of the screening number will be the number 
assigned to the country where the investigational center is 
located, the next 3 digits will be the investigational center 
number, and the last 3 digits will be the patient number 
assigned at the investigator center (eg, the 3rd patient screened 
in Italythe US [country 01] at center 101 would be assigned 
the number of 01101003). 
The first 2 digits of the screening number will 
be the number assigned to the country where 
the investigational center is located, the next 
3 digits will be the investigational center 
number, and the last 3 digits will be the 
patient number assigned at the investigator 
center (eg, the 3rd patient screened in the US 
[country 01] at center 101 would be assigned 
the number of 01101003). 
Country 01 is the US. 
3.14.2.1.2 Baseline (Visit 2 [Day 0 (+5 Days)]) (Other sections affected by this change: Table 1, Table 2 and Sections 3.14.3.1.2 through 

 
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3.14.3.1.5 and 3.14.3.1.8 through 3.14.3.1.9) 
• 
Perform physical examination (including weight). 
• 
Perform vital signs measurements (includes systolic and 
diastolic blood pressure, pulse, body temperature, and 
respiratory rate). 
• 
Perform 12-lead ECG. 
• 
Perform clinical laboratory tests (serum chemistry, 
hematology, coagulation, and urinalysis). 
• 
Perform physical examination (including 
weight). 
• 
Perform vital signs measurements 
(includes systolic and diastolic blood 
pressure, pulse, body temperature, and 
respiratory rate). 
• 
Perform 12-lead ECG. 
• 
Perform clinical laboratory tests (serum 
chemistry, hematology, coagulation, and 
urinalysis). 
Additional baseline assessments 
were added for patients not 
rolling over for consistency with 
the pivotal efficacy studies. 
 
Additionally, physical 
examinations at visits 3, 4, and 5 
were specified to be for 
nonrollover patients only and 
physical examinations at visits 
6, 9, 10, 11, and 12 were deleted 
for all patients. 
3.14.4.1 
Patients Rolling Over from the Pivotal Efficacy Studies and New Patients (Final Visit [Visit 15 (Day 533)]) (Other sections 
affected by this change: Table 1) 
Patients Rolling Over from the Pivotal Efficacy Studies and 
New Patients (End of Study/Early TerminationFinal Visit) 
[Visit 15 (Day 533)]) 
• 
[…] 
• 
Perform physical examination (including weight). 
Patients Rolling Over from the Pivotal 
Efficacy Studies and New Patients (Final Visit 
[Visit 15 (Day 533)]) 
• 
[…] 
• 
Perform physical examination 
(including weight). 
The visit name was corrected.  
 
A physical examination was 
added to the assessments. 
4 
SELECTION AND WITHDRAWAL OF PATIENTS 
4.1.2 
Patients Not Rolling Over from the Pivotal Efficacy Studies (Other sections affected by this change: Synopsis) 
d. […] 
-Patients with EM: 
headache occurring on ≥34 and ≤14 days 
on ≥4 days, fulfilling any of the following: 
 
ICHD-3 diagnostic criteria C and D for 1.1 Migraine 
without aura (Appendix D) 
 
[…] 
 
Probable migraine (a migraine subtype where only 
d. […] 
-Patients with EM: 
headache occurring on ≥4 and ≤14 days 
on ≥4 days, fulfilling any of the following: 
 
ICHD-3 diagnostic criteria C and D 
for 1.1 Migraine without aura 
(Appendix D) 
 
[…] 
Headache criteria were made 
internally consistent. 
 
A criterion of a probable 
migraine was added to further 
define the patient population. 

 
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146 
 
1 migraine criterion is missing) 
 
-Patients with CM: 
on ≥8 days, fulfilling any of the following: 
 
[…] 
 
Probable migraine (a migraine subtype where only 
1 migraine criterion is missing) 
 
e. Not using preventive medications (presented in 
Appendix B) (ie, at least 5 half-lives have passed since 
last use) or using no more than 21 preventive medications 
(presented in Appendix A) for migraine or other 
medical conditions (eg, topiramate) 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 beginning the 28-day run-in period. A 
list of preventive medications is presented in Appendix A. 
f. Body mass index of 17.5 to 37.5 kg/m2 and a total body 
weight between 45 and 115120 kg, inclusive 
g. […] 
if of childbearing potential, patients must meet any of the 
following criteria: 
[…] 
− 
Sexual abstinence is only considered a highly 
effective method if defined as refraining from 
heterosexual intercourse in the defined period. The 
reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the clinical 
study and the preferred and usual lifestyle of the 
subject. Periodic abstinence (eg, calendar, 
ovulation, symptothermal, post-ovulation methods), 
declaration of abstinence for the duration of a 
 
Probable migraine (a migraine subtype 
where only 1 migraine criterion is 
missing) 
 
-Patients with CM: 
on ≥8 days, fulfilling any of the following: 
 
[…] 
 
Probable migraine (a migraine subtype 
where only 1 migraine criterion is 
missing) 
e. Not using preventive medications 
(presented in Appendix B) (ie, at least 
5 half-lives have passed since last use) or 
using no more than 1 preventive 
medication (presented in Appendix A) 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 beginning the 28-
day run-in period.  
f. Body mass index of 17.5 to 37.5 kg/m2 and 
a total body weight between 45 and 120 kg, 
inclusive 
g. […] 
if of childbearing potential, patients must 
meet any of the following criteria: 
[…] 
− 
Sexual abstinence is only considered a 
highly effective method if defined as 
refraining from heterosexual 
intercourse in the defined period. The 
reliability of sexual abstinence needs to 
be evaluated in relation to the duration 
 
Allowed/disallowed preventive 
medication was clarified. 
 
Upper boundary of the total 
body weight was expanded up to 
120 kg. This limit was used in 
Phase 2 studies; no associated 
safety signals were detected. 
 
Contraception criteria were 
updated and clarified to comply 
with the current Teva standards. 
 
Language regarding the timing 
of the serum β-HCG pregnancy 
testing was clarified. 

 
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study, and withdrawal are not acceptable methods 
of contraception. 
− 
Patients will remain abstinent throughout the study in 
the context of the preferred and usual lifestyle. 
Declaration of abstinence for the duration of the study 
and withdrawal are not acceptable methods of 
contraception. 
− 
Patients have sexual preference that precludes the 
possibility of pregnancy. 
h. Female patients of childbearing potential must have a 
negative serum β-HCG pregnancy test at screeningprior to 
randomization (confirmed by urine dipstick β-HCG 
pregnancy test at baseline). 
of the clinical study and the preferred 
and usual lifestyle of the subject. 
Periodic abstinence (eg, calendar, 
ovulation, symptothermal, post-
ovulation methods), declaration of 
abstinence for the duration of a study, 
and withdrawal are not acceptable 
methods of contraception. 
h. Female patients of childbearing potential 
must have a negative serum β-HCG 
pregnancy test at screening (confirmed by 
urine dipstick β-HCG pregnancy test at 
baseline). 

 
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4.2.2 
Patients Not Rolling Over from the Pivotal Efficacy Studies (Other sections affected by this change: Synopsis) 
b. Evidence or medical history of clinically significant 
psychiatric issues, including major depression, panic 
disorder, or generalized anxiety disorderany suicide 
attempt in the past, or suicidal ideation with a specific plan 
in the past 2 years 
 
e. Past or current history of cancer in the past 5 years, 
except for appropriately treated nonmelanoma skin 
carcinoma in the last 5 years 
 
m. Lifetime History of alcohol or drug abuse during the past 
2 years, or alcohol or drug dependence during the past 
5 years 
 
n. The patient cannon participate or successfully complete the 
study, in the opinion of their healthcare provider or the 
investigator, for any of the following reasons: 
− 
[…] 
− 
in custody due to an administrative or a legal decision, 
under tutelageguardianship, or institutionalized 
b. 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 
 
e. Past or current history of cancer in the past 
5 years, except for appropriately treated 
nonmelanoma skin carcinoma 
 
m. History of alcohol or drug abuse during the 
past 2 years, or alcohol or drug dependence 
during the past 5 years 
 
n. The patient cannon participate or 
successfully complete the study, in the 
opinion of their healthcare provider or the 
investigator, for any of the following 
reasons: 
− 
[…] 
− 
in custody due to an administrative or a 
legal decision, under guardianship, or 
institutionalized 
Editorial change was made to 
the prior history of cancer 
criterion. 
 
Minor editorial changes were 
also made to other exclusion 
criteria. 
 
Psychiatric history criterion was 
updated to specifically address 
suicidal ideation or behavior 
within the past 2 years. 
 
History of alcohol and drug 
abuse and dependence criterion 
was modified to align with 
Teva’s current practice. 
 
Language was updated to reflect 
commonly used terminology. 
5 
TREATMENT OF PATIENTS 
5.2 Restrictions 
Highly effective contraception methods include the following 
hormonal and other methods of birth control: 
• 
combined (estrogen and gestagen) oral 
contraceptives, hormone implants, hormone rings, 
Highly effective contraception methods 
include the following hormonal and other 
methods of birth control: 
• combined (estrogen and gestagen) oral 
Contraception criteria were 
updated. 

 
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contraceptive patch, and hormone injectables initiated 
at least 7 days before study drug administration 
• 
hormone containing intrauterine device in place for a 
period of at least 2 months before study drug 
administration 
• 
[…] 
There were no additional restrictions in this study. 
In addition, male patients may not donate sperm for the 
duration of the study and for 7.5 months after 
discontinuation of study drug. 
contraceptives, hormone implants, 
hormone rings, contraceptive patch, and 
hormone injectables initiated at least 
7 days before study drug administration 
• intrauterine device in place for a period of 
at least 2 months before study drug 
administration 
• […] 
There were no additional restrictions in this 
study. 
In addition, male patients may not donate 
sperm for the duration of the study and for 7.5 
months after discontinuation of study drug. 
5.3 Prior and Concomitant Therapy or Medication 
Any prior or concomitant therapy, medication, or procedure 
(ie, procedures for the treatment of migraine [eg, nerve 
blocks])that a patient has had within 6 months before study 
drug administration and up to the end of the study period will 
be recorded on the CRF. In addition, migraine preventive 
medication that a patient took within 2 years before study 
drug administration will be recorded. Generic or trade 
name, indication, and dosage will be recorded. 
Any prior or concomitant therapy, medication, 
or procedure that a patient has had within 
6 months before study drug administration and 
up to the end of the study period will be 
recorded on the CRF. In addition, migraine 
preventive medication that a patient took 
within 2 years before study drug 
administration will be recorded. Generic or 
trade name, indication, and dosage will be 
recorded. 
Parenthetical clarification was 
considered to be limiting and 
was therefore removed. 
 
Process clarification was added. 
5.3 Prior and Concomitant Therapy or Medication (Other sections affected by this change: Synopsis, Sections 3.1 and 4.1, and Appendix 
A) 
Patients on preventive medication must be on a stable dose for 
at least 2 months of consecutive use prior to study entry. 
Alternatively, patients must have discontinued the 
preventive medication at least 5 half-lives prior to 
screening. If discontinuation of preventive medication is 
Patients on preventive medication must be on 
a stable dose for at least 2 months of 
consecutive use prior to study entry. 
Alternatively, patients must have discontinued 
the preventive medication at least 5 half-lives 
An alternative option was 
provided for patients to 
discontinue preventive 
medication at least 5 half-lives 
prior to screening. 

 
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clinically indicated by the investigator (eg, due to no further 
need or safety concerns), the medications may be stopped, 
and the reason must be recorded. For all patients not 
remaining on preventive migraine medications, disallowed 
mediations are presented in Appendix B. 
Patients will be allowed to use acute medication to treat acute 
migraine attacks, as needed, with the exception of 
medications containing opioids and barbiturates, which 
cannot be used more than 4 times per month prior to study 
entry.  
Use of concomitant therapies for indications other than 
migraine prevention is allowed throughout the course of the 
study, provided they are not effective for migraine or they 
meet the criteria for permitted concomitant preventive 
medication. 
All concomitant medications taken during the study… 
 
prior to screening. If discontinuation of 
preventive medication is clinically indicated 
by the investigator (eg, due to no further need 
or safety concerns), the medications may be 
stopped, and the reason must be recorded. For 
all patients not remaining on preventive 
migraine medications, disallowed mediations 
are presented in Appendix B. 
Patients will be allowed to use acute 
medication to treat acute migraine attacks, as 
needed. 
All concomitant medications taken during the 
study… 
 
Clarifying editorial change was 
made. 
 
Provision regarding the use of 
medications containing opioids 
and barbiturates was removed, 
as it was redundant with 
exclusion criterion b. 
 
Provision regarding the use of 
other concomitant medications 
was removed to further align 
with current approach. 
 
A clarification was made. In this 
study, acute medications can be 
used to treat acute migraine 
attacks. 
5.5 Total Blood Volume, Tables 5 and 6 
For each 18.5-mL sample, individual volumes will be 6 mL 
each for serum and plasma and 6.5 mL for RNA. 
For each 18.5-mL sample, individual volumes 
will be 6 mL each for serum and plasma and 
6.5 mL for RNA. 
A footnote was added for 
consistency with the blood 
volumes described throughout 
the protocol. 
6 
ASSESSMENT OF EFFICACY 
6.5 Two-Item Patient Health Questionnaire/9-Item Patient Health Questionnaire Points (Other sections affected by this change: Synopsis 
and Sections 3.6, 3.14 [Tables 1 and 2], 3.14.2.1.2, 3.14.3.1.7, and 3.14.3.1.11) 
Each of the items is scored on a scale of 0 (“not at all”), 1 
(“several days”), 2 (“more than half the days”), and to 3 
(“nearly every day”) based on the frequency of symptoms 
during the past 2 weeks (Spitzer et al 1999). The PHQ-2 was 
developed from the PHQ-9 to rapidly screen for depression 
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 (Spitzer et al 1999). 
Time period for symptom 
frequency in the PHQ was 
specified. 
 
Update/correction was made 

 
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and consists of the first 2 questions from the PHQ-9. […]  
If the PHQ-2 is positive (ie, a score of ≥3), patients will 
complete questions 3 through 9 (unique questions) of the 
PHQ-9. 
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. […]  
If the PHQ-2 is positive (ie, a score of ≥3), 
patients will complete questions 3 through 9 
([unique questions) of the PHQ-9. 
indicating that patients will only 
complete the unique portions of 
the PHQ-9 after a positive 
PHQ-2 score.  
6.8 Patient Global Impression of Change Scale 
The PGIC scale is a validated generic tool for assessment of 
overall change in the severity of illness following treatment. 
Patients will rate how they feel now compared with how they 
felt before receiving study drug on a 7 point scale where 3 is 
“very much worse,” 0 is “no change,” and 3 is “very much 
improved”. Patients 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 study on a 7-point scale where 1=no 
change (or condition 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. 
The PGIC scale is a validated generic tool for 
assessment of overall change in the severity of 
illness following treatment. Patients 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 study on a 7-
point scale where 1=no change (or condition 
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. 
Correction was made regarding 
PGIC scale numbering and 
descriptors. 
7 
ASSESSMENT OF SAFETY 
7.1.6 
Protocol-Defined Adverse Events of Special Interest (Other sections affected by this change: Section 3.14 [Table 1], Section 16, and 
Appendices [Appendix F added]) 
7.1.6 
Protocol-Defined Adverse Events of Special Interest 
The following are considered protocol-defined adverse events 
to be sent to the sponsor’s Global Patient Safety and 
Pharmacovigilance Department for evaluation: ophthalmic 
7.1.6 
Protocol-Defined Adverse Events of 
Special Interest 
The following are considered protocol-defined 
adverse events to be sent to the sponsor’s 
The title of this section was 
updated, adding the word 
“Special”. 
 
Adverse events of special 

 
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related adverse events of at least moderate severity, events of 
possible drug-induced liver injury (AST or ALT ≥3 × the 
ULN, total bilirubin ≥2 × the ULN or INR >1.5), or Hy’s 
Law events, or events of suspected anaphylaxis and severe 
hypersensitivity reactions. Severe hypersensitivity 
reactions will be monitored using the diagnostic criteria 
for anaphylaxis as outlined by the 2006 Joint National 
Institute of Allergy and Infectious Disease/Food Allergy 
and Anaphylaxis Network Second Symposium on 
Anaphylaxis (Sampson et al, 2006 [also see Appendix F]). 
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. 
The process for reporting a protocol-defined adverse 
event is the same as that for reporting a serious adverse 
event (see Section 7.1.5.3). 
Global Patient Safety and Pharmacovigilance 
Department for evaluation: ophthalmic 
adverse events of at least moderate severity, 
events of possible drug-induced liver injury 
(AST or ALT ≥3 × the ULN, total bilirubin ≥2 
× the ULN or INR >1.5), Hy’s Law events, or 
events of suspected anaphylaxis and severe 
hypersensitivity reactions. Severe 
hypersensitivity reactions will be monitored 
using the diagnostic criteria for anaphylaxis as 
outlined by the 2006 Joint National Institute 
of Allergy and Infectious Disease/Food 
Allergy and Anaphylaxis Network Second 
Symposium on Anaphylaxis (Sampson et al, 
2006 [also see Appendix F]). 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. 
The process for reporting a protocol-defined 
adverse event is the same as that for reporting 
a serious adverse event (see Section 7.1.5.3). 
interest were updated to include 
anaphylaxis and severe 
hypersensitivity reactions. 
 
Relatedly, Appendix F (clinical 
criteria for diagnosing 
anaphylaxis) was added. 
7.3.1 
Serum Chemistry (Other sections affected by this change: Sections 7.1.1, 7.1.6, 7.3.4, and Appendix E) 
The following serum chemistry tests will be performed: 
• 
[…] 
• 
total bilirubin 
• 
direct bilirubin 
• 
indirect bilirubin (calculated) 
• 
ALP 
• 
[…] 
The following serum chemistry tests will be 
performed: 
• 
[…] 
• 
total bilirubin 
• 
direct bilirubin 
• 
indirect bilirubin (calculated) 
• 
ALP 
• 
[…] 
Total and direct bilirubin tests 
will be conducted at all visits 
that have chemistry laboratory 
assessments. Previously, direct 
bilirubin collection was 
triggered only under certain 
conditions. 
 
Relatedly, editorial changes 

 
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were made throughout the 
protocol to clarify when total or 
direct (or both) bilirubin was 
being referred to. 
7.3.2 
Hematology 
The following hematology tests will be performed: 
• 
[…] 
• 
white blood cell (WBC) count and differential count 
(absolute values and percentages) 
− 
neutrophils 
− 
lymphocytes 
− 
eosinophils 
− 
monocytes 
− 
basophils 
− 
atypical lymphocytes 
The following hematology tests will be 
performed: 
• 
[…] 
• 
white blood cell (WBC) count and 
differential count (absolute values and 
percentages) 
− 
neutrophils 
− 
lymphocytes 
− 
eosinophils 
− 
monocytes 
− 
basophils 
A hematology test that was 
determined not to be needed was 
removed. 
7.4 Vital Signs 
In addition, potentially clinically significant values may be 
predefined by the sponsor for selected vital signs (see 
Section 9.7.2) and, if so, will be documented in the 
statistical analysis plan or other relevant documents (eg, 
medical monitoring plan). 
In addition, potentially clinically significant 
values may be predefined by the sponsor for 
selected vital signs (see Section 9.7.2) and, if 
so, will be documented in the statistical 
analysis plan or other relevant documents (eg, 
medical monitoring plan). 
This language was added to 
align with Teva’s standard 
practices. 
7.5 Electrocardiography 
The ECGs performed during the additional visits for 
pharmacokinetic sampling (patients not rolling over from the 
pivotal efficacy studies only) will be performed in triplicate, 
with approximately 1 minute between recordings. 
The ECGs performed during the additional 
visits for pharmacokinetic sampling (patients 
not rolling over from the pivotal efficacy 
studies only) will be performed in triplicate. 
Specification for approximately 
1-minute interval between 
recordings was removed, as it 
was deemed unnecessary. 
7.9 Immunogenicity 
7.9 Injection Site Assessments Immunogenicity  
7.9 Immunogenicity  
A dedicated immunogenicity 

 
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Blood samples for serum ADA assessment will be collected 
at visits 5, 8, 14 (EOT/early withdrawal visit), and 15 
(final visit) for patients rolling over from the pivotal 
efficacy studies and at those time points as well as visit 2 
for patients not rolling over from the pivotal efficacy 
studies. Blood samples for ADA assessment will also be 
collected upon observation of any severe hypersensitivity 
reaction (eg, anaphylaxis). See Appendix F for the clinical 
criteria for diagnosing anaphylaxis. Bioanalytical 
personnel should be made aware of any anaphylaxis 
occurrence as soon as possible in case an anti-TEV-48125 
immunoglobulin E assay is required. For patients rolling 
over from the pivotal efficacy studies for ADA assessment 
only, blood samples for serum ADA assessment will be 
collected at visit 16 (follow-up visit). 
7.10 Injection Site Assessments 
Blood samples for serum ADA assessment 
will be collected at visits 5, 8, 14 (EOT/early 
withdrawal visit), and 15 (final visit) for 
patients rolling over from the pivotal efficacy 
studies and at those time points as well as visit 
2 for patients not rolling over from the pivotal 
efficacy studies. Blood samples for ADA 
assessment will also be collected upon 
observation of any severe hypersensitivity 
reaction (eg, anaphylaxis). See Appendix F for 
the clinical criteria for diagnosing 
anaphylaxis. Bioanalytical personnel should 
be made aware of any anaphylaxis occurrence 
as soon as possible in case an anti-TEV-48125 
immunoglobulin E assay is required. For 
patients rolling over from the pivotal efficacy 
studies for ADA assessment only, blood 
samples for serum ADA assessment will be 
collected at visit 16 (follow-up visit). 
7.10 Injection Site Assessments 
subsection was added for clarity 
and completeness; it includes 
anaphylaxis-related text 
according to the change to 
Section 7.1.6 (above). 
8 
ASSESSMENT OF PHARMACOKINETICS/ BIOMARKERS/ IMMUNOGENICITY 
8.1.1 
Specimen Sampling and Handling (Other sections affected by this change: Section 8.2.1)  
Blood samples will be centrifuged (1500g, ~10 minutes, 20°C 
to 65°C) between 5 minutes and 1 hour after sampling… 
Separated plasma will be transferred in approximately equal 
portions into 2 opaque, labeled, 2-mL polypropylene tubes 
(sets A and B). 
Blood samples will be centrifuged (1500g, 
~10 minutes, 2°C to 6°C) between 5 minutes 
and 1 hour after sampling… Separated plasma 
will be transferred in approximately equal 
portions into 2 labeled, 2-mL polypropylene 
tubes (sets A and B). 
Procedures for plasma and 
serum collection were updated. 
8.2.2 
Shipment and Analysis of Samples 
Serum samples for all patients will be shipped frozen on dry 
ice from the investigational center to the central laboratory 
Serum samples for all patients will be shipped 
frozen on dry ice from the investigational 
center to the central laboratory 
Shipping requirements for 
serum were clarified and aligned 
with those for plasma (Section 
8.1.2). 

 
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8.3 Assessment of Exploratory Biomarkers (Other sections affected by this change: Synopsis and Sections 3.14 [Table 1 and Table 2], 
3.14.2.1.2, 3.14.3.1.7, 3.14.3.1.11, 3.14.4.1, 5.5, 8.3.2, and 9.9) 
In the current study, exploratory analysis may be conducted 
on blood (serum, plasma, and RNA) and urine biomarkers 
for extracellular matrix turnover, bone formation, and bone 
resorption. 
[…] 
The validated Multiplex immunoassay panels will be applied 
to measure changes in urine, serum, and plasma, and RNA 
biomarkers. 
In the current study, exploratory analysis may 
be conducted on blood (serum, plasma, and 
RNA) and urine biomarkers for extracellular 
matrix turnover, bone formation, and bone 
resorption. 
[…] 
Multiplex immunoassay panels will be applied 
to measure changes in urine, serum, plasma, 
and RNA biomarkers. 
Clarification was made for 
internal consistency throughout 
the protocol specifying that 
serum, plasma, and RNA would 
be collected from blood. The 
blood volume required for each 
separate biomarker assessment 
is now reiterated in Table 2. 
Statement regarding the assays 
being validated was removed to 
allow for operational flexibility. 
9 
STATISTICS 
9.2.4 
Antidrug Antibody Only Analysis Sets 
The ADA only analysis set will include all patients rolling 
over from the pivotal efficacy studies for ADA assessment 
only who have ADA data. 
 
The ADA only analysis set will include all 
patients rolling over from the pivotal efficacy 
studies for ADA assessment only. 
The clarification was removed, 
as it was deemed unnecessary.  
9.4.1 
Patient Disposition 
Data from patients screened, patients screened but not 
enrolledrandomized and reason not enrolledrandomized, 
patients who are randomized (ie, in the ITT set), patients 
randomized but not treated and reason, patients in the ITT, 
safety, and FAS analysis sets, patients who complete the 
study, and patients who withdraw from the study will be 
summarized using descriptive statistics. 
Data from patients screened, patients screened 
but not randomized and reason not 
randomized, patients who are randomized (ie, 
in the ITT set), patients randomized but not 
treated, patients in the safety and other 
analysis sets, patients who complete the study, 
and patients who withdraw from the study will 
be summarized using descriptive statistics. 
Editorial language alignment 
changes were made (including 
alignment with Section 3.1 
above). 
9.5 Efficacy Analysis (Other sections affected by this change: Synopsis) 
Individuals with CM… headache days of at least moderate 
severity for both CM and EM patients will be defined for 
Individuals with CM… headache days of at 
least moderate severity for both CM and EM 
Correction was made to align 
internally and with pivotal 

 
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the purpose of this study as a calendar day (0:00 to 23:59) 
when the patient reports: 
• 
a day with headache pain that lasts ≥4 hours with a 
peak severity of at least moderate severity  
or 
• 
a day when the patient used an acute migraine-
specific medication (triptans or ergots) to treat a 
headache of any severity or duration 
Additional analysis will be performed considering the 
following definition of  
• 
a day with headache pain that lasts ≥2 hours with a 
peak severity of at least moderate severity  
or 
• 
a day when the patient used an acute migraine
specific medication (triptans or ergots) to treat a 
headache of any severity or duration 
For Migraine day is endorsed based on the purpose of this 
studysame criteria as described in the pivotal studies. For 
CM patients, a migraine day is endorsed when at least 1 of 
the following situations occur:  
• 
a calendar day (0:00 to 23:59) demonstrating ≥2 
consecutive hours of a headache meeting criteria for 
migraine with or without aura 
• 
a calendar day (0:00 to 23:59) demonstrating ≥2 
consecutive hours of a headache meeting criteria for 
probable migraine, a migraine subtype where only 
1 migraine criterion is missing 
• 
a calendar day (0:00 to 23:59) demonstrating a 
patients will be defined for the purpose of this 
study as a calendar day (0:00 to 23:59) when 
the patient reports: 
• 
a day with headache pain that lasts ≥4 
hours with a peak severity of at least 
moderate severity  
or 
• 
a day when the patient used an acute 
migraine-specific medication (triptans 
or ergots) to treat a headache of any 
severity or duration 
Migraine day is endorsed based on the same 
criteria as described in the pivotal studies. For 
CM patients, a migraine day is endorsed when 
at least 1 of the following situations occur: 
• 
a calendar day (0:00 to 23:59) 
demonstrating ≥4 consecutive hours of 
a headache meeting criteria for 
migraine with or without aura 
• 
a calendar day (0:00 to 23:59) 
demonstrating ≥4 consecutive hours of 
a headache meeting criteria for 
probable migraine, a migraine subtype 
where only 1 migraine criterion is 
missing 
• 
a calendar day (0:00 to 23:59) 
demonstrating a headache of any 
duration that was treated with 
migraine-specific medications (triptans 
and ergot compounds) 
efficacy protocols. 

 
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headache of any duration that was treated with 
migraine specific medications (triptans and ergot 
compounds) 
Additional analysis will be performed using the following 
definition of migraine day: 
• 
a calendar day (0:00 to 23:59) demonstrating ≥4 
consecutive hours of a headache meeting criteria for 
migraine with or without aura 
• 
a calendar day (0:00 to 23:59) demonstrating ≥4 
consecutive hours of a headache meeting criteria for 
probable migraine, a migraine subtype where only 
1 migraine criterion is missing 
• 
a calendar day (0:00 to 23:59) demonstrating a 
headache of any duration that was treated with 
migraine-specific medications (triptans and ergot 
compounds) 
For EM patients, a migraine day is endorsed when at least 
1 of the following situations occur:  
• 
a calendar day (0:00 to 23:59) demonstrating ≥2 
consecutive hours of a headache meeting criteria 
for migraine with or without aura 
• 
a calendar day (0:00 to 23:59) demonstrating ≥2 
consecutive hours of a headache meeting criteria 
for probable migraine, a migraine subtype where 
only 1 migraine criterion is missing 
• 
a calendar day (0:00 to 23:59) demonstrating a 
headache of any duration that was treated with 
migraine-specific medications (triptans and ergot 
compounds) 
For EM patients, a migraine day is endorsed 
when at least 1 of the following situations 
occur:  
• 
a calendar day (0:00 to 23:59) 
demonstrating ≥2 consecutive hours of 
a headache meeting criteria for 
migraine with or without aura 
• 
a calendar day (0:00 to 23:59) 
demonstrating ≥2 consecutive hours of 
a headache meeting criteria for 
probable migraine, a migraine subtype 
where only 1 migraine criterion is 
missing 
• 
a calendar day (0:00 to 23:59) 
demonstrating a headache of any 
duration that was treated with 
migraine-specific medications (triptans 
and ergot compounds) 

 
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9.5.4 
Planned Method of Analysis 
Summaries will be presented overall, by indication and by 
treatment group for new patients and rollover patients 
separately, unless otherwise specified. 
Summaries will be presented by indication 
and treatment group for new patients and 
rollover patients separately, unless otherwise 
specified. 
Analysis plans were updated. 
9.11 
Immunogenicity Analysis (Other sections affected by this change: Synopsis) 
This impact analysis will be reported separately. 
This impact analysis will be reported 
separately. 
Clarification was added. 
9.12 
Planned Interim Analysis 
No interim analysis is planned for this study. After database 
lock in the pivotal study, safety and/or efficacy summaries 
will be generated based on interim data cut to be included 
in the BLA submission. 
No interim analysis is planned for this study. 
After database lock in the pivotal study, safety 
and/or efficacy summaries will be generated 
based on interim data cut to be included in the 
BLA submission. 
Addition was made for clarity of 
approach. 
11.1.1 Protocol Amendments 
No changes from the final approved (signed) protocol will be 
initiated without the prior written approval or favorable 
opinion of a written amendment by the IEC/IRB and national 
and local competent authorities, (as applicable), except when 
necessary to address immediate safety concerns to the 
patients, or when the change involves only nonsubstantial 
logistics or administration. Each investigator The principal 
investigator at each investigational center, the 
coordinating investigator (if applicable), and the sponsor 
will sign the protocol amendment. 
No changes from the final approved (signed) 
protocol will be initiated without the prior 
written approval or favorable opinion of a 
written amendment by the IEC/IRB and 
national and local competent authorities, as 
applicable, except when necessary to address 
immediate safety concerns to the patients, or 
when the change involves only nonsubstantial 
logistics or administration. The principal 
investigator at each investigational center, the 
coordinating investigator (if applicable), and 
the sponsor will sign the protocol amendment. 
Updates were made to align 
with the latest Teva practices. 
11.1.2 Protocol Violations 
A protocol deviation is any change, divergence, or departure 
from the study design or procedures defined in the protocol. 
Any deviation from the protocol that affects, 
to a significant degree, (a) the safety, physical, 
Updates were made to align 
with the latest Teva practices. 

 
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Important protocol deviations, referred to as protocol 
violations, are a subset of protocol deviations that may 
significantly impact the completeness, accuracy, and/or 
reliability of the study data or that may significantly affect a 
patient’s rights, safety, or well being. Protocol violations 
include enrolling patients in violation of key eligibility criteria 
designed to ensure a specific subject population, failing to 
collect data necessary to interpret primary endpoints, 
noncompliance to study drug administration, use of prohibited 
medications, GCP noncompliance, or any other deviations 
that may have an impact on the processes put in place for the 
care and safety of the patients or compromise the scientific 
value of the trial. 
Any deviation from the protocol that affects, to a 
significant degree, (a) the safety, physical, or mental 
integrity of the subjects of the study and/or (b) the 
scientific value of the study will be considered a protocol 
violation. Protocol violations may include nonadherence 
on the part of the patient, the investigator, or the sponsor 
to protocol-specific inclusion and exclusion criteria, 
primary objective variable criteria, or GCP guidelines; 
noncompliance to study drug administration; and use of 
prohibited medications. Protocol violations will be 
identified and recorded by investigational center personnel 
onin the CRF. All protocol violations will be reported to the 
responsible IEC/IRB, as required. 
When a protocol violation is reported, the sponsor will 
determine whether to discontinue the patient from the study or 
permit the patient to continue in the study, with documented 
approval from the medical representativeexpert. The decision 
will be based on ensuring the safety of the patient and 
preserving the integrity of the study.  
Deviations from Changes in the inclusion/ and exclusion 
criteria of the protocol are not prospectively granted by the 
sponsor. If investigational center personnel learn that a patient 
who did not meet protocol eligibilityinclusion and exclusion 
or mental integrity of the subjects of the study 
and/or (b) the scientific value of the study will 
be considered a protocol violation. Protocol 
violations may include nonadherence on the 
part of the patient, the investigator, or the 
sponsor to protocol-specific inclusion and 
exclusion criteria, primary objective variable 
criteria, or GCP guidelines; noncompliance to 
study drug administration; and use of 
prohibited medications. Protocol violations 
will be identified and recorded by 
investigational center personnel in the CRF. 
All protocol violations will be reported to the 
responsible IEC/IRB, as required. 
When a protocol violation is reported, the 
sponsor will determine whether to discontinue 
the patient from the study or permit the patient 
to continue in the study, with documented 
approval from the medical expert. The 
decision will be based on ensuring the safety 
of the patient and preserving the integrity of 
the study.  
Changes in the inclusion and exclusion criteria 
of the protocol are not prospectively granted 
by the sponsor. If investigational center 
personnel learn that a patient who did not 
meet protocol inclusion and exclusion criteria 
was entered in a study, they must immediately 
inform the sponsor of the protocol violation. If 
such patient has already completed the study 
or has withdrawn early, no action will be 
taken but the violation will be recorded. 

 
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criteria was entered into a study, they must immediately 
inform the sponsor of the protocol violation. If such patient 
has already completed the study or has withdrawn early, no 
action will be taken, but the violation will be recorded. If such 
patient is still participating in the study, a determination will 
be made by the sponsor and the investigator as to whether it is 
in the best interest of the patient to continue in the study. 
15 REPORTING AND PUBLICATION OF RESULTS 
Publication of the results will occur in a timely manner 
according to applicable regulations. Authorship will be 
restricted to parties who have editorial or conceptual 
input to protocol design, collection of data and/or 
analysis, interpretation of data, and manuscript 
preparation. 
Authorship will be substantial contributions to the 
conception or design of the work or the acquisition, 
analysis, or interpretation of data for the work. 
Authorship will be based on meeting all the following 
4 criteria: 
• substantial contributions to the conception or 
design of the work; or the acquisition, 
analysis, or interpretation of data for the work 
Publication of the results will occur in a 
timely manner according to applicable 
regulations. Authorship will be based on 
meeting all the following 4 criteria: 
• 
substantial contributions to the 
conception or design of the work; 
or the acquisition, analysis, or 
interpretation of data for the work 
Language was updated for 
consistency with the current 
Teva practices. 
16. REFERENCES (Other sections affected by this change: Synopsis; Sections 1.1, 1.7, 4.1.2, and 4.3; and Appendix D) 
Classification Committee of the International Headache 
Society. The International Classification of Headache 
Disorders, 3rd edition (beta version). Cephalalgia 
2013;33(9):629-808. 
Classification Committee of the International 
Headache Society. The International 
Classification of Headache Disorders, 3rd 
edition (beta version). Cephalalgia 
2013;33(9):629-808. 
An error in the reference was 
corrected. 
APPENDIX A PREVENTIVE MEDICATIONS ALLOWED FOR THE DURATION OF THE STUDY 
Preventive migraine medications allowed for the duration of 
Patients using preventive medications for 
Appendix A was updated for 

 
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the study specifically include the following (only if they were 
previously prescribed for migraine or for another indication if 
used at an approved dose for migraine prophylaxis): Patients 
using preventive medications for migraine at baseline 
(previously prescribed for migraine or for another 
indication) will continue using them for the duration of 
the study. These medications specifically include the 
following: 
• 
beta-blockers: atenolol, propranolol, metoprolol, 
nadolol, and timolol 
• 
calcium channel blocker/benzocycloheptene: 
verapamilflunarizine and pizotifen 
• 
tricyclic antidepressants: amitriptyline, venlafaxine, 
nortriptiline, and duloxetine 
• 
serotonin norepinephrine reuptake inhibitor: 
venlafaxine  
• 
triptans: frovatriptan, naratriptan, and zolmitriptan if 
they were used as preventive medications for the 
treatment of menstrual migraine. (Note: They cannot 
be used daily for the preventive treatment of 
migraine.) 
• 
anti-epileptic medications: topiramate, valproate, 
anddivalproate 
migraine at baseline (previously prescribed for 
migraine or for another indication) will 
continue using them for the duration of the 
study. These medications specifically include 
the following: 
• 
beta-blockers: atenolol, propranolol, 
metoprolol, nadolol, and timolol 
• 
calcium channel 
blocker/benzocycloheptene: 
flunarizine and pizotifen 
• 
antidepressants: amitriptyline, 
venlafaxine, nortriptyline, and 
duloxetine 
• 
anti-epileptic medications: topiramate, 
valproate, and divalproate 
clarity and to reflect the most 
recent list of preventive 
medications allowed for the 
duration of the study. 
APPENDIX B. DISALLOWED MEDICATIONS FOR THE DURATION OF THE STUDY  
Patients not using preventive medications for migraine at 
baseline will be asked not to initiate preventive 
medications de novo during the safety extension study. 
Preventive migraine medications/treatments disallowed for 
these patients for the duration of the study specifically 
include the following: 
• 
beta-blockers: atenolol, propranolol, metoprolol, 
nadolol, and timolol 
Patients not using preventive medications for 
migraine at baseline will be asked not to 
initiate preventive medications de novo during 
the safety extension study. Preventive 
migraine medications/treatments disallowed 
for these patients for the duration of the study 
specifically include the following: 
• 
beta-blockers: atenolol, propranolol, 
A new Appendix B was added 
to show the most recent list of 
preventive medications 
disallowed for the duration of 
the study. The numbering of all 
subsequent appendices was 
shifted. 

 
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• 
calcium channel blocker/benzocycloheptene: 
flunarizine and pizotifen 
• 
antidepressants: amitriptyline, venlafaxine, 
nortriptiline, and duloxetine 
• 
anti-epileptic medications: topiramate, valproate, 
carbamazepine, and divalproate 
• 
angiotensin receptor blocker: candesartan, 
lisinopril 
• 
onabotulinimtoxinA: botox 
• 
triptans/ergots: used as preventive therapies for 
migraine 
• 
NSAIDs: used as preventive therapy for migraine 
or on a daily basis for other indications 
• 
devices for migraine prophylaxis 
• 
nerve blocks in the head and neck 
Any of the listed medications are allowed if given as 
topical or eye drops. 
Other medications in the same classes but not included in 
this list are allowed. 
metoprolol, nadolol, and timolol 
• 
calcium channel 
blocker/benzocycloheptene: 
flunarizine and pizotifen 
• 
antidepressants: amitriptyline, 
venlafaxine, nortriptyline, and 
duloxetine 
• 
anti-epileptic medications: topiramate, 
valproate, carbamazepine, and 
divalproate 
• 
angiotensin receptor blocker: 
candesartan, lisinopril 
• 
onabotulinimtoxinA: botox 
• 
triptans/ergots: used as preventive 
therapies for migraine 
• 
NSAIDs: used as preventive therapy 
for migraine or on a daily basis for 
other indications 
• 
devices for migraine prophylaxis 
• 
nerve blocks in the head and neck 
Any of the listed medications are allowed if 
given as topical or eye drops. 
Other medications in the same classes but not 
included in this list are allowed. 
APPENDIX F. CLINICAL CRITERIA FOR DIAGNOSING ANAPHYLAXIS 
Anaphylaxis is highly likely when any 1 of the following 3 
criteria are fulfilled: 
a. 
Acute onset of an illness (minutes to several hours) 
Anaphylaxis is highly likely when any 1 of the 
following 3 criteria are fulfilled: 
a. Acute onset of an illness (minutes to 
Appendix F was added to 
provide the criteria for diagnosis 
of anaphylaxis. 

 
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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 
− 
Respiratory compromise (eg, dyspnea, wheeze-
bronchospasm, stridor, reduced peak 
expiratory flow [PEF], hypoxemia) 
− 
Reduced blood pressure (BP) or associated 
symptoms of end-organ dysfunction (eg, 
hypotonia [collapse], syncope, incontinence) 
b. 
Two or more of the following that occur rapidly 
after exposure to a likely allergen for that subject 
(minutes to several hours): 
− 
Involvement of the skin-mucosal tissue (eg, 
generalized hives, itch-flush, swollen lips-
tongue-uvula) 
− 
Respiratory compromise (eg, dyspnea, wheeze-
bronchospasm, stridor, reduced PEF, 
hypoxemia) 
− 
Reduced BP or associated symptoms (eg, 
hypotonia [collapse], syncope, incontinence) 
− 
Persistent gastrointestinal symptoms (eg, 
crampy abdominal pain, vomiting) 
c. 
Reduced BP after exposure to known allergen for 
that subject (minutes to several hours): 
− 
Infants and children: low systolic BP (age 
specific) or greater than 30% decrease in 
systolic BP 
− 
Adults: systolic BP of less than 90 mm Hg or 
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 
− 
Respiratory compromise (eg, 
dyspnea, wheeze-bronchospasm, 
stridor, reduced peak expiratory flow 
[PEF], hypoxemia) 
− 
Reduced blood pressure (BP) or 
associated symptoms of end-organ 
dysfunction (eg, hypotonia 
[collapse], syncope, incontinence) 
b. Two or more of the following that occur 
rapidly after exposure to a likely allergen 
for that subject (minutes to several 
hours): 
− 
Involvement of the skin-mucosal 
tissue (eg, generalized hives, itch-
flush, swollen lips-tongue-uvula) 
− 
Respiratory compromise (eg, 
dyspnea, wheeze-bronchospasm, 
stridor, reduced PEF, hypoxemia) 
− 
Reduced BP or associated symptoms 
(eg, hypotonia [collapse], syncope, 
incontinence) 
− 
Persistent gastrointestinal symptoms 
(eg, crampy abdominal pain, 
vomiting) 
c. Reduced BP after exposure to known 

 
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greater than 30% decrease from that person’s 
baseline 
Source: Modified from Sampson HA, Munoz-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 Apr;47(4):373-80; PMID:16546624]. J Allergy 
Clin Immunol 2006 Feb;117(2):391-7. 
allergen for that subject (minutes to 
several hours): 
− 
Infants and children: low systolic BP 
(age specific) or greater than 30% 
decrease in systolic BP 
− 
Adults: systolic BP of less than 90 
mm Hg or greater than 30% decrease 
from that person’s baseline 
Source: Modified from Sampson HA, Munoz-
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 Apr;47(4):373-80; 
PMID:16546624]. J Allergy Clin Immunol 
2006 Feb;117(2):391-7. 
 

 
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17.2. 
Administrative Letter Dated 01 March 2016 

 
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17.3. 
Administrative Letter Dated 22 January 2016 
 

 
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APPENDIX A. PREVENTIVE MEDICATIONS ALLOWED FOR THE 
DURATION OF THE STUDY 
Patients using preventive medications for migraine at baseline (previously prescribed for 
migraine or for another indication) will continue using them for the duration of the study. These 
medications specifically include the following: 
• beta-blockers: atenolol, propranolol, metoprolol, nadolol, and timolol 
• calcium channel blocker/benzocycloheptene: flunarizine and pizotifen 
• antidepressants: amitriptyline, venlafaxine, nortriptyline, and duloxetine 
• anti-epileptic medications: topiramate, valproate, and divalproate 

 
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APPENDIX B. DISALLOWED MEDICATIONS FOR THE DURATION 
OF THE STUDY 
Patients not using preventive medications for migraine at baseline will be asked not to initiate 
preventive medications/treatments de novo during the safety extension study. Preventive 
migraine medications disallowed for these patients for the duration of the study specifically 
include the following: 
• beta-blockers: atenolol, propranolol, metoprolol, nadolol, and timolol 
• calcium channel blocker/benzocycloheptene: flunarizine and pizotifen 
• antidepressants: amitriptyline, venlafaxine, nortriptyline, and duloxetine 
• anti-epileptic medications: topiramate, valproate, carbamazepine, and divalproate 
• angiotensin receptor blocker: candesartan and lisinopril 
• onabotulinimtoxinA: botox 
• triptans/ergots: used as preventive therapies for migraine 
• NSAIDs: used as preventive therapy for migraine or on a daily basis for other 
indications 
• devices for migraine prophylaxis 
• nerve blocks in the head and neck 
Any of the listed medications are allowed if given as topical or eye drops. 
Other medications in the same classes but not included in this list are allowed. 
 

 
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APPENDIX C. NATIONAL INSTITUTES OF HEALTH PATIENT 
EDUCATION GUIDELINES OF JUNE 2012 

 
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APPENDIX D. ICHD-3 DIAGNOSTIC CRITERIA 
For further details, refer to Classification Committee of the IHS, 2013. 
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. 1 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 

 
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APPENDIX E. GUIDANCE ON SAFETY MONITORING 
Guidance on Monitoring Patients with Elevated Liver Function Tests 
Liver enzymes (ALT, AST, GGT, and ALP) as well as total and direct bilirubin will be measured 
(and indirect bilirubin will be calculated) at each study 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 study), a 
thorough medical history and physical examination with a focus on liver disease should be 
undertaken.1 In addition, the patient should be instructed to refrain from alcoholic beverages. 
In case of symptoms compatible with drug-induced liver injury during the study, patients will be 
instructed to return to the study center for an unscheduled visit or to go to the emergency room 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 according to the discretion of the 
treating physician. 
Elevation of Either ALT or AST to ≥3× ULN 
Confirmation is required prior to study drug 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 study drug discontinuation, but the assessments below should be performed). 
The following procedures should be followed: 
• The day in which the abnormal value is received from the laboratory will be 
considered as day 0.  
• The investigator should repeat the test for confirmation purposes (this may be 
performed in a local laboratory along with complete blood count [CBC] and 
differential to assess for eosinophilia. In general, in case a blood sample is sent to a 
local laboratory, the following assessments [and reference ranges] are mandatory: 
ALT [serum glutamic pyruvic transaminase], AST [serum glutamic oxaloacetic 
transaminase], ALP, total and direct bilirubin, CBC [with differential for eosinophil 
count, separate tube], and INR [separate tube; not to be sent in a confirmatory test]). 
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: 
                                                 
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 investigator. Physical examination, including signs of chronic liver disease. 

 
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Upon confirmation of the abnormality as noted above, the following additional evaluations 
should be performed and results should be recorded in the CRF: 
• serology for hepatitis A (antibody and immunoglobulin M [IgM] and IgG), B (core 
antibody total, core IgM, and surface antigen), and C viruses (central laboratory) 
• serology for autoimmune hepatitis: anti-nuclear antibodies (titer), anti-smooth muscle 
antibodies, and anti-liver kidney microsomal antibodies (central laboratory); further 
testing may be required in case of a positive result for hepatitis B or C 
• ultrasound examination of the liver and biliary tract at the investigator’s discretion 
• other diagnostic tests/consultations as deemed necessary by the investigator 
(eg, serology for hepatitis E virus in case of travel to endemic geography) 
• 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: 
• Alanine aminotransferase, AST, GGT, ALP, total and direct bilirubin, CBC and 
differential (to assess for eosinophilia), and INR should be monitored on days 5 
(±2 days), 8 (±2 days), 14 (±3 days), and 28 (±3 days). On at least 1 of these days, the 
test should be performed centrally. (The INR should be sent to a local laboratory 
only.) 
• In cases where a local laboratory is used, the results should be recorded in the CRF, 
accompanied by the reference range of the relevant measurements. 
• Should the abnormality (≥3× the ULN in case baseline was within the normal range 
or ≥2× the ULN in case the baseline value was above ULN but still <5× the ULN) 
persist further, the patient will be followed according to the investigator’s discretion, 
but a blood sample for ALT, AST, GGT, ALP, and total and direct bilirubin should 
be sent to the central laboratory at least once a month. 
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: 
• Alanine aminotransferase, AST, GGT, ALP, total and direct bilirubin, CBC and 
differential count (to assess for eosinophilia), and INR should be monitored twice a 
week. 
• At least for every other measurement, the tests should be sent to the central 
laboratory. The rest of the tests may be sent to a local laboratory. The INR should 
always be sent to a local laboratory. 
ALT or AST ≥8× the ULN 
In addition to the above procedures required for any elevation to levels >3× the ULN: 

 
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• The study drug should be discontinued immediately, and the early withdrawal visit 
should be performed. 
• For follow-up guidance, please see below section “Follow-Up of Liver Enzymes 
After Stopping Rules Are Met.” 
Stopping Rules 
In the following circumstances, the study drug 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 study drug should be 
invited to the site to return the study drug. Early withdrawal visit activities should be 
performed as soon as possible. 
• Liver enzymes should be monitored until normalization or stabilization of the 
abnormality, according to the discretion of the investigator. 
• In any case, following the early withdrawal visit, the minimal follow-up period will 
be 30 days and will include measurement of liver enzymes at least once weekly (may 
be performed in local laboratory, with at least 1 test being sent to the central 
laboratory). 
• Every effort should be made to complete the additional tests/evaluations, as described 
above. 
 

 
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APPENDIX F. CLINICAL CRITERIA FOR DIAGNOSING 
ANAPHYLAXIS 
Anaphylaxis is highly likely when any 1 of the following 3 criteria are fulfilled: 
a. 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 
− Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced 
peak expiratory flow [PEF], hypoxemia) 
− Reduced blood pressure (BP) or associated symptoms of end-organ dysfunction 
(eg, hypotonia [collapse], syncope, incontinence) 
a. Two or more of the following that occur rapidly after exposure to a likely allergen for 
that subject (minutes to several hours): 
− Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, swollen 
lips-tongue-uvula) 
− Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced 
PEF, hypoxemia) 
− Reduced BP or associated symptoms (eg, hypotonia [collapse], syncope, 
incontinence) 
− Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting) 
e. Reduced BP after exposure to known allergen for that subject (minutes to several 
hours): 
− Infants and children: low systolic BP (age specific) or greater than 30% decrease 
in systolic BP 
− Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from that 
person’s baseline 
Source: Modified from Sampson HA, Munoz-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 Apr;47(4):373-80; 
PMID:16546624]. J Allergy Clin Immunol 2006 Feb;117(2):391-7.