A Multicenter, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Study With an Open-Label Period to Evaluate the Efficacy and Safety of Fremanezumab for the Prophylactic Treatment of Migraine in Patients With Inadequate Response to Prior Preventive Treatments
Phase: PHASE3
Conditions: Migraine Prophylaxis
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc.

Clinical Study Protocol with Amendment 01 
A Multicenter, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Study with 
an Open-Label Period to Evaluate the Efficacy and Safety of Fremanezumab for the 
Prophylactic Treatment of Migraine in Patients with Inadequate Response to Prior 
Preventive Treatments 
Study Number TV48125-CNS-30068 
NCT03308968 
Protocol with Amendment 01 Approval Date: 23 October 2017 

 
Placebo-Controlled Study–Migraine 
Clinical Study Protocol with Amendment 01 
Study TV48125-CNS-30068 
 
1 
Protocol Version 2 with Amendment 01, 23 October 2017 
 
          
Clinical Study Protocol Amendment 01 
 
Study Number TV48125-CNS-30068 
A Multicenter, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Study with 
an Open-Label Period to Evaluate the Efficacy and Safety of Fremanezumab for the 
Prophylactic Treatment of Migraine in Patients with Inadequate Response to Prior 
Preventive Treatments 
 
A Randomized, Double-Blind, Placebo-Controlled Study with an Open-Label Period on 
Efficacy and Safety of Fremanezumab in Adults with Migraine 
 
A Study to Test if Fremanezumab is Effective in Preventing Migraine in Patients Who Did 
Not Respond to Prior Preventive Migraine Treatments 
Efficacy and Safety Study (Phase 3) 
IND number: 106,533;   NDA number: Not applicable;  BLA number: Not applicable; 
EudraCT number: 2017-002441-30 
EMA Decision number of Pediatric Investigation Plan: Not applicable 
Article 45 or 46 of 1901/2006 does not apply 
 
Protocol Approval Date: 27 July 2017 
Protocol with Amendment 1 Approval Date: 23 October 2017 
 
Sponsor 
Teva Branded Pharmaceutical 
Products R&D, Inc. 
41 Moores Road 
Frazer, Pennsylvania 19355 
United States of America 
 
Information regarding clinical laboratories and other departments and institutions is 
found in Appendix A  

 
Placebo-Controlled Study–Migraine 
Clinical Study Protocol with Amendment 01 
Study TV48125-CNS-30068 
 
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Protocol Version 2 with Amendment 01, 23 October 2017 
This clinical study will be conducted in accordance with current Good Clinical Practice (GCP) as directed 
by the provisions of the International Council for Harmonisation (ICH); United States (US) Code of 
Federal Regulations (CFR), and European Union (EU) Directives and Regulations (as applicable in the 
region of the study); national country legislation; and the sponsor’s Standard Operating Procedures 
(SOPs). 
Confidentiality Statement 
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. 
© 2017 Teva Branded Pharmaceutical Products R&D, Inc. All rights reserved. 

 
Placebo-Controlled Study–Migraine 
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Protocol Version 2 with Amendment 01, 23 October 2017 
AMENDMENT HISTORY 
The protocol for study TV48125-CNS-30068 (original protocol dated 27 July 2017) has been 
amended and reissued as follows: 
Amendment 01 
23 October 2017 
0 patients randomized/enrolled to date 
The Summary of Changes to the Protocol includes the corresponding reason/justification for 
each change and is provided in Section 16. 

 
Placebo-Controlled Study–Migraine 
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Protocol Version 2 with Amendment 01, 23 October 2017 
INVESTIGATOR AGREEMENT 
Original Protocol Dated 27 July 2017 
Clinical Study Protocol with Amendment 01 
IND number:  106,533; NDA number: Not applicable; BLA number: Not applicable; 
EudraCT number: 2017-002441-30 
EMA Decision number of Pediatric Investigation Plan: not applicable 
Article 45 or 46 of 1901/2006 does not apply 
A Multicenter, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Study with 
an Open-Label Period to Evaluate the Efficacy and Safety of Fremanezumab for the 
Prophylactic Treatment of Migraine in Patients with Inadequate Response to Prior 
Preventive Treatments 
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 agreement with 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 investigational medicinal product 
(IMP) that were furnished to me by the sponsor to all physicians and other study personnel 
reporting to me who participate in this study and will discuss this material with them to ensure 
that they are fully informed regarding the IMP and the conduct of the study. I agree to keep 
records on all patient information, investigational medicinal products (IMP) shipment and return 
forms, and all other information collected during the study, in accordance with national and local 
Good Clinical Practice (GCP) regulations as well as all other national and international laws and 
regulations. 
Principal Investigator 
 
Signature 
Date 

 
Place b o - C o ntr olle d St u d y –Mi grai n e  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 1  
St u d y T V 4 8 1 2 5 -C N S - 3 0 0 6 8 
 
5 
Pr ot oc ol Versi o n 2 wit h A me n d me nt 0 1, 2 3 Oct o ber 2 0 1 7 
S P O N S O R P R O T O C O L A P P R O V A L  
 
 
 

 
Placebo-Controlled Study–Migraine 
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Protocol Version 2 with Amendment 01, 23 October 2017 
COORDINATING INVESTIGATOR AGREEMENT 
 

 
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Protocol Version 2 with Amendment 01, 23 October 2017 
CLINICAL STUDY PROTOCOL SYNOPSIS 
with Amendment 01 
Study TV48125-CNS-30068 
Title of Study: A Multicenter, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled, 
Study with an Open-Label Period to Evaluate the Efficacy and Safety of Fremanezumab for the 
Prophylactic Treatment of Migraine in Patients with Inadequate Response to Prior Preventive 
Treatments 
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc. 
Investigational New Drug (IND) Number: 106,533 
 
New Drug Application (NDA) Number: Not Applicable  
Biological License Application (BLA) Number: Not Applicable  
EudraCT Number: 2017-002441-30 
EMA Decision number of Pediatric Investigation Plan: Not applicable  
Article 45 or 46 of 1901/2006 does not apply 
Name of Test Investigational Medicinal Product (IMP): Fremanezumab (TEV-48125) 
EudraVigilance (EV) code for the IMP, if applicable: SUB181665 
Type of the Study: Efficacy and Safety Study (Phase 3) 
Indication: Fremanezumab is intended for migraine prophylaxis 
Is this study conducted to investigate the New Use of an approved, marketed product? No 
Number of Investigational Centers Planned: The study is planned to be conducted in 
approximately 120 investigational centers. 
Countries Planned: The study is planned to be conducted in approximately 15 countries. 
Planned Study Period: 4Q 2017 to 4Q 2019 
Number of Patients Planned (total): Approximately 804 patients (268 patients per treatment 
group) 
Study Population: The study population will be composed of male and female patients, aged 18 
to 70 years, inclusive, with a history of migraine (as defined by International Classification of 
Headache Disorders, 3rd revision [ICHD-3] criteria [IHS 2013]) for at least 12 months prior to 
screening and diagnosis of episodic migraine (EM) or chronic migraine (CM) prospectively 
documented via a review of headache data recorded daily in an electronic headache diary device 
during a 28-day run-in period. 
At the time of screening, patients must have documented inadequate response to 2 to 4 classes of 
prior preventive migraine medications (as defined in Appendix H) within the past 10 years (in 
medical chart or by treating physician’s confirmation, see Appendix I for acceptable 
documentation of previous treatment failure).  
A subset of these patients (at least 120 patients) must have documented inadequate response to 
2 to 3 classes of prior preventive medications (as defined in Appendix H) and in addition 
inadequate response to valproic acid. All inadequate responses must be within the past 10 years 

 
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(in medical chart or by treating physician’s confirmation; see Appendix I for acceptable 
documentation of previous treatment failure).  
Inadequate response to prior preventive migraine medications (including valproic acid) is 
defined as (see also Appendix H): no clinically meaningful improvement per treating physician’s 
judgment, after at least 3 months of therapy at a stable dose considered appropriate for migraine 
prevention according to accepted country guidelines, or when treatment has to be interrupted 
because of adverse events that made it intolerable by the patient, or the medication is 
contraindicated or not suitable for the prophylactic treatment of migraine for the patient. The 
3-month period does not apply if the drug is intolerable or contraindicated or not suitable. If 
onabotulinumtoxinA is the previously failed preventive medication, at least 2 sets of injections 
and 3 months must have passed since the last set of injections prior to the screening visit. 
Primary and Secondary Objectives and Endpoints 
Primary and secondary objectives and endpoints are presented in the table below. 
Objectives 
Endpoints 
The primary objective of the 
study is to demonstrate the 
efficacy of fremanezumab 
administered as monthly and 
quarterly subcutaneous (sc) 
injections to adult patients with 
migraine with inadequate 
response to 2 to 4 classes of prior 
preventive treatments as 
compared with placebo 
The primary efficacy endpoint is the mean change from baseline 
(28-day run-in period) in the monthly average number of migraine 
days during the 12-week period after the 1st dose of fremanezumab 
The secondary objective of the 
study is to further evaluate the 
efficacy of fremanezumab 
administered as monthly and 
quarterly sc injections to adult 
patients with migraine with 
inadequate response to 2 to 4 
classes of prior preventive 
treatments as compared with 
placebo 
The secondary endpoints are as follows: 
• 
proportion of patients reaching at least 50% reduction in 
the monthly average number of migraine days during 
the 12-week period after the 1st dose of fremanezumab 
• 
mean change from baseline (28-day run-in period) in the 
monthly average number of headache days of at least 
moderate severity during the 12-week period after the 1st 
dose of fremanezumab 
• 
mean change from baseline (28-day run-in period) in the 
monthly average number of migraine days during the 4-
week period after the 1st dose of fremanezumab 
• 
proportion of patients reaching at least 50% reduction in 
the monthly average number of migraine days during 
the 4-week period after the 1st dose of fremanezumab 
• 
mean change from baseline (28-day run-in period) in the 
monthly average number of days of use of any acute 

 
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Objectives 
Endpoints 
headache medications during the 12-week period after 
the 1st dose of fremanezumab 
• 
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 
fremanezumab 
A secondary objective of the 
study is to evaluate the safety and 
tolerability of fremanezumab 
administered as monthly and 
quarterly sc injections to adult 
patients with migraine with 
inadequate response to 2 to 4 
classes of prior preventive 
treatments as compared with 
placebo  
Secondary safety/tolerability endpoints: 
• 
occurrence of adverse events throughout the study 
• 
clinical laboratory (serum chemistry, hematology, 
coagulation and urinalysis) test results at specified time 
points 
• 
vital signs (systolic and diastolic blood pressure, oral 
temperature, and pulse rate) measurements at each visit. 
Note: In addition, oxygen saturation and respiratory rate 
will be measured in cases of suspected anaphylaxis and 
severe hypersensitivity 
• 
12-lead ECG findings at specified time points 
• 
use of concomitant medication for adverse events during 
the study 
• 
number (%) of patients who did not complete the study 
due to adverse events 
• 
clinically significant changes in physical examinations, 
including body weight 
• 
occurrence of severe hypersensitivity/anaphylaxis 
reactions 
• 
suicidal ideations and behaviors as measured by the 
eC-SSRS 
ECG=electrocardiogram; eC-SSRS= electronic Columbia-Suicide Severity Rating Scale; sc=subcutaneous. 
Exploratory Objectives and Endpoints 
The exploratory objectives are as follows: 
• to further evaluate the efficacy of fremanezumab in adult migraine patients with 
inadequate response to 2 to 4 classes of prior preventive treatments  
• to evaluate immunogenicity and impact of antidrug antibody (ADA) on clinical 
outcome 
• to explore the correlation between pharmacokinetic parameters and efficacy of 
fremanezumab 

 
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Protocol Version 2 with Amendment 01, 23 October 2017 
• to explore the relationship between genetic polymorphisms, migraine onset/severity 
and efficacy and safety of fremanezumab 
• to explore the relationship between soluble exploratory biomarkers versus migraine 
response  
The exploratory endpoints for the double-blind period are as follows: 
• proportion of patients reaching at least 75% reduction in the monthly average number 
of migraine days during the 12-week period after the 1st dose of study drug  
• proportion of patients reaching total (100%) response (no headache)  during the 
12-week period after the 1st dose of study drug  
• proportion of patients reaching total (100%) response (no headache) for at least one 
month during the 12-week period after the 1st dose of study drug  
• mean change from baseline (28-day run-in period) in the monthly average number of 
headache hours of at least moderate severity during the 12-week period after the 1st 
dose of the study drug 
• proportion of patients reaching at least 50% reduction in the number of migraine days 
during the 4-week period after the 1st dose of study drug for whom this level of effect 
is sustained throughout the 12-week period after the 1st dose of study drug 
• proportion of patients reaching at least 75% reduction in the number of migraine days 
during the 4-week period after the 1st dose of study drug for whom this level of effect 
is sustained throughout the 12-week period after the 1st dose of study drug 
• mean change from baseline (28-day run-in period) in the monthly average number of 
days with nausea or vomiting during the 12-week period after the 1st dose of study 
drug 
• mean change from baseline (28-day run-in period) in the monthly average number of 
days with photophobia and phonophobia during the 12-week period after the 1st dose 
of study drug 
• mean change from baseline (28-day run-in period) in the monthly average number of 
days of use of migraine-specific acute headache medications (triptans and ergot 
compounds) during the 12-week period after the 1st dose of study drug 
• mean change from baseline (28-day run-in period) in the number of migraine days 
during the 12-week period after the 1st dose of study drug for patients who failed 
topiramate for migraine in the past 
• mean change from baseline (28-day run-in period) in the number of migraine days 
during the 12-week period after the 1st dose of study drug for patients who failed 
onabotulinumtoxinA for migraine in the past 
• mean change from baseline (28-day run-in period) in the number of migraine days 
during the 12-week period after the 1st dose of study drug for patients who failed 
valproic acid for migraine in the past 

 
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• mean change from baseline (28-day run-in period) in the number of migraine days 
during the 12-week period after the 1st dose of study drug for the subset of patients 
who failed  2 to 3 classes of preventive medications and valproic acid for migraine in 
the past 
• proportion of patients reaching at least 50% reduction in the monthly average number 
of migraine days during the 12-week period after the 1st dose of fremanezumab for 
the subset of  patients who failed 2 to 3 classes of preventive medications and 
valproic acid for migraine in the past 
• mean change from baseline (day 0) in disability score, as measured by the 6-item 
Headache Impact Test (HIT-6), at 4 weeks after administration of the 3rd dose of 
study drug 
• mean change from baseline (day 0) in disability score, as measured by the Migraine 
Disability Assessment (MIDAS) questionnaire, at 4 weeks after the administration of 
the 3rd dose of study drug 
• 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 administration of 
the 3rd dose of study drug 
• mean change from baseline (day 0) in the health status, as measured by the EuroQol-5 
Dimension (EQ-5D-5L) questionnaire at 4 weeks after administration of the 3rd dose 
of study drug 
• 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 4 weeks after administration of the 3rd dose of study drug 
• 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 4 weeks after administration of the 3rd dose of study drug 
• mean change from baseline (day 0) of patient satisfaction, as measured by the Patient 
Global Impression of Change (PGIC) scale, at 4 weeks after the 3rd dose of study drug 
The exploratory endpoints for the open-label period are as follows: 
• mean change from baseline (28-day run-in period) in the monthly average number of 
migraine days during the 12-week period after the 4th dose of fremanezumab 
• proportion of patients reaching at least 50% reduction from baseline (28-day run-in 
period)  in the monthly average number of migraine days during the 12-week period 
after the 4th dose of fremanezumab 
• mean change from baseline (28-day run-in period) in the monthly average number of 
headache days of at least moderate severity during the 12-week period after the 
1st dose of fremanezumab 

 
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• 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 12-week period after the 
4th dose of fremanezumab 
• proportion of patients reaching at least 75% reduction from baseline (28-day run-in 
period)  in the monthly average number of migraine days during the 12-week period 
after the 4th dose of study drug  
• proportion of patients reaching total (100%) response (no headache) during the 12-
week period after the 4th dose of study drug 
• proportion of patients reaching total (100%) response (no headache) for at least one 
month during the 12-week period after the 4th dose of study drug  
• mean change from baseline (28-day run-in period) in the monthly average number of 
headache hours of at least moderate severity during the 12-week period after the 
4th dose of the study drug 
• proportion of patients reaching at least 50% reduction from baseline (28-day run-in 
period) in the number of migraine days during the 4-week period after the 4th dose of 
study drug for whom this level of effect is sustained throughout the 12-week period 
after the 4th dose of study drug 
• proportion of patients reaching at least 75% reduction from baseline (28-day run-in 
period) in the number of migraine days during the 4-week period after the 4th dose of 
study drug for whom this level of effect is sustained throughout the 12-week period 
after the 4th dose of study drug 
• mean change from baseline (28-day run-in period) in the monthly average number of 
days with nausea or vomiting during the 12-week period after the 4th dose of study 
drug 
• mean change from baseline (28-day run-in period) in the monthly average number of 
days with photophobia and phonophobia during the 12-week period after the 4th dose 
of study drug 
• mean change from baseline (28-day run-in period) in the monthly average number of 
days of use of migraine-specific acute headache medications (triptans and ergot 
compounds) during the 12-week period after the 4th dose of study drug 
• mean change from baseline (28-day run-in period) in the number of migraine days 
during the 12-week period after the 4th dose of study drug for patients who failed 
topiramate for migraine in the past 
• mean change from baseline (28-day run-in period) in the number of migraine days 
during the 12-week period after the 4th dose of study drug for patients who failed 
onabotulinumtoxinA for migraine in the past 
• mean change from baseline (28-day run-in period) in the number of migraine days 
during the 12-week period after the 4th dose of study drug for patients who failed 
valproic acid for migraine in the past 

 
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• mean change from baseline (28-day run-in period) in the number of migraine days 
during the 12-week period after the 4th dose of study drug for patients who failed 2 to 
3 classes of preventive medications in addition to valproic acid for migraine in the 
past 
• proportion of patients reaching at least 50% reduction from baseline (28-day run-in 
period) in the monthly average number of migraine days during the 12-week period 
after the 4th dose of fremanezumab for patients who failed 2 to 3 classes of preventive 
medications in addition to valproic acid for migraine in the past 
• mean change from baseline (day 0) in disability score, as measured by the HIT-6, at 
4 weeks after administration of the 6th dose of study drug 
• mean change from baseline (day 0) in disability score, as measured by the MIDAS 
questionnaire, at 4 weeks after the administration of the 6th dose of study drug 
• mean change from baseline (day 0) in quality of life, as measured by the MSQOL 
questionnaire, at 4 weeks after administration of the 6th dose of study drug 
• mean change from baseline (day 0) in the health status, as measured by the 
EQ-5D-5L questionnaire at 4 weeks after administration of the 6th dose of study drug 
• mean change from baseline (day 0) in patient depression status, as measured by the 
PHQ-2 and PHQ-9, at 4 weeks after administration of the 6th dose of study drug 
• mean change from baseline (day 0) in patient work productivity and activity 
impairment, as measured by the WPAI questionnaire, at 4 weeks after administration 
of the 6th dose of study drug 
• mean change from baseline (day 0) of patient satisfaction, as measured by the PGIC 
scale, at 4 weeks after the last 6th dose of study drug 
The exploratory endpoints for both the double-blind and open-label periods are as follows: 
• to evaluate the immunogenicity response of fremanezumab and the impact of ADAs 
on clinical outcomes in patients exposed to sc fremanezumab.  
• to explore the relationship between genetic polymorphisms (including those within 
the calcitonin gene-related peptide (CGRP) receptor-ligand complex, in migraine-
associated susceptibility genes, and in as-yet undiscovered loci) versus migraine 
onset/severity, adverse events to medication and fremanezumab efficacy 
• to explore the relationship between  exploratory biofluid biomarkers versus 
fremanezumab concentrations, adverse events and fremanezumab efficacy 
General Study Design: 
This is a multicenter, randomized, double-blind, parallel-group, placebo-controlled, study with 
an open-label period to evaluate the efficacy, safety, and tolerability of monthly and quarterly sc 
fremanezumab compared with placebo in patients with CM and EM with inadequate response to 
prior preventive treatments. 

 
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The study will consist of a screening visit, a run-in period (28 days), a 12-week double-blind, 
placebo-controlled treatment period, a 12-week open-label period, and a follow-up visit 
6.0 months after the last dose of fremanezumab for ADA blood sample collection. 
At the end of the open-label treatment period (4 weeks after the last dose) an end of treatment 
study visit (visit 8) will be scheduled and patients should return to the care of their treating 
physicians. Patients should be treated with standard of care after withdrawal from or termination 
of the 24-week treatment period/study, as appropriate. 
Double-blind period 
At the baseline visit (visit 2), patients will be randomly assigned to a treatment group with 
fremanezumab (2 different dose regimens) or placebo in a 1:1:1 ratio as follows: 
• For patients with CM: 
− sc administration of 675 mg of fremanezumab at visit 2 followed by monthly sc 
administration of 225 mg of fremanezumab for 2 months or 
− sc administration of 675 mg of fremanezumab at visit 2 followed by monthly sc 
administration of matching placebo for 2 months or 
− 3 monthly doses of matching placebo 
• For patients with EM: 
− sc administration of fremanezumab at 225 mg plus 2 matching placebo injections 
as first dose followed by monthly sc administration of 225 mg of fremanezumab 
for 2 months or 
− sc administration of fremanezumab at 675 mg as first dose followed by monthly 
sc administration  of matching placebo for 2 months or 
− 3 monthly doses of matching placebo 
Open-label period 
After visit 4, all patients completing the double-blind period will enter the open-label period. All 
patients (CM and EM) will receive sc 225 mg of fremanezumab monthly for 3 months.  (visits 5, 
6, and 7). 
Randomization and treatment assignment for the double-blind period will be performed using 
electronic interactive response technology (IRT). The study will be stratified based on CM or 
EM, gender, country, and a special treatment failure group defined as patients who must have 
had inadequate response to valproic acid. In addition, patients in the special treatment failure 
group must have had inadequate response to 2 to 3 other classes of migraine preventive 
medications as defined in Appendix H. The proportion of CM and EM patients in the study 
should be approximately 50:50 in each subgroup.  
The open-label period will not be randomized as all patients will receive the same monthly dose 
(225 mg fremanezumab). 

 
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CM is defined as: 
Patient fulfills the following criteria for CM in prospectively collected baseline information 
during the 28-day run-in period: 
• Headache occurring on ≥15 days 
• Οn ≥8 days, fulfilling any of the following: 
− ICHD-3 diagnostic criteria C and D for 1.1 Migraine without aura (Appendix U) 
− ICHD-3 criteria B and C for 1.2 Migraine with aura (Appendix U) 
− Probable migraine (a migraine subtype where only 1 migraine criterion is 
missing) 
− The patient used a triptan or ergot derivative to treat established headache. 
EM is defined as: 
The patient fulfills the following criteria for EM in prospectively collected baseline information 
during the 28-day run-in period: 
• Headache occurring ≥6 days but <15 
• On ≥4 days, fulfilling any of the following: 
− ICHD-3 diagnostic criteria C and D for 1.1 Migraine without aura 
− ICHD-3 criteria B and C for 1.2 Migraine with aura 
− Probable migraine (a migraine subtype where only 1 migraine criterion is 
missing) 
− The patient used a triptan or ergot derivative to treat an established headache 
Blinded treatment will be administered sc once a month (approximately every 28 days) for a total 
of 3 doses (visits 2,3, and 4) and open-label treatment will administered for a total of 3 doses. 
(visits 5, 6, and 7). Final study assessments will be performed at visit 8 (end-of-treatment [EOT] 
visit), approximately 4 weeks after administration of last dose of fremanezumab. A follow-up 
visit will be scheduled 6.0 months (> 5 half-lives) after the last study drug administration for 
ADA blood sampling. Patients who discontinue early will have the follow-up visit 6.0 months 
after the last dose. 
The total duration of patient participation in the study is planned to be 50 weeks including a run-
in period lasting 28 days, a double-blind treatment period lasting 12 weeks, an open-label period 
lasting 12 weeks, and 1 follow-up visit at week 46. 
Patients are expected to complete the entire duration of the study, including the open-label period 
and the follow-up visit. 
The end of study is defined as the last visit of the last patient (follow-up visit, visit 9). However, 
an interim database lock will occur following the end of the double-blind treatment period of the 
last patient for analysis of that portion of the study data. Final database lock will occur following 
the end of the open-label period. 

 
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The total study duration, including the 6.0-month follow-up-period, will be approximately 
2 years (from approximately 4Q 2017 to 4 Q 2019). 
Brief Summary of Study Design for the Trial Registry(s): 
The purpose of this study is to evaluate the efficacy, safety, and tolerability of monthly and 
quarterly sc doses of fremanezumab compared with sc doses of placebo in patients with CM or 
EM who have responded inadequately to 2 to 4 classes of prior preventive treatments. A subset 
of patients (at least 120) must have documented inadequate response to 2 to 3 classes of prior 
preventive medications and in addition inadequate response to valproic acid. All inadequate 
responses must be within the past 10 years (in medical chart or by treating physician’s 
confirmation). 
The study will consist of a screening visit, a run-in period (28 days), a 12-week double-blind 
treatment period and a 12-week open-label treatment period, which includes a last study visit 4 
weeks after the last dose administration. At the end of the study, patients will return to the care of 
their treating physicians. A follow-up visit will be scheduled 6.0 months after the last dose for 
ADA blood sample collection. The total duration of patient participation in the study is planned 
to be 50 weeks.  
During the double-blind period, patients will be randomly assigned in a 1:1:1 ratio to receive 1 of 
2 fremanezumab dose regimes or placebo as follows:  
• For patients with CM: 
− sc administration of 675 mg of fremanezumab at visit 2 followed by monthly sc 
administration of 225 mg of fremanezumab for 2 months or 
− sc administration of 675 mg of fremanezumab at visit 2 followed by monthly sc 
administration of matching placebo for 2 months or  
− 3 monthly doses of matching placebo 
• For patients with EM: 
− sc administration of fremanezumab at 225 mg plus 2 matching placebo injections 
as first dose followed by monthly sc administration of 225 mg of fremanezumab 
for 2 months or 
− sc administration of fremanezumab at 675 mg as first dose followed by monthly 
sc administration  of matching placebo for 2 months or 
− 3 monthly doses of matching placebo 
During the open-label period, all patients (CM and EM) will receive 3 monthly sc 
administrations of fremanezumab at 225 mg. 
Efficacy will be evaluated using information entered daily by the patients in an electronic 
headache diary throughout the treatment period and administration of questionnaires to evaluate 
headache-related disability, change in quality of life, health status, and satisfaction with 
treatment. 
Safety of fremanezumab will be evaluated through adverse event and concomitant medication 
inquiries, electrocardiograms (ECGs), vital sign measurements, clinical laboratory tests, physical 

 
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examinations, injection site reaction/pain assessments, assessments for anaphylaxis and 
hypersensitivity, and administration of the eC-SSRS. In addition, blood will be collected for 
pharmacokinetics, immunogenicity, biomarker, and pharmacogenomics analyses (unless not 
allowed per local regulation) and urine will be collected for biomarker analysis. 
Method of Randomization and Blinding: 
The sponsor, investigators, study staff (except for staff involved in bioanalytical analyses), and 
patients will be blinded to treatment assignment during the double-blind period.  A computer-
generated master randomization list will be provided to drug packaging facilities. Packaging 
vendor(s) will package active drug and placebo into single-visit kits according to Good 
Manufacturing Practice procedures. Kits will be identical in appearance and contain 1 prefilled 
syringe with active drug or placebo. Adequate kit supply for upcoming study visits will be 
managed by IRT and kept (refrigerated at 2°C to 8°C) on site. 
In this randomized study, the double-blind period will be stratified based on CM or EM, gender, 
country, and a special treatment failure group defined as patients who must have had inadequate 
response to valproic acid. In addition, patients in the special treatment failure group must have 
had inadequate response to 2 to 3 other classes of migraine preventive medications as defined 
in Appendix H. 
Each patient will undergo randomization in a 1:1:1 ratio within the stratum to which he or she 
belongs to receive 1 of the 2 fremanezumab dose regimens or placebo, as assigned by the IRT. 
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). 
The open-label period will not be randomized as all patients will receive the same monthly dose 
(225 mg fremanezumab). 
Investigational Medicinal Products: Dose, Pharmaceutical Form, Route of Administration, 
and Administration Rate 
The investigational medicinal products used in the study (double-blind and open-label periods) 
are described in the table below. 
IMP name 
Recombinant humanized 
IgG2a/kappa mAb  
Test IMP 
Fremanezumab 
Placebo IMP 
Placebo 
Trade name and INN, if 
applicable, or 
company-assigned number 
Fremanezumab 
Known also as: TEV-48125, LBR-101, 
PF-04427429, RN307 
Placebo 

 
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IMP name 
Recombinant humanized 
IgG2a/kappa mAb  
Test IMP 
Fremanezumab 
Placebo IMP 
Placebo 
Formulation 
 
Prefilled syringes contain 1.5 mL 
solution for injection with 150 mg/mL 
(ie 225 mg total) of active ingredient 
fremanezumab 
Inactive ingredients include: 
L-histidine, sucrose, polysorbate-80, 
ethylenediaminetetraacetic 
acid (EDTA) and water for injection 
Prefilled syringes contain 1.5 mL of 
the same vehicle and excipients as 
those for active injection. 
Inactive ingredients include: 
L-histidine, sucrose, polysorbate-80, 
ethylenediaminetetraacetic 
acid (EDTA) and water for injection 
Unit dose strength(s)/Dosage 
level(s) 
225 mg/1.5 mL 
None 
Route of administration 
sc injection 
sc injection 
Dosing instructions/Dosing 
schedule/Titration 
periods/Treatment periods for 
the double-blind period 
For CM patients: A dose of 675 mg 
fremanezumab as 3 active injections 
(225 mg/1.5 mL) at visit 2 and 225 mg 
fremanezumab as 1 active injection 
(225 mg/1.5 mL) at visits 3 and 4. 
Or a dose of 675 mg fremanezumab as 
3 active injections (225 mg/1.5 mL) at 
visit 2 
No placebo injections 
 
 
 
Single 1.5-mL placebo injection at 
visits 3 and 4 
For EM patients: 225 mg 
fremanezumab as 1 active injection 
(225 mg/1.5 mL) at visit 2, 3, and 4 
Or a dose of 675 mg fremanezumab as 
3 active injections (225 mg/1.5 mL) at 
visit 2 
Two 1.5-mL placebo injections at 
visit 2 
 
Single 1.5-mL placebo injection at 
visits 3 and 4 
For both CM and EM patients who 
are on treatment placebo only: 
No active injections 
Three 1.5-mL placebo injections at 
visit 2 and a single 1.5-mL placebo 
injection at visits 3 and 4 
Dosing instructions/Dosing 
schedule/Titration 
periods/Treatment periods for 
the open-label period 
For all CM and EM patients:  
225 mg fremanezumab as 1 active 
injection (225 mg/1.5 mL) at visits 5, 
6, and 7 
No placebo injections 
Packaging 
A kit uniquely numbered containing 1 
prefilled syringe stored (refrigerated at 
2°C to 8°C) on site 
A kit uniquely numbered containing 
1 prefilled syringe stored 
(refrigerated at 2°C to 8°C) on site 

 
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IMP name 
Recombinant humanized 
IgG2a/kappa mAb  
Test IMP 
Fremanezumab 
Placebo IMP 
Placebo 
Manufacturer 
Drug Substance: 
Celltrion 
23, Academy-ro 
Yeonsu-gu, Incheon, 
South Korea 
 
Drug Product: 
Vetter Pharma Fertigung GmbH & Co. 
KG  
Schuetzenstrasse 87, 99-101, 
Ravensburg,  
Baden-Wuerttemberg 88212 
Germany 
Vetter Pharma Fertigung GmbH & Co. 
KG Mooswiesen 2, Ravensburg, 
Baden-Wuerttemberg 88214, Germany  
Vetter Pharma Fertigung GmbH & 
Co. KG  
Schuetzenstrasse 87, 99-101, 
Ravensburg,  
Baden-Wuerttemberg 88212 
Germany 
 
Vetter Pharma Fertigung GmbH & 
Co. KG Mooswiesen 2, Ravensburg, 
Baden-Wuerttemberg 88214, 
Germany 
CM=chronic migraine; EDTA= ethylene diamine tetra acetate; EM=episodic migraine; IMP=Investigational 
Medicinal Product; INN=international nonproprietary name; mAb=monoclonal antibody; sc=subcutaneous. 
The suggested sites of injection are back of upper arms, lower abdomen/belly/waistline, and 
front of thighs. Each of the injections during an administration should be given in a different 
location (eg, not in precisely the same place/not on top of the previous injection site), 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 45-60 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 (visits 2, 3, 4, 5, 
6, and 7). 
Duration of Patient Participation and Maximal Exposure to IMP:  
The total duration of patient participation in the study is planned to be 50 weeks including a 
run-in period lasting 28 days, a double-blind treatment period lasting 12 weeks, an open-label 
period lasting 12 weeks and 1 follow-up visit at week 46. 
For the double-blind period, the starting dose for patients with CM will be 675 mg sc and the 
starting dose for patients with EM will be 225 mg sc or 675 mg sc. Further doses of 225 mg or 
placebo will be administered sc once monthly. The maximal dose administered sc per treatment 
will be 675 mg. For the open-label period, all patients will receive 225 mg fremanezumab 
monthly. 
Study Duration: 2 years (from 4Q 2017 to 4Q 2019) 
End of Study: End of study is defined as the last visit of the last patient of the follow-up period. 

 
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Plans for Treatment or Care after the Patient Has Ended Participation in the Study: 
At the end of the 24-week treatment period, it is expected that patients should return to the care 
of their treating physicians.  
Patients will return to the investigational center approximately 6.0 months following 
administration of the last dose of IMP for safety evaluation. No treatment is planned by the 
sponsor after completion of the 24-week treatment period and the study. Patients should be 
treated with standard of care after withdrawal from or termination of the 24-week treatment 
period, as appropriate. 
Inclusion Criteria:  
Patients may be included in the study only if they meet all of the following criteria: 
a. The patient is capable of giving signed informed consent. 
b. Male or female patient aged 18 to 70 years, inclusive. 
c. The patient has a diagnosis of migraine with onset at ≤50 years of age. 
d. The patient is in good health in the opinion of the investigators as determined by 
medical history, physical examination, laboratory tests, and ECG. 
e. Body weight ≥45 kg and body mass index (BMI) within the range 17.5 to 34.9 kg/m2 
(inclusive). 
f. The patient has a history of migraine (according to ICHD-3 criteria [IHS 2013]) or 
clinical judgment suggests a migraine diagnosis (not better accounted for by another 
ICHD-3 diagnosis) for ≥12 months prior to screening. 
g. The patient fulfills the following criteria for CM or EM in prospectively collected 
baseline information during the 28-day run-in period: 
For 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 
○ ICHD-3 criteria B and C for 1.2 Migraine with aura 
○ Probable migraine (a migraine subtype where only 1 migraine criterion is 
missing) 
○ The patient used a triptan or ergot derivative to treat an established headache 
For patients with EM: 
−  Headache occurring on ≥6 days but <15 
− On ≥4 days, fulfilling any of the following: 
○ ICHD-3 diagnostic criteria C and D for 1.1 Migraine without aura 
○ ICHD-3 criteria B and C for 1.2 Migraine with aura 

 
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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 
h. At the time of screening, the patient must have documented inadequate response to 
2 to 4 classes of prior preventive migraine medications (as defined in Appendix H) 
within the past 10 years (in medical chart or by treating physician’s confirmation; see 
Appendix I for acceptable documentation of previous treatment failure). Inadequate 
response to prior preventive migraine medications (including valproic acid) is defined 
as: no clinically meaningful improvement per treating physician’s judgment, after at 
least 3 months of therapy at a stable dose considered appropriate for migraine 
prevention according to accepted country guidelines, or when treatment has to be 
interrupted because of adverse events that made it intolerable for the patient, or the 
medication (as defined in Appendix H) is contraindicated or unsuitable for the 
prophylactic treatment of migraine for the patient. The 3- month period does not 
apply if the drug is intolerable or contraindicated. If onabotulinumtoxinA is the 
previous preventive medication, at least 2 sets of injections and 3 months must have 
passed since the last set of injections prior to the screening visit.  
i. The patient agrees not to initiate any preventive migraine medications (as defined in 
Appendix H) during the run-in period double-blind treatment period and open-label 
period. At the screening visit, at least 5 half-lives of these medications must have 
passed since the patient has been on any migraine preventive medication as defined in 
Appendix H. 
j. Other prescription medications not in Appendix H must have been on stable doses for 
at least 2 months at the screening visit with no expectation to change during the 
double-blind treatment period of the study. 
k. The patient demonstrated compliance with the electronic headache diary during the 
run-in period by entry of headache data on a minimum of 24 days cumulative during 
the run-in period (~85% diary compliance). 
l. Women may be included only if they have a negative serum beta-human chorionic 
gonadotropin (β-HCG) test at screening, are sterile, or postmenopausal. Definitions of 
sterile and postmenopausal are given in Appendix E. 
m. Women of childbearing potential (WOCBP) whose male partners are potentially 
fertile (ie, no vasectomy) must use highly effective birth control methods for the 
duration of the study and the follow-up period (ie, starting at screening) and for 
6.0 months after discontinuation of IMP (for details of WOCBP, sterile, and 
postmenopausal women, see Appendix E). 
n. Men must be sterile, or if they are potentially fertile/reproductively competent (not 
surgically [eg, vasectomy] or congenitally sterile) and their female partners are of 
childbearing potential, must use, together with their female partners, acceptable birth 
control methods for the duration of the study and for 6.0 months after discontinuation 
of the IMP. 

 
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o. 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 evaluations, as specified in this protocol. 
Exclusion Criteria: 
Patients will be excluded from participating in this study if they meet any of the following 
criteria: 
a. At the time of screening visit, patient is receiving any preventive migraine 
medications, regardless of the medical indication (as defined in Appendix H) for 
more than 5 days and expects to continue with these medications.  
b. Patient has received onabotulinumtoxinA for migraine or for any medical or cosmetic 
reasons requiring injections in the head, face, or neck during the 3 months before 
screening visit.  
c. The patient uses medications containing opioids (including codeine) or barbiturates 
(including butalbital/aspirin/caffeine [Fiorinal®, Actavis plc], 
butalbital/paracetamol/caffeine [Fioricet®, Cardinal Health], or any other combination 
containing butalbital) on more than 4 days during the run-in period for the treatment 
of migraine or for any other reason. 
d. The patient has used an intervention/device (eg, scheduled nerve blocks and 
transcranial magnetic stimulation) for migraine during the 2 months prior to 
screening. 
e. The patient uses triptans/ergots as preventive therapies for migraine. 
f. Patient uses non-steroidal anti-inflammatory drugs (NSAIDs) as preventive therapy 
for migraine on nearly daily basis for other indications. Note: Low dose aspirin (eg, 
81 mg) used for cardiovascular disease prevention is allowed. 
g. The patient suffers from unremitting headaches, defined as having headaches for 
more than 80% of the time he/she is awake, and less than 4 days without headache 
per month. Daily headache is acceptable if patient has headaches 80% or less of the 
time he/she is awake on most days. 
h. The patient has a clinically significant hematological, cardiac, renal, endocrine, 
pulmonary, gastrointestinal, genitourinary, neurologic, hepatic, or ocular disease that, 
in the opinion of the investigator, could jeopardize or would compromise the patient’s 
ability to participate in this study. 
i. Evidence or medical history of clinically significant psychiatric issues that, in the 
opinion of the investigator, could jeopardize or would compromise the patient’s 
ability to participate in this study including major depression, panic disorder, or 
generalized anxiety disorder, any suicide attempt in the past or suicidal ideation with 
a specific plan the past two years prior to screening or current suicidal ideation as 
measured by eC-SSRS.  
j. History of clinically significant cardiovascular disease or vascular ischemia (such as 
myocardial, neurological [e.g., cerebral ischemia], peripheral extremity ischemia, or 

 
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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. 
k.  History of human immunodeficiency virus, tuberculosis, or chronic hepatitis B or C 
infection. 
l. Past or current history of cancer, except for appropriately treated non-melanoma skin 
carcinoma in the last 5 years. 
m. Pregnant or lactating female patients or female patients who plan to become pregnant 
during the study. 
n. Participation in a clinical study of a new chemical entity or a prescription medicine 
within 2 months before screening (or 3 months in case of biologics if the half-life of 
the biologics is unknown) or 5 half-lives, whichever is longer, or is currently 
participating in another study of an IMP (or a medical device). 
o. Any prior exposure to a monoclonal antibody targeting the CGRP pathway (such as 
AMG 334, ALD304, LY2951742, or fremanezumab). 
p. Any finding in the baseline 12-lead ECG considered clinically significant in the 
judgment of the investigator. 
q. 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). 
r. Hepatic enzymes (alanine aminotransferase, aspartate aminotransferase, and alkaline 
phosphatase) >1.5 × the upper limit of the normal (ULN) range after confirmation in 
a repeat test or suspected hepatocellular damage that fulfills criteria for Hy’s law at 
screening. 
s. Serum creatinine >1.5 × the ULN, clinically significant proteinuria, or evidence of 
renal disease at screening. 
t. The patient has a history of alcohol abuse during the 2 years prior to screening. 
u. The patient has a history of drug abuse during the past 2 years or drug dependence 
during the past 5 years.  
v. 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 tutelage, or being 
admitted to a sanitarium or social institution 
− 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 

 
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w. The patient is a study center or sponsor employee who is directly involved in the 
study or the relative of such an employee. 
x. The patient has been previously screen failed for the study. 
Statistical Considerations: 
Sample Size Rationale: In the Phase 2b study for CM (Study LBR-101-021), the treatment 
difference between 675/225/225 mg and placebo in change from baseline in monthly average 
migraine days was 2.1 days (SD=5.2 days). In the phase 2b study for EM (Study LBR-101-022), 
the treatment difference between 225 mg monthly dose and placebo in change from baseline in 
monthly average migraine days was 2.7 days (SD=4.1 days). In the Phase 3 study for CM (Study 
TV48125-CNS-30049), the treatment differences to placebo in change from baseline in monthly 
average migraine days were 1.7 days and 1.8 days for the quarterly dose and the monthly dose, 
respectively (SD=5.4 days). In the Phase 3 study for EM (Study TV48125-CNS-30050), the 
treatment differences to placebo in change from baseline in monthly average migraine days were 
1.3 days and 1.5 days for the quarterly dose and the monthly dose, respectively (SD=3.4 days). 
Combining the information above, a treatment difference of 1.8 days is used. Considering the 
patient population is different from the previous studies, a SD of 6 days is used to account for the 
complexity and uncertainty of this study. 
A sample size of 705 (235 patients per treatment group) evaluable patients completing the study 
is needed for 90% power to show a 1.8 difference in migraine days (assuming a common 
standard deviation [SD] of 6 days) at an alpha level of 0.05. Assuming a 12% discontinuation 
rate for the double-blind period, 268 patients per treatment group will be randomized. 
Analysis of Primary Endpoint: For the purpose of this study, a migraine day is endorsed when 
at least one of the following occurs: 
• a calendar day (0:00 to 23:59) demonstrating at least 4 consecutive hours of a 
headache, meeting criteria for migraine with or without aura (see Appendix U) 
• a calendar day (0:00 to 23:59) demonstrating at least 4 consecutive hours of a 
headache meeting criteria for probable migraine, a migraine subtype where only 
1 migraine criterion is missing (see Appendix U) 
• a calendar day (0:00 to 23:59) demonstrating a headache of any duration that was 
treated with migraine- specific acute medications (triptans and ergot compounds)  
A headache day of at least moderate severity is endorsed when at least 1 of the following 
situations occurs:  
• a calendar day (0:00 to 23:59) demonstrating at least 4 consecutive hours of headache 
of at least moderate severity 
• a calendar day (0:00 to 23:59) demonstrating a headache of any duration that was 
treated with migraine- specific acute medications (triptans and ergot compounds) 
Analysis of Secondary Endpoints: The analysis of the secondary endpoints is specified in the 
statistical section of the protocol (Section 9.5.2). 
Primary Efficacy Analysis: The primary efficacy endpoint will be analyzed using an analysis of 
covariance (ANCOVA) method. The model will include treatment, gender, region, special group 

 
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of treatment failure (Yes or No), migraine classification (ie, CM or EM), and treatment-by-
migraine classification interaction as fixed effects, and baseline number of migraine days and 
years since onset of migraines as covariates. The treatment comparison between each 
fremanezumab treatment group (monthly dose and quarterly dose) and placebo for monthly 
average migraine days will be conducted under this model using the estimate statement. Ninety-
five percent confidence intervals will be constructed for the least squares means differences 
between each fremanezumab treatment group (monthly dose and quarterly dose) and placebo. 
Note: Special treatment failure group defined as patients who must have had inadequate response 
to valproic acid. In addition, patients in the special treatment failure group must have had 
inadequate response to 2 to 3 other classes of migraine preventive medications as defined 
in Appendix H. 
Sensitivity Analysis: Sensitivity analysis will be performed by imputing missing migraine days 
of months 1-3 using multiple imputation method. The average migraine days of months 1 to 3 
from each imputed data set will be analyzed using the same ANCOVA model as the primary 
efficacy analysis. Ninety-five percent confidence intervals for the least square means differences 
between each fremaezumab treatment group (monthly dose and quarterly dose) and placebo will 
be constructed. The detailed SAS code for imputation and analysis procedure will be provided in 
the statistical analysis plan. This sensitivity analysis will be performed on the ITT analysis set. 
Sensitivity analysis will also be performed using a mixed-effects repeated measures (MMRM) 
analysis model. If a patient is early terminated or has intermittent missing days and has fewer 
than 10 days of e-diary entries for a month, that month’s value will be considered as missing. 
The MMRM model will include  treatment, gender, region, special group of treatment failure 
(Yes or No), migraine classification (ie, CM or EM),  month, treatment-by-migraine 
classification interaction, and treatment-by-month interaction as fixed effects, baseline value and 
years since onset of migraines as covariates, and patient in the repeated statement as a random 
effect. The treatment comparison between each fremanezumab treatment group (monthly dose 
and quarterly dose) and placebo for monthly average migraine days will be conducted under this 
model using the estimate statement. Ninety-five percent confidence intervals will be constructed 
for the least squares means differences between each fremanezumab treatment group (monthly 
dose and quarterly dose) and placebo. This sensitivity analysis will be performed on the mITT 
analysis set. 
Note: Special treatment failure group defined as patients who must have had inadequate response 
to valproic acid. In addition, patients in the special treatment failure group must have had 
inadequate response to 2 to 3 other classes of migraine preventive medications as defined 
in Appendix H. 
Secondary Efficacy Analysis: The continuous secondary efficacy endpoints will be analyzed 
similarly as the primary efficacy endpoint. For the proportion of responders, defined as 50% or 
more reduction from baseline in the monthly average number of migraine days, a logistic 
regression model will be used with the following effects: treatment, gender, region, special group 
of treatment failure (Yes or No), and migraine classification (ie, CM or EM). The odds ratios, 
95% confidence intervals, for odds ratios, and p-values will be presented for each fremanezumab 
treatment group (monthly dose and quarterly dose) comparing to placebo. 

 
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Multiple Comparisons and Multiplicity: The Hochberg’s method along with hierarchical 
testing procedure for multiple comparisons between treatment groups (2 comparisons: 
fremanezumab monthly dose compared with placebo and fremanezumab quarterly dose 
compared with placebo) for the primary and secondary endpoint analyses will be used to 
maintain the experiment-wise type I error of 5%. 
In the primary analysis, according to the Hochberg’s method, if the null hypothesis is rejected for 
both the fremanezumab monthly and quarterly treatment groups at an alpha level of 5%, then no 
adjustment to the alpha level will be performed and both comparisons will be declared as 
statistically significant. The secondary variables will then be tested in the order as specified in 
Section 9.5.2 for both the fremanezumab monthly and quarterly treatment groups using the same 
procedure as the primary analysis. If the null hypothesis is not rejected for 1 of the doses at an 
alpha level of 5%, then the other dose will be tested using an alpha level of 5%/2=2.5%, and the 
sequential testing will stop. 
No multiplicity adjustments will be made for the exploratory efficacy analyses. 
Analysis of Exploratory Endpoints: For the double-blind period, the continuous exploratory 
efficacy endpoints will be analyzed similarly as the primary efficacy endpoint. For the 
proportions of responders for the double-blind period, a logistic regression model will be used 
similarly as the secondary efficacy endpoint.  
For the open-label period, the exploratory efficacy endpoints for the open-label period will be 
summarized using descriptive statistics. 
Safety Analyses: Safety analyses will be performed on the safety analysis set. 
Safety assessments and time points are provided in Table 2. 
All adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Each patient will be counted only once in each preferred term or system organ class 
(SOC) 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 test IMP 
(ie, reasonable possibility) (defined as related or with missing relationship) (overall and by 
severity), serious adverse events, and adverse events causing withdrawal from the study. 
Summaries will be presented by treatment group and for all patients. Patient listings of serious 
adverse events and adverse events leading to withdrawal will be presented. 
Changes in laboratory, ECG, and vital signs measurements data will be summarized 
descriptively. All values will be compared with predefined criteria to identify potentially 
clinically significant values or changes, and such values will be listed. 
Safety data will be summarized descriptively overall and by treatment group. For continuous 
variables, descriptive statistics (n, mean, standard deviation, 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. The denominator for categorical 
variables will exclude missing observations. 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 be provided as well. 

 
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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. 
Tolerability Analysis: Local tolerability findings will be listed and summarized descriptively. 
Pharmacokinetic Analysis: Pharmacokinetic plasma concentration results (fremanezumab) will 
be tabulated descriptively at each planned sampling time point by treatment group and 
indication. 
In addition, the most appropriate population pharmacokinetic model may be developed, and 
covariates that may affect it will be tested for inclusion in the model. If performed, this analysis 
will be reported separately. 
Pharmacokinetic/Pharmacodynamic Analysis: The pharmacokinetic/pharmacodynamic 
relationship may be estimated by compartmental techniques. The pharmacokinetic parameters 
will be based on IMP measurements. The pharmacodynamics analysis will be the efficacy 
response(s).  
The pharmacokinetic/pharmacodynamic relationship may 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. If performed, this analysis will be reported separately. 
Exploratory Biomarker Analysis: Exploratory biomarker measurements will be made using 
appropriately validated assays. Results, if generated, will typically be expressed as % change 
from baseline and reported in a separate report.  
Pharmacogenomic Analysis: Pharmacogenomic analysis will be conducted to correlate clinical 
observations (pharmacokinetics, safety, efficacy, or other effects) with genotypes observed in the 
study. Pharmacogenomic analysis may be conducted at a later time and will be reported in a 
separate report. 
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 if data allowed. This 
analysis will be reported separately. 
Planned Interim Analysis: An interim analysis is planned when the last patient has completed 
the double-blind period. A second interim lock is planned following the end of the open-label 
period. 
The inferential analysis of efficacy variables for comparison between each fremanezumab 
treatment group (monthly dose and quarterly dose) and placebo will be done at the time of the 
first interim lock. The appropriate method for type 1 error control will be applied to the first 
interim analysis. 
Efficacy analysis for the open-label portion of this study is considered exploratory and mainly 
descriptive. This analysis will be done at the time of the final database lock. 

 
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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
AMENDMENT HISTORY .............................................................................................................3 
INVESTIGATOR AGREEMENT...................................................................................................4 
SPONSOR PROTOCOL APPROVAL ...........................................................................................5 
COORDINATING INVESTIGATOR AGREEMENT ...................................................................6 
CLINICAL STUDY PROTOCOL SYNOPSIS...............................................................................7 
LIST OF ABBREVIATIONS ........................................................................................................35 
1. 
INTRODUCTION AND BACKGROUND INFORMATION ..................................38 
1.1. 
Introduction .................................................................................................................38 
1.1.1. 
Disease Overview .......................................................................................................38 
1.1.2. 
Rationale for Fremanezumab Development as a Preventive Treatment for 
Migraine ......................................................................................................................38 
1.1.3. 
Study Purpose .............................................................................................................39 
1.2. 
Findings from Nonclinical and Clinical Studies .........................................................39 
1.2.1. 
Nonclinical Studies .....................................................................................................39 
1.2.2. 
Clinical Studies ...........................................................................................................40 
1.2.2.1. 
Clinical Pharmacology Studies ...................................................................................41 
1.2.2.2. 
Clinical Safety and Efficacy Studies ..........................................................................41 
1.3. 
Known and Potential Benefits and Risks to Patients ..................................................43 
1.3.1. 
Known and Potential Benefits and Risks of Fremanezumab ......................................43 
1.3.1.1. 
Identified Risks ...........................................................................................................43 
1.3.1.2. 
Potential Risks ............................................................................................................44 
1.3.2. 
Overall Benefit and Risk Assessment for This Study ................................................45 
2. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................46 
2.1. 
Primary and Secondary Study Objectives and Endpoints ..........................................46 
2.1.1. 
Justification of Primary Endpoint ...............................................................................47 
2.2. 
Exploratory Efficacy Objectives and Endpoints .........................................................47 
3. 
GENERAL STUDY DESIGN AND STUDY SCHEMATIC DIAGRAM ...............52 
3.1. 
Planned Number of Patients and Countries ................................................................55 
3.2. 
Justification for Study Design and Selection of Population .......................................55 
3.3. 
Stopping Rules for the Study ......................................................................................56 

 
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3.4. 
Schedule of Study Procedures and Assessments ........................................................56 
4. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................62 
4.1. 
Patient Inclusion Criteria ............................................................................................62 
4.2. 
Patient Exclusion Criteria ...........................................................................................64 
4.3. 
Withdrawal Criteria and Procedures for the Patient ...................................................66 
4.4. 
Replacement of Patients .............................................................................................67 
4.5. 
Rescreening .................................................................................................................67 
4.6. 
Screening Failure ........................................................................................................67 
5. 
TREATMENTS ..........................................................................................................68 
5.1. 
Investigational Medicinal Products Used in the Study ...............................................68 
5.1.1. 
Test Investigational Medicinal Product (Fremanezumab) ..........................................70 
5.1.1.1. 
Starting Dose and Dose Levels ...................................................................................70 
5.1.1.2. 
Dose Modification and Dose Stratification ................................................................70 
5.1.2. 
Placebo Investigational Medicinal Product ................................................................70 
5.2. 
Preparation, Handling, Labeling, Storage, and Accountability for IMPs ...................70 
5.3. 
Justification for Investigational Medicinal Products ..................................................70 
5.3.1. 
Justification for Dose of Test Investigational Medicinal Product ..............................70 
5.3.2. 
Justification for Use of Placebo Investigational Medicinal Product ..........................71 
5.4. 
Treatment after the End of the Study ..........................................................................71 
5.5. 
Restrictions .................................................................................................................71 
5.5.1. 
Activity .......................................................................................................................72 
5.5.2. 
Blood Donation ...........................................................................................................72 
5.5.3. 
Pregnancy ...................................................................................................................72 
5.6. 
Prior and Concomitant Medication or Therapy ..........................................................72 
5.7. 
Procedures for Monitoring Patient Compliance .........................................................73 
5.8. 
Randomization and Blinding ......................................................................................73 
5.9. 
Maintenance of Randomization and Blinding ............................................................73 
5.9.1. 
Maintenance of Randomization ..................................................................................73 
5.9.2. 
Blinding and Unblinding ............................................................................................73 
5.9.3. 
Data Monitoring Committee .......................................................................................74 
5.10. 
Total Blood Volume ...................................................................................................74 
6. 
ASSESSMENT OF EFFICACY ................................................................................75 

 
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6.1. 
Assessments of Efficacy .............................................................................................75 
6.1.1. 
Six-Item Headache Impact Test ..................................................................................76 
6.1.2. 
Migraine Disability Assessment .................................................................................76 
6.1.3. 
Two-Item Patient Health Questionnaire/9-Item Patient Health Questionnaire ..........76 
6.1.4. 
Migraine-Specific Quality of Life Questionnaire .......................................................76 
6.1.5. 
EuroQol-5 Dimension Questionnaire .........................................................................77 
6.1.6. 
Patient Global Impression of Change Scale ...............................................................77 
6.1.7. 
Work Productivity and Activity Impairment Questionnaire ......................................77 
7. 
ASSESSMENT OF SAFETY .....................................................................................78 
7.1. 
Adverse Events ...........................................................................................................78 
7.1.1. 
Definition of an Adverse Event ..................................................................................78 
7.1.2. 
Recording and Reporting of Adverse Events .............................................................79 
7.1.3. 
Severity of an Adverse Event .....................................................................................80 
7.1.4. 
Relationship of an Adverse Event to the Investigational Medicinal Product .............80 
7.1.5. 
Serious Adverse Events ..............................................................................................81 
7.1.5.1. 
Definition of a Serious Adverse Event .......................................................................81 
7.1.5.2. 
Expectedness ...............................................................................................................82 
7.1.5.3. 
Reporting a Serious Adverse Event ............................................................................83 
7.1.6. 
Protocol-Defined Adverse Events not for Expedited Reporting ................................84 
7.1.7. 
Protocol-Defined Adverse Events of Special Interest ................................................85 
7.1.8. 
Protocol Deviations Because of an Adverse Event ....................................................85 
7.2. 
Pregnancy ...................................................................................................................85 
7.3. 
Medication Error and Special Situations Related to the Investigational 
Medicinal Products .....................................................................................................86 
7.4. 
Clinical Laboratory Tests ...........................................................................................87 
7.4.1. 
Other Clinical Laboratory Tests .................................................................................87 
7.4.1.1. 
Human Chorionic Gonadotropin Test ........................................................................87 
7.4.1.2. 
Follicle-Stimulating Hormone Test ............................................................................87 
7.4.1.3. 
Saliva Collection .........................................................................................................87 
7.5. 
Physical Examinations ................................................................................................88 
7.6. 
Vital Signs ..................................................................................................................88 
7.7. 
Electrocardiography ....................................................................................................88 
7.8. 
Immunogenicity ..........................................................................................................89 

 
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7.9. 
Assessment of Local Tolerability and Pain ................................................................89 
7.10. 
Assessment of Suicidality ...........................................................................................89 
7.11. 
Concomitant Therapy or Medication ..........................................................................90 
8. 
ASSESSMENT OF PHARMACOKINETICS/BIOMARKERS/ 
PHARMACOGENOMICS/IMMUNOGENICITY ....................................................91 
8.1. 
Pharmacokinetic Assessment ......................................................................................91 
8.2. 
Pharmacodynamics Assessment .................................................................................91 
8.3. 
Immunogenicity Testing .............................................................................................91 
8.4. 
Assessment of Exploratory Biomarkers .....................................................................91 
8.5. 
Pharmacogenetics .......................................................................................................92 
9. 
STATISTICS ..............................................................................................................93 
9.1. 
Sample Size and Power Considerations .....................................................................93 
9.2. 
Analysis Sets ...............................................................................................................93 
9.2.1. 
Intent-to-Treat Analysis Set ........................................................................................93 
9.2.2. 
Modified Intent-to-Treat Analysis Set ........................................................................93 
9.2.3. 
Safety Analysis Set .....................................................................................................94 
9.2.4. 
Per-Protocol Analysis Set ...........................................................................................94 
9.3. 
Data Handling Conventions ........................................................................................94 
9.4. 
Study Population .........................................................................................................94 
9.4.1. 
Patient Disposition ......................................................................................................94 
9.4.2. 
Demographic and Baseline Characteristics ................................................................95 
9.5. 
Efficacy Analysis ........................................................................................................95 
9.5.1. 
Primary Endpoint ........................................................................................................95 
9.5.2. 
Secondary Endpoints ..................................................................................................95 
9.5.3. 
Exploratory Endpoints ................................................................................................96 
9.5.4. 
Planned Method of Analysis .....................................................................................100 
9.5.4.1. 
Primary Efficacy Analysis ........................................................................................100 
9.5.4.2. 
Sensitivity Analysis ..................................................................................................100 
9.5.4.3. 
Secondary Efficacy Analysis ....................................................................................101 
9.5.4.4. 
Exploratory Efficacy Analysis ..................................................................................101 
9.5.4.5. 
Subgroup Analysis ....................................................................................................101 
9.6. 
Multiple Comparisons and Multiplicity....................................................................102 
9.7. 
Safety Analysis .........................................................................................................102 

 
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9.8. 
Tolerability Analysis ................................................................................................103 
9.9. 
Pharmacokinetic Analysis ........................................................................................103 
9.10. 
Pharmacokinetic/Pharmacodynamic Analysis ..........................................................103 
9.11. 
Exploratory Biomarker Analysis ..............................................................................103 
9.12. 
Pharmacogenomic Analysis......................................................................................103 
9.13. 
Immunogenicity Analysis .........................................................................................103 
9.14. 
Planned Interim Analysis ..........................................................................................104 
9.15. 
Reporting Deviations from the Statistical Plan ........................................................104 
10. 
QUALITY CONTROL AND QUALITY ASSURANCE .......................................105 
11. 
COMPLIANCE STATEMENT ................................................................................105 
12. 
DATA MANAGEMENT AND RECORD KEEPING ............................................105 
13. 
FINANCING AND INSURANCE ...........................................................................106 
14. 
PUBLICATION POLICY ........................................................................................106 
15. 
REFERENCES .........................................................................................................107 
16. 
SUMMARY OF CHANGES TO PROTOCOL .......................................................110 
16.1. 
Amendment 01 Dated 23 October 2017 ...................................................................110 
APPENDIX A. CLINICAL LABORATORIES AND OTHER DEPARTMENTS AND 
INSTITUTIONS .......................................................................................................116 
APPENDIX B. STUDY PROCEDURES AND ASSESSMENTS BY VISIT .........................118 
APPENDIX C. QUALITY CONTROL AND QUALITY ASSURANCE ..............................126 
APPENDIX D. ETHICS ...........................................................................................................128 
APPENDIX E. BIRTH CONTROL METHODS AND PREGNANCY TESTING .................129 
APPENDIX F. LOST TO FOLLOW-UP .................................................................................131 
APPENDIX G. HANDLING, LABELING, STORAGE, AND ACCOUNTABILITY 
FOR INVESTIGATIONAL MEDICINAL PRODUCT(S) .....................................132 
APPENDIX H. MEDICATIONS TO EVALUATE PATIENT QUALIFICATION 
FOR INADEQUATE RESPONSE TO PRIOR TREATMENTAND 
DISALLOWED DURING THE RUN-IN TREATMENT PERIOD, AND 
FOLLOW-UP PERIOD ............................................................................................133 
APPENDIX I. ACCEPTABLE DOCUMENTATION OF PREVIOUS TREATMENT 
FAILURES ...............................................................................................................134 
APPENDIX J. TOTAL BLOOD VOLUME.............................................................................135 
APPENDIX K. PHARMACOKINETICS SAMPLES .............................................................136 
APPENDIX L. IMMUNOGENICITY SAMPLES ...................................................................137 

 
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APPENDIX M. EXPLORATORY BIOMARKERS SAMPLES .............................................138 
APPENDIX N. PHARMACOGENETIC ASSESSMENTS .....................................................140 
APPENDIX O. PRODUCT COMPLAINTS ............................................................................141 
APPENDIX P. DATA MANAGEMENT AND RECORD KEEPING ....................................143 
APPENDIX Q. PUBLICATION POLICY ...............................................................................146 
APPENDIX R. GUIDANCE ON SAFETY MONITORING ...................................................147 
APPENDIX S. CLINICAL CRITERIA FOR DIAGNOSING ANAPHYLAXIS ...................150 
APPENDIX T. CLINICAL LABORATORY TESTS ..............................................................151 
APPENDIX U. ICHD-3 DIAGNOSTIC CRITERIA ...............................................................152 
APPENDIX V. INJECTION INSTRUCTIONS .......................................................................153 

 
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LIST OF TABLES 
Table 1: 
Primary and Secondary Objectives and Endpoints .....................................................46 
Table 2: 
Study Procedures and Assessments ............................................................................57 
Table 3: 
Investigational Medicinal Products Used in the Study ...............................................68 
Table 4: 
The Relationship of an Adverse Event to the IMP .....................................................81 
 
LIST OF FIGURES 
Figure 1: 
Overall Study Schematic Diagram for Patients with Chronic Migraine ....................54 
Figure 2: 
Overall Study Schematic Diagram for Patients with Episodic Migraine ...................55 
 

 
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LIST OF ABBREVIATIONS 
Abbreviation 
Term 
β-HCG 
beta-human chorionic gonadotropin 
ADA 
antidrug antibody 
ALT 
alanine aminotransferase 
ALP 
alkaline phosphatase 
ANCOVA 
analysis of covariance 
ANOVA 
analysis of variance 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
AUClast 
area under the plasma concentration-time curve from time 0 to the time of the last measurable 
IMP concentration 
BLA 
Biological License Application 
BMI 
body mass index 
CDMS 
clinical data management system 
CFR 
Code of Federal Regulations (USA) 
CGRP 
calcitonin gene-related peptide 
CL/F 
apparent total body clearance 
CM 
chronic migraine 
Cmax 
maximum observed concentration 
CRF 
case report form (refers to any media used to collect study data [ie, paper or electronic]) 
CRO 
contract research organization 
EC 
Ethics Committee 
ECG 
electrocardiogram 
eC-SSRS 
electronic Columbia-Suicide Severity Rating Scale 
EM 
episodic migraine 
EMA 
European Medicines Agency 
EOT 
end of treatment 
EQ-5D-5L 
EuroQol-5 Dimension (5-level) 
EudraCT 
European Clinical Trials 
EV 
EudraVigilance  
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 

 
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Abbreviation 
Term 
GGT 
gamma glutamyl transpeptidase 
HIT-6 
6-item Headache Impact Test 
ICDH 
International Classification of Headache Disorders 
ICF 
informed consent form 
ICH 
The International Council on Harmonisation 
IEC 
Independent Ethics Committee 
IMP 
investigational medicinal product 
INN 
international nonproprietary name 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IRT 
interactive response technology 
ITT 
intent-to-treat 
iv 
Intravenous 
LSO 
local safety officer 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified intent to treat 
MSQOL 
Migraine Specific Quality of Life questionnaire 
n 
Number 
NDA 
New Drug Application 
NSAID 
non-steroidal anti-inflammatory drug 
PGIC 
Patient Global Impression of Change scale 
PHQ-2 
2-item Patient Health Questionnaire 
PHQ-9 
9-item Patient Health Questionnaire 
PP 
per-protocol 
RTSM 
Randomization and Trial Supply Management 
sc 
subcutaneous 
SD 
standard deviation 
SOP 
Standard Operating Procedure 
SUSAR 
suspected unexpected serious adverse reaction 
t½  
terminal elimination half-life 
ULN 
upper limit of normal 
V 
Visit 
VHP 
Voluntary Harmonisation Procedure 
Vz/F 
apparent volume of distribution 

 
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Abbreviation 
Term 
W 
Week 
WOCBP 
women of childbearing potential 
WPAI 
Work Productivity and Activity Impairment questionnaire 
XML 
Extensible Markup Language 

 
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1. 
INTRODUCTION AND BACKGROUND INFORMATION 
1.1. 
Introduction 
1.1.1. 
Disease Overview 
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 (EM) (Lipton et al 2007). However, 3% to 6% of 
individuals with EM evolve, in any given year, to a significantly more disabling condition called 
chronic migraine (CM) (Scher et al 2003). Individuals with CM present with headaches of any 
severity on 15 or more days per month and have migraine on at least 8 days per month. A sizable 
proportion of individuals with CM experience daily headaches and, therefore, faces considerable 
disability (Bigal and Lipton 2008). 
1.1.2. 
Rationale for Fremanezumab Development as a Preventive Treatment for 
Migraine 
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 preventive medications.  
Preventive drug treatment may be appropriate in a number of instances, including where 
frequency of attacks per month is two or higher, or where a patient’s quality of life is severely 
impaired (Evers et al 2009). A number of drugs from different pharmacological categories 
(eg, beta blockers, anticonvulsants) have been approved for migraine prevention or have class A 
evidence to support their use. However, compliance and adherence to these medications can be 
poor, and there is a need for preventive medications which are more effective and better tolerated 
than the current standard of care (Puledda et al 2017). 
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). Jugular 
levels of CGRP are increased during migraine attacks, and intravenous CGRP administration 
induces migraine-like headache in most individuals with migraine (Ashina et al 2000, Hansen et 
al 2010). CGRP is 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). Studies have shown that inhibition of CGRP was efficacious in the 
treatment of EM (Hewitt et al 2011, Ho et al 2008, Olesen et al 2004) and CM (Bigal et al 
2015b). 
Fremanezumab (TEV-48125 [formerly LBR-101, PF-04427429, and RN307]) is a fully 
humanized IgG 2a/kappa monoclonal antibody, which is being developed for administration by 
the sc route for the preventive treatment of migraine. Fremanezumab is a potent, selective CGRP 
binder that blocks both CGRP isoforms (α- and β-CGRP) from binding to the CGRP receptor. 
Fremanezumab is specific for CGRP and does not bind to closely related family members 
(eg, amylin, calcitonin, intermedin, and adrenomedullin). Two mutations were introduced into 

 
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the constant region of the fremanezumab heavy chain to limit antibody effector functions. This 
loss of function prevents fremanezumab from stimulating antibody-dependent cell-mediated 
cytotoxicity and triggering complement-mediated lysis, which can lead to unwanted 
consequences such as cell lysis, opsonization, and cytokine release and inflammation (Armour et 
al 1999, Zeller et al 2008). 
The safety and tolerability of fremanezumab (intravenous [iv] doses ranging from 0.2 to 
2000 mg and sc doses of 225 mg and 900 mg) has been well-characterized in the Phase 1 
development program (see the Investigator’s Brochure for more details). Furthermore, the safety 
and efficacy of fremanezumab of fremanezumab has been demonstrated in a randomized 
double-blind, placebo controlled Phase 2 study of 2 sc dosing regimens of fremanezumab 
(monthly fremanezumab at 900 mg or fremanezumab at 675 mg followed by monthly 
fremanezumab at 225 mg) in patients with CM and a randomized, double-blind, 
placebo-controlled Phase 2 study of 2 sc dosing regimens of fremanezumab (monthly 
fremanezumab at 675 or 225 mg) in patients with EM. Furthermore, the efficacy and tolerability 
profile have been confirmed in the Phase 3 development program. 
The demonstrated efficacy, acceptable tolerability, long terminal elimination half-life 
(t½, approximately 32-36 days), and ability to administer sc, make fremanezumab a potential 
therapeutic candidate for patients who failed prior preventive treatment for CM and EM. 
1.1.3. 
Study Purpose 
The purpose of the study is to determine whether fremanezumab is effective in the prophylactic 
treatment of migraine in patients with inadequate response to 2 to 4 classes of prior preventive 
treatments. 
1.2. 
Findings from Nonclinical and Clinical Studies 
Brief summaries of nonclinical pharmacology, pharmacokinetics, and toxicology studies and 
clinical studies are provided in the following sections. More detailed information is provided in 
the Investigator’s Brochure. 
1.2.1. 
Nonclinical Studies 
In vivo pharmacology studies of fremanezumab in animal models indicate that fremanezumab 
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. 
Safety pharmacology parameters of fremanezumab 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 fremanezumab 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 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 

 
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of immune complex formation/deposition from the monkeys’ immunogenic response to the drug 
(fremanezumab). 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 no-observed-adverse-effect level 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 fremanezumab 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 (AUC) 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 
fremanezumab were conducted and completed. Preliminary data suggest that weekly dosing with 
fremanezumab 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. 
1.2.2. 
Clinical Studies  
The clinical program to date is composed of 7 completed Phase 1 clinical studies in healthy 
subjects (Studies B0141001, B0141002, B0141006, B0141007, LBR-101-008, LBR-101-011 
and TV48125-PK-10078), 1 ongoing Phase 1 bioequivalence study (TV48125-BE-10114), 
2 completed Phase 2b clinical studies in patients with migraine (Studies LBR-101-021 and 
LBR-101-022), and 2 completed Phase 3 clinical studies in patients with migraine (Studies 
TV48125-CNS-30049 and TV48125-CNS-30050). A total of 2884 subjects/patients (318 healthy 
subjects and 2566 patients with migraine) have participated across these clinical studies, and 
1958 of these subjects/patients (256 healthy subjects and 1702 patients with migraine [929 
patients with CM and 773 patients with EM]) have received at least 1 dose (iv or sc) of 
fremanezumab. One Phase 3 study (TV48125-CNS-30051) is currently ongoing to further 
evaluate the efficacy, safety, and tolerability of various dose regimens of fremanezumab in the 
preventive treatment of migraine (CM and EM). 
In addition, 2 Phase 3 studies (Studies TV48125-CNS-30056 and TV48125-CNS-30057) are 
ongoing and 1 Phase 3 study (TV48125-CNS-30058) is planned to evaluate the efficacy, safety, 
and tolerability of various dose regimens of fremanezumab in the preventive treatment of cluster 
headache. 
A brief summary of clinical pharmacology and clinical safety and efficacy studies of 
fremanezumab follows. 

 
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1.2.2.1. 
Clinical Pharmacology Studies 
A total of 118 healthy subjects received fremanezumab across 6 completed Phase 1 studies in 
doses ranging from 0.2 through 2000 mg. Studies included 2 single-ascending-dose 
pharmacokinetic and pharmacodynamic studies in healthy men (Studies B0141001 and 
B0141002); a 2-cohort, placebo-controlled crossover study to examine the acute effects of 
administration of fremanezumab on capsaicin flare response in healthy men (Study B0141006); a 
parallel-group, repeat-dose study of fremanezumab in healthy subjects (Study B0141007); a 
single-dose study evaluating the safety, tolerability, and pharmacokinetics of doses up to 
2000 mg administered iv in healthy women (Study LBR-101-008 [formerly referred to as 
Study B0141008]); and a study assessing the safety, tolerability, absolute bioavailability, and 
pharmacokinetics of single iv or sc doses of fremanezumab in healthy subjects (Study 
LBR-101-011).These Phase 1 studies were analyzed using the original bioanalytical method that 
has been determined to be unreliable and underestimate measured plasma concentrations 
compared to the current validated assay. 
A recently completed pharmacokinetic, safety, and tolerability study in healthy Japanese and 
Caucasian subjects (TV48125-PK-10078) dosed fremanezumab as a single sc dose of 225, 
675 or 900 mg. Plasma concentration-time profile was measured using the current validated 
bioanalytical method and the pharmacokinetic results are described below. The pharmacokinetics 
(non-compartmental analysis) of fremanezumab demonstrated an increase in Cmax and AUCs 
values slightly greater than dose proportionality over sc dose range of 225 to 900 mg. Median 
time to maximum observed concentration (tmax) values generally occurred 5 to 7 days post sc 
doses. Mean values for apparent volume of distribution (Vz/F) after a single sc dose ranged from 
5.7 to 6.4 L at 225 mg to 900 mg sc doses. The mean apparent total body clearance (CL/F) 
ranged from 0.0777 to 0.0895 mL/min at this dose range. The mean t½ ranged from 32.2 to 
36.2 days. Fremanezumab exposure parameters and overall pharmacokinetic profile was similar 
for healthy Japanese and Caucasian subjects. Absolute bioavailability following sc 
administration of fremanezumab was approximately 54% to 57%. 
1.2.2.2. 
Clinical Safety and Efficacy Studies 
The safety, tolerability, and efficacy of fremanezumab have been evaluated in 2 completed 
Phase 2b studies, Studies LBR-101-021 and LBR-101-022, in patients with migraine (Bigal et al 
2015a, Bigal et al 2015b). The results of both studies showed fremanezumab to be superior to 
placebo for primary and secondary endpoints (benefit at 3 months of therapy). 
Fremanezumab was well tolerated with favorable safety profile across the 6 completed Phase 1, 
2 completed Phase 2b studies, and 2 completed Phase 3 studies. The treatment-emergent adverse 
events reported in the Phase 1, Phase 2b, and Phase 3 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 fremanezumab has not been identified, nor has a maximally tolerated dose 
been identified. Overall, the nature and occurrence of the reported treatment-related adverse 
events across the clinical program have not raised any specific safety concerns.  
Two pivotal phase 3 studies in EM and CM patients confirmed efficacy findings in phase 2 
(Studies TV48125-CNS-30049 and TV48125-CNS-30050). Study TV48125-CNS-30049 was a 
16-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study to 

 
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compare the efficacy, safety, and tolerability of 2 dose regimens of sc fremanezumab (quarterly 
dosing with fremanezumab at 675 mg [675/225/225-mg; N=376] and a loading dose of 
fremanezumab at 675 mg followed by monthly doses of fremanezumab at 225 mg [675 mg/ 
placebo/placebo; N=379]) and placebo (N=375) in adults (18 through 70 years of age) with CM. 
Patients who were on monotherapy (79%) and patients on stable doses of preventive medications 
(21%) were included in the study. The study consisted of a screening visit, a run-in period lasting 
approximately 4 weeks (~28 days), and a treatment period lasting approximately 12 weeks.  
The analysis of the primary efficacy endpoint, the mean change from baseline in the monthly 
average number of headache days of at least moderate severity during the 12-week period after 
the 1st dose of study drug, demonstrated statistically significant differences from placebo in favor 
of fremanezumab (p<0.0001) for both active treatment groups. The median for the overall 
change from baseline of -4.2 and -4.5 (mean reduction of 4.7 and 4.9 days) vs. -2.5 (mean 
reduction of 2.9 days) headache days of at least moderate severity for the 
675 mg/placebo/placebo and 675/225/225 mg treatment groups vs. placebo, respectively. The 
least square (LS) mean difference with placebo was 1.8 days for 675 mg/placebo/placebo and 
2.1 days for 675/225/225 mg. 
Statistically significant improvements (p<0.0001 for both comparisons versus placebo) were 
evident as early as month 1 (secondary endpoint), and a treatment effect in favor of the 
fremanezumab treatment groups was also evident in months 2 and 3 (exploratory endpoints). The 
results of the analyses of each of the other secondary endpoints further support the efficacy of 
both fremanezumab dose regimens; all comparisons versus placebo were statistically significant. 
Thus, patients treated with fremanezumab were significantly more likely to be responders 
(≥50% reduction in the number of headache days of at least moderate severity), had significantly 
fewer migraine days and days with use of acute headache medication, and they reported 
significantly less disability than patients treated with placebo. In addition, the overall treatment 
effect on headache days of at least moderate severity was also observed in the subset of patients 
(79% of patients) who were not receiving concomitant preventive medication.  
Fremanezumab at the doses tested was generally safe and well tolerated for 3 months in patients 
with CM. Serious adverse events and adverse events leading to discontinuation from the study 
occurred infrequently and with similar incidence across the treatment groups. Most adverse 
events were mild to moderate. Injection site-related adverse events were the most frequent 
treatment-related adverse event and were overall comparable across all treatment groups. 
Study TV48125-CNS-30050 was a 16-week, multicenter, randomized, double-blind, 
placebo-controlled, parallel-group study to compare the efficacy, safety, and tolerability of 
2 dose regimens of sc fremanezumab (quarterly dosing with fremanezumab at 675 mg 
[675-mg/placebo/placebo; N=291] and monthly doses of fremanezumab at 225 mg 
[225/225/225-mg; N=290]) and placebo (N=294) in adults (18 through 70 years of age) with 
EM. Patients who were on monotherapy (79%) and patients on stable doses of preventive 
medications (21%) were included in the study. The study consisted of a screening visit, a run-in 
period lasting approximately 4 weeks (~28 days), and a treatment period lasting approximately 
12 weeks.  
The analysis of the primary efficacy endpoint, the mean change from baseline in the monthly 
average number of migraine days during the 12-week period after the 1st dose of study drug, 

 
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demonstrated statistically significant differences from placebo in favor of fremanezumab 
(p<0.0001) for both active treatment groups. The median for the overall change from baseline 
was -4.0 and -4.2 days (mean reduction of 3.9 and 4.0 days) vs. -2.7 days (mean reduction 
2.6 days) for the 675 mg/placebo/placebo and 225/225/225 mg treatment groups vs. placebo, 
respectively. The LS mean difference with placebo of 1.3 days for 675 mg/placebo/placebo and 
1.5 days for 225/225/225 mg. 
Statistically significant improvements (p<0.0001 for both comparisons versus placebo) were 
evident as early as month 1 (secondary endpoint), and a treatment effect in favor of the 
fremanezumab treatment groups was also evident in months 2 and 3 (exploratory endpoints). The 
results of the analyses of each of the other secondary endpoints further support the efficacy of 
both fremanezumab dose regimens; all comparisons versus placebo were statistically significant. 
Thus, patients treated with fremanezumab were significantly more likely to be responders 
(≥50% reduction in the number of migraine days), had significantly fewer days with use of acute 
headache medication, and they reported significantly less disability than patients treated with 
placebo. In addition, the overall treatment effect on migraine days was also observed in the 
subset of patients (79% of patients) who were not receiving concomitant preventive medication. 
Fremanezumab at the doses tested was generally safe and well tolerated for 3 months in patients 
with EM. Serious adverse events and adverse events leading to discontinuation from the study 
occurred infrequently and with similar frequency across the treatment groups. Injection 
site-related adverse events were the most frequent treatment-related adverse events and were 
comparable across all treatment groups. 
No clinically relevant changes in clinical laboratory values, vital signs measurements, or ECG 
findings have been observed in any of the studies to date. 
1.3. 
Known and Potential Benefits and Risks to Patients 
1.3.1. 
Known and Potential Benefits and Risks of Fremanezumab 
Additional information regarding benefits and risks to patients may be found in the Investigator’s 
Brochure. 
1.3.1.1. 
Identified Risks 
1.3.1.1.1. General Disorders and Administrative Site Conditions 
Reports of transient administration site disorders/reactions, including injection site bruising, 
injection site swelling, administration site pain, injection site pain, injection site pruritus, 
injection site induration, injection site erythema, injection site inflammation, injection site 
warmth, injection site extravasation, injection site dermatitis, injection site rash, injection site 
edema, injection site discomfort, injection site hemorrhage, injection site irritation, injection site 
mass, and injection site hematoma, have occurred with sc administration. In addition, mild and 
transient infusion site pain and swelling after iv administration were reported. Among these 
events, the following have been identified as adverse drug reactions (identified risks): injection 
site erythema, administration site pain, injection site pain, injection site pruritus, and injection 
site dermatitis. None of the identified risks were considered important risks. 

 
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1.3.1.1.2. Injury, Poisoning, and Procedural Complications/Immune System Disorders 
The general risks of infusion reactions with monoclonal antibody administration include fever, 
headache, nausea, vomiting, and hypotension. These adverse events are generally ascribed to 
lysis of cellular targets, cytokine release, or complement activation. 
Type I hypersensitivity or allergic reactions (eg, shortness of breath, urticaria, anaphylaxis, 
angioedema) are theoretically possible with any injected protein. 
Type III hypersensitivity reactions occur as a consequence of an antibody response to the 
injected protein resulting in immune complex formation. Such immune complex formation and 
subsequent deposition in tissues may result in symptoms, including rash, urticaria, polyarthritis, 
myalgias, polysynovitis, fever, neuritis, or angioedema, and if untreated and severe, can progress 
to glomerulonephritis. 
Infusion-related reaction and drug hypersensitivity have been identified as adverse drug 
reactions. To date, 1 subject 
 in Study LBR-101-008 has had an infusion-
related reaction considered related to the study drug, and 1 subject 
 in 
Study LBR-101-021 has had drug hypersensitivity considered related to the study drug. 
• 
 with no relevant medical history, had 
a non-serious infusion-related reaction assessed as moderate in severity and related to 
the study drug. The event, which started 11 minutes after starting the iv dose of 
fremanezumab at 2000 mg, resulted in discontinuation of study drug administration 
after 380 mg. The subject was treated with diphenhydramine and methylprednisolone 
sodium succinate injection (125 mg), and the event resolved. Oxygen saturation was 
monitored during the infusion per protocol and was normal throughout. No reports of 
hypotension or tachycardia were made by the investigator. The first protocol 
scheduled vital signs assessment was performed approximately 1 hour and 40 minutes 
after event onset and was normal. At the 4-hour post-dose adverse event assessment, 
the event was reported as resolved. No delayed hypersensitivity-type reactions have 
been observed in clinical studies. 
• 
 (monthly sc fremanezumab 900-mg treatment group), a 
 
 with a medical history of hypersensitivity and drug hypersensitivity to 
sulfa drugs, had a treatment-emergent adverse event of drug hypersensitivity assessed 
as moderate in severity and related to the study drug. The event led to permanent 
discontinuation of the study drug. The patient received diphenhydramine 
hydrochloride and methylprednisolone for the event that started 1 day after the patient 
received 
 second dose of study drug, and the event was reported as resolved after 
23 days. No reports of hypotension or tachycardia were made by the investigator. 
1.3.1.2. 
Potential Risks 
1.3.1.2.1. Perivascular Inflammation 
In the 3-month monkey toxicology study, inflammation around the ciliary vessel of the eye was 
observed. Based on the low-grade increase in immune complex deposits observed in the intima 
and/or media of ciliary vessels in the animals with perivascular inflammation, these events were 
assessed as being due to the monkeys’ immunogenic response to humanized monoclonal 

 
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antibody rather than a pharmacologic toxicity and are not likely to be relevant in a clinical 
setting. Moreover, a confirmatory 6-month study could not repeat the findings. 
1.3.1.2.2. Consequences of Calcitonin Gene-Related Peptide Inhibition 
Because CGRP is a vasodilator, the following 4 major cardiovascular effects are of potential 
concern with CGRP inhibition, a priori: medication-induced hypertension, counterbalancing the 
effect of anti-hypertensive drugs that have vasodilatory properties, inhibition of stress- (or 
ischemia-) induced vasodilation, and impairment of cardioprotective mechanisms. Extensive 
research conducted with the CGRP receptor antagonists has not identified relevant safety 
cardiovascular concerns in humans. Dedicated studies conducted in monkey and in humans using 
fremanezumab have not identified clinically relevant changes in heart rate, blood pressure, or 
other cardiovascular parameters. No relevant cardiovascular event has been seen in the 
completed studies. 
1.3.2. 
Overall Benefit and Risk Assessment for This Study 
In summary, the benefit/risk assessment for fremanezumab is favorable following review of all 
available efficacy and safety data. 

 
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2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1. 
Primary and Secondary Study Objectives and Endpoints 
The primary and secondary study objectives and endpoints are presented in Table 1: 
Table 1: 
Primary and Secondary Objectives and Endpoints 
Objectives 
Endpoints 
The primary objective of the 
study is to demonstrate the 
efficacy of fremanezumab 
administered as monthly and 
quarterly subcutaneous (sc) 
injections to adult patients with 
migraine with inadequate 
response to 2 to 4 classes of prior 
preventive treatments as 
compared with placebo 
The primary efficacy endpoint is the mean change from baseline 
(28-day run-in period) in the monthly average number of migraine 
days during the 12-week period after the 1st dose of fremanezumab 
The secondary objective of the 
study is to further evaluate  the 
efficacy of fremanezumab 
administered as monthly and 
quarterly sc injections to adult 
patients with migraine with 
inadequate response to 2 to 4 
classes of prior preventive 
treatments as compared with 
placebo 
The secondary endpoints are as follows: 
• 
proportion of patients reaching at least 50% reduction in 
the monthly average number of migraine days during 
the 12-week period after the 1st dose of fremanezumab 
• 
mean change from baseline (28-day run-in period) in the 
monthly average number of headache days of at least 
moderate severity during the 12-week period after the 1st 
dose of fremanezumab 
• 
mean change from baseline (28-day run-in period) in the 
monthly average number of migraine days during the 4-
week period after the 1st dose of fremanezumab 
• 
proportion of patients reaching at least 50% reduction in 
the monthly average number of migraine days during 
the 4-week period after the 1st dose of fremanezumab 
• 
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 12-week period after 
the 1st dose of fremanezumab 
• 
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 
fremanezumab 

 
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Objectives 
Endpoints 
A secondary objective of the 
study is to evaluate the safety and 
tolerability of fremanezumab 
administered as monthly and 
quarterly sc injections to adult 
patients with migraine with 
inadequate response to 2 to 4 
classes of prior preventive 
treatments as compared with 
placebo  
Secondary safety/tolerability endpoints: 
• 
occurrence of adverse events throughout the study 
• 
clinical laboratory (serum chemistry, hematology, 
coagulation and urinalysis) test results at specified time 
points 
• 
vital signs (systolic and diastolic blood pressure, oral 
temperature, and pulse rate) measurements at each visit. 
Note: In addition, oxygen saturation and respiratory rate 
will be measured in cases of suspected anaphylaxis and 
severe hypersensitivity 
• 
12-lead ECG findings at specified time points 
• 
use of concomitant medication for adverse events during 
the study 
• 
number (%) of patients who did not complete the study 
due to adverse events 
• 
clinically significant changes in physical examinations, 
including body weight 
• 
occurrence of severe hypersensitivity/anaphylaxis 
reactions 
• 
suicidal ideations and behaviors as measured by the eC-
SSRS 
ECG=electrocardiogram; eC-SSRS= electronic Columbia-Suicide Severity Rating Scale; Test; sc=subcutaneous. 
2.1.1. 
Justification of Primary Endpoint  
The primary endpoint was chosen based on the IHS guidelines for trials in migraine which 
suggest that the most appropriate primary endpoint to capture efficacy of treatment is the change 
from baseline in the monthly average number of migraine days (Silberstein et al 2008). 
2.2. 
Exploratory Efficacy Objectives and Endpoints 
The exploratory objectives are as follows: 
• to further evaluate the efficacy of fremanezumab in adult migraine patients with 
inadequate response to 2 to 4 classes of prior preventive treatments  
• to evaluate immunogenicity and impact of antidrug antibody (ADA) on clinical 
outcome 
• to explore the correlation between pharmacokinetic parameters and efficacy of 
fremanezumab 

 
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• to explore the relationship between genetic polymorphisms, migraine onset/severity 
and efficacy and safety of fremanezumab 
• to explore the relationship between soluble exploratory biomarkers versus migraine 
response 
The exploratory endpoints for the double-blind period are as follows: 
• proportion of patients reaching at least 75% reduction in the monthly average number 
of migraine days during the 12-week period after the 1st dose of study drug  
• proportion of patients reaching total (100%) response (no headache)  during the 12-
week period after the 1st dose of study drug 
• proportion of patients reaching total (100%) response (no headache) for at least one 
month during the 12-week period after the 1st dose of study drug 
• mean change from baseline (28-day run-in period) in the monthly average number of 
headache hours of at least moderate severity during the 12-week period after the 
1st dose of the study drug 
• proportion of patients reaching at least 50% reduction in the number of migraine days 
during the 4-week period after the 1st dose of study drug for whom this level of effect 
is sustained throughout the 12-week period after the 1st dose of study drug 
• proportion of patients reaching at least 75% reduction in the number of migraine days 
during the 4-week period after the 1st dose of study drug for whom this level of effect 
is sustained throughout the 12-week period after the 1st dose of study drug 
• mean change from baseline (28-day run-in period) in the monthly average number of 
days with nausea or vomiting during the 12-week period after the 1st dose of study 
drug 
• mean change from baseline (28-day run-in period) in the monthly average number of 
days with photophobia and phonophobia during the 12-week period after the 1st dose 
of study drug 
• mean change from baseline (28-day run-in period) in the monthly average number of 
days of use of migraine-specific acute headache medications (triptans and ergot 
compounds) during the 12-week period after the 1st dose of study drug 
• mean change from baseline (28-day run-in period) in the number of migraine days 
during the 12-week period after the 1st dose of study drug for patients who failed 
topiramate for migraine in the past 
• mean change from baseline (28-day run-in period) in the number of migraine days 
during the 12-week period after the 1st dose of study drug for patients who failed 
onabotulinumtoxinA for migraine in the past 
• mean change from baseline (28-day run-in period) in the number of migraine days 
during the 12-week period after the 1st dose of study drug for patients who failed 
valproic acid for migraine in the past 

 
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• mean change from baseline (28-day run-in period) in the number of migraine days 
during the 12-week period after the 1st dose of study drug for the subset of patients 
who failed 2 to 3 classes of preventive medications and valproic acid for migraine in 
the past 
• proportion of patients reaching at least 50% reduction in the monthly average number 
of migraine days during the 12-week period after the 1st dose of fremanezumab for 
the subset of patients who failed 2 to 3 classes of preventive medications and valproic 
acid for migraine in the past 
• mean change from baseline (day 0) in disability score, as measured by the 6-item 
Headache Impact Test (HIT-6), at 4 weeks after administration of the 3rd dose of 
study drug 
• mean change from baseline (day 0) in disability score, as measured by the Migraine 
Disability Assessment (MIDAS) questionnaire, at 4 weeks after the administration of 
the 3rd dose of study drug 
• 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 administration of 
the 3rd dose of study drug 
• mean change from baseline (day 0) in the health status, as measured by the EuroQol-5 
Dimension (EQ-5D-5L) questionnaire at 4 weeks after administration of the 3rd dose 
of study drug 
• 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 4 weeks after administration of the 3rd dose of study drug 
• 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 4 weeks after administration of the 3rd dose of study drug 
• mean change from baseline (day 0) of patient satisfaction, as measured by the Patient 
Global Impression of Change (PGIC) scale, at 4 weeks after the 3rd dose of study drug 
The exploratory endpoints for the open-label period are as follows: 
• mean change from baseline (28-day run-in period) in the monthly average number of 
migraine days during the 12-week period after the 4th dose of fremanezumab 
• proportion of patients reaching at least 50% reduction from baseline (28-day run-in 
period) in the monthly average number of migraine days during the 12-week period 
after the 4th dose of fremanezumab 
• mean change from baseline (28-day run-in period) in the monthly average number of 
headache days of at least moderate severity during the 12-week period after the 
4th dose of fremanezumab 

 
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• 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 12-week period after the 
4th dose of fremanezumab 
• proportion of patients reaching at least 75% reduction from baseline (28-day run-in 
period) in the monthly average number of migraine days during the 12-week period 
after the 4th dose of study drug  
• proportion of patients reaching total (100%) response (no headache)  during the 12-
week period after the 4th dose of study drug 
• proportion of patients reaching total (100%) response (no headache) for at least one 
month during the 12-week period after the 4th dose of study drug  
• mean change from baseline (28-day run-in period) in the monthly average number of 
headache hours of at least moderate severity during the 12-week period after the 
4th dose of the study drug 
• proportion of patients reaching at least 50% reduction from baseline (28-day run-in 
period) in the number of migraine days during the 4-week period after the 4th dose of 
study drug for whom this level of effect is sustained throughout the 12-week period 
after the 4th dose of study drug 
• proportion of patients reaching at least 75% reduction from baseline (28-day run-in 
period) in the number of migraine days during the 4-week period after the 4th dose of 
study drug for whom this level of effect is sustained throughout the 12-week period 
after the 4th dose of study drug 
• mean change from baseline (28-day run-in period) in the monthly average number of 
days with nausea or vomiting during the 12-week period after the 4th dose of study 
drug 
• mean change from baseline (28-day run-in period) in the monthly average number of 
days with photophobia and phonophobia during the 12-week period after the 4th dose 
of study drug 
• mean change from baseline (28-day run-in period) in the monthly average number of 
days of use of migraine-specific acute headache medications (triptans and ergot 
compounds) during the 12-week period after the 4th dose of study drug 
• mean change from baseline (28-day run-in period) in the number of migraine days 
during the 12-week period after the 4th dose of study drug for patients who failed 
topiramate for migraine in the past 
• mean change from baseline (28-day run-in period) in the number of migraine days 
during the 12-week period after the 4th dose of study drug for patients who failed 
onabotulinumtoxinA for migraine in the past 
• mean change from baseline (28-day run-in period) in the number of migraine days 
during the 12-week period after the 4th dose of study drug for patients who failed 
valproic acid for migraine in the past 

 
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• mean change from baseline (28-day run-in period) in the number of migraine days 
during the 12-week period after the 4th dose of study drug for patients who failed 
2 to 3 classes of preventive medications in addition to valproic acid for migraine in 
the past 
• proportion of patients reaching at least 50% reduction from baseline (28-day run-in 
period) in the monthly average number of migraine days during the 12-week period 
after the 4th dose of fremanezumab for patients who failed 2 to 3 classes of preventive 
medications in addition to valproic acid for migraine in the past 
• mean change from baseline (day 0) in disability score, as measured by the HIT-6, at 
4 weeks after administration of the 6th dose of study drug 
• mean change from baseline (day 0) in disability score, as measured by the MIDAS 
questionnaire, at 4 weeks after the administration of the 6th dose of study drug 
• mean change from baseline (day 0) in quality of life, as measured by the MSQOL 
questionnaire, at 4 weeks after administration of the 6th dose of study drug 
• mean change from baseline (day 0) in the health status, as measured by the 
EQ-5D-5L questionnaire at 4 weeks after administration of the 6th dose of study drug 
• mean change from baseline (day 0) in patient depression status, as measured by the 
PHQ-2 and PHQ-9, at 4 weeks after administration of the 6th dose of study drug 
• mean change from baseline (day 0) in patient work productivity and activity 
impairment, as measured by the WPAI questionnaire, at 4 weeks after administration 
of the 6th dose of study drug 
• mean change from baseline (day 0) of patient satisfaction, as measured by the PGIC 
scale, at 4 weeks after the last 6th dose of study drug 
The exploratory endpoints for both the double-blind and open-label periods are as follows: 
• to evaluate the immunogenicity response of fremanezumab and the impact of ADAs 
on clinical outcomes in patients exposed to sc fremanezumab.  
• to explore the relationship between genetic polymorphisms (including those within 
the calcitonin gene-related peptide (CGRP) receptor-ligand complex, in migraine-
associated susceptibility genes, and in as-yet undiscovered loci) versus migraine 
onset/severity, adverse events to medication and fremanezumab efficacy 
• to explore the relationship between  exploratory biofluid biomarkers versus 
fremanezumab concentrations, adverse events and fremanezumab efficacy 

 
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3. 
GENERAL STUDY DESIGN AND STUDY SCHEMATIC 
DIAGRAM 
This is a multicenter, randomized, double-blind, parallel-group, placebo-controlled study with an 
open-label period to evaluate the efficacy, safety, and tolerability of monthly and quarterly sc 
fremanezumab compared with placebo in patients with CM and EM with inadequate response to 
prior preventive treatments.  
The study will consist of a screening visit, a run-in period (28 days), a 12-week double-blind, 
placebo-controlled treatment period, a 12-week open-label period, and a follow-up visit 
6.0 months after the last dose of fremanezumab for ADA blood sample collection. 
At the end of the open-label treatment period (4 weeks after the last dose) an end of treatment 
study visit (visit 8) will be scheduled and patients should return to the care of their treating 
physicians. Patients should be treated with standard of care after withdrawal from or termination 
of the 24-week treatment period/study, as appropriate. 
Double-blind period 
At the baseline visit (visit 2), patients will be randomly assigned to a treatment group with 
fremanezumab (2 different dose regimens) or placebo in a 1:1:1 ratio as follows: 
• For patients with CM: 
− sc administration of 675 mg of fremanezumab at visit 2 followed by monthly sc 
administration of 225 mg of fremanezumab for 2 months or 
− sc administration of 675 mg of fremanezumab at visit 2 followed by monthly sc 
administration of matching placebo for 2 months or  
− 3 monthly doses of matching placebo 
• For patients with EM: 
− sc administration of fremanezumab at 225 mg plus 2 matching placebo injections 
as first dose followed by monthly sc administration of 225 mg of fremanezumab 
for 2 months or 
− sc administration of fremanezumab at 675 mg as first dose followed by monthly 
sc administration  of matching placebo for 2 months or 
− 3 monthly doses of matching placebo 
Randomization and treatment assignment for the double-blind period will be performed using 
electronic interactive response technology (IRT). The study will be stratified based on CM or 
EM, gender, country, and a special treatment failure group defined as patients who must have 
had inadequate response to valproic acid. In addition, patients in the special treatment failure 
group must have had inadequate response to 2 to 3 other classes of migraine preventive 
medications as defined in Appendix H.  
The proportion of CM and EM patients in the study should be approximately 50:50 in each 
subgroup.  

 
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CM is defined as: 
Patient fulfills the following criteria for CM in prospectively collected baseline information 
during the 28-day run-in period: 
• Headache occurring on ≥15 days 
• Οn ≥8 days, fulfilling any of the following: 
− ICHD-3 diagnostic criteria C and D for 1.1 Migraine without aura (Appendix U) 
− ICHD-3 criteria B and C for 1.2 Migraine with aura (Appendix U) 
− Probable migraine (a migraine subtype where only 1 migraine criterion is 
missing) 
− The patient used a triptan or ergot derivative to treat established headache. 
EM is defined as: 
The patient fulfills the following criteria for EM in prospectively collected baseline information 
during the 28-day run-in period: 
• Headache occurring ≥6 days but <15 
• On ≥4 days, fulfilling any of the following: 
− ICHD-3 diagnostic criteria C and D for 1.1 Migraine without aura 
− ICHD-3 criteria B and C for 1.2 Migraine with aura 
− Probable migraine (a migraine subtype where only 1 migraine criterion is 
missing) 
− The patient used a triptan or ergot derivative to treat an established headache 
Blinded treatment will be administered sc once a month (approximately every 28 days) for a total 
of 3 doses (visits 2,3, and 4)  
Open-label period 
After visit 4, all patients completing the double-blind period will enter the open-label period. All 
patients (CM and EM) will receive sc 225 mg of fremanezumab monthly for 3 months (visits 5, 
6, and 7). 
The open-label period will not be randomized as all patients will receive the same monthly dose 
(225 mg fremanezumab). 
Open-label treatment will administered for a total of 3 doses (visits 5, 6, and 7). Final study 
assessments will be performed at visit 8 (end-of-treatment [EOT] visit), approximately 4 weeks 
after administration of last dose of fremanezumab.  
Follow up period 
A follow-up visit will be scheduled 6.0 months (> 5 half-lives) after the last study drug 
administration for ADA blood sampling. Patients who discontinue early will have the follow-up 
visit 6.0 months after the last dose. 

 
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The total duration of patient participation in the study is planned to be 50 weeks including a run-
in period lasting 28 days, a double-blind treatment period lasting 12 weeks, an open-label period 
lasting 12 weeks, and 1 follow-up visit at week 46. 
Patients are expected to complete the entire duration of the study, including the open-label period 
and the follow-up visit. 
The end of study is defined as the last visit of the last patient (follow-up visit, visit 9). However, 
an interim database lock will occur following the end of the double-blind treatment period of the 
last patient for analysis of that portion of the study data. A second interim lock will occur 
following the end of the open-label period. 
The total study duration, including the 6.0-month follow-up-period, will be approximately 
2 years (from approximately 4Q 2017 to 4 Q 2019). 
The study schematic diagram for patients with CM is presented in Figure 1 and for patients with 
EM in Figure 2. 
Figure 1: 
Overall Study Schematic Diagram for Patients with Chronic Migraine 
 
EOT=end of treatment; PBO=placebo; V=visit. 
 
Week 46 

 
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Figure 2: 
Overall Study Schematic Diagram for Patients with Episodic Migraine 
 
EOT=end of treatment; PBO=placebo; V=visit. 
3.1. 
Planned Number of Patients and Countries 
Approximately 804 patients (268 patients per treatment group) are planned to be enrolled in this 
study to have approximately 705 completers (235 completers per treatment group). A 12% 
drop-out rate is anticipated. 
The study is planned to be conducted in approximately 15 countries in 
approximately120 investigational centers. 
3.2. 
Justification for Study Design and Selection of Population 
The study population will be composed of female and male patients, aged 18 to 70 years, 
inclusive, with a history of migraine (as defined by International Classification of Headache 
Disorders, 3rd revision [ICHD-3] criteria [IHS 2013]) for at least 12 months prior to screening 
and diagnosis of EM and CM prospectively documented via a review of headache data recorded 
daily in an electronic headache diary device during a 28-day run-in period. In addition, patients 
need to have documented history of inadequate response to 2 to 4 classes of prior preventive 
medication treatments for migraine and a subset of patients (at least 120) will have documented 
inadequate response to 2 to 3 classes of prior preventive medications and in addition inadequate 
response to valproic acid. All inadequate responses must be within the past 10 years (in medical 
chart or by treating physician’s confirmation, see Appendix I. Fremanezumab is expected to be a 
later line treatment in the EU. This study is intended to generate data for that specific population 
defined within EM and CM. 
The same dosing regimens used in the phase 3 studies will be investigated in the double-blind 
period. One of the dosing regimens from the phase 3 studies expected to be efficacious for this 
study population will be used in the open-label period. 
A randomized, double-blind, parallel-group, placebo-controlled design is appropriate given the 
objectives of this study. Furthermore, this design is consistent with the recommendations of the 
Week 46 

 
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Classifications Committee of the IHS for controlled trials of preventive drugs in migraine 
(Tfelt-Hansen et al 2012). 
3.3. 
Stopping Rules for the 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 centers to identify safety concerns. 
The study may be terminated by the sponsor for any reason at any time. For example, the 
sponsor should terminate the study in the event of: 
• new toxicological or pharmacological findings or safety issues invalidating the earlier 
positive benefit-risk assessment 
• development of the IMP being discontinued 
A patient may discontinue participation in the study at any time for any reason (eg, lack of 
efficacy, consent withdrawn, or adverse event). The investigator and/or sponsor can withdraw a 
patient from the study at any time for any reason (eg, protocol deviation as defined in 
Appendix C, noncompliance, or adverse event). In addition, patients with positive eC-SSRS 
findings or abnormal hepatic laboratory values (eg, alanine aminotransferase [ALT], aspartate 
aminotransferase [AST], alkaline phosphatase [ALP], gamma-glutamyl transpeptidase [GGT], 
bilirubin [total, direct, or indirect], or international normalized ratio [INR]) may meet criteria for 
discontinuation from the IMP as summarized in Appendix R.  
3.4. 
Schedule of Study Procedures and Assessments 
Study procedures and assessments with their time points are presented in Table 2. 
Note that blood samples for plasma drug concentration determination will be collected prior to 
dosing (where applicable) at visits 2, 3, 4, 5, 6, and 8. 
Detailed descriptions of each method of procedures and assessments are provided in Section 6 
(efficacy assessments), Section 7 (safety assessments), and Section 8 (pharmacokinetic and other 
assessments). Study procedures and assessments by visit are listed in Appendix B. 

 
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Table 2: 
Study Procedures and Assessments 
Study period 
Pretreatment 
(incl. screening 
visit and run-in 
period) 
Double-blind treatment period 
Open-label period 
 
Follow up 
period 
Visit number 
V1 
V2a 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
Day and allowed time 
windows 
Screening 
(Days -28 to -1) 
Month 0 
(Day 0+3 
days) 
Month 1 
(Day 28±3 
days) 
Month 2 
(Day 56±3 
days) 
Month 3 
(Day 84±3 
days) 
Month 4 
(Day 112±5 
days) 
Month 5 
(Day 140±5 
days) 
End of 
Treatment/ 
Early 
termination 
(Day 168±5 
days) 
6.0 months 
after the last 
dose of IMP 
(Day 320±15 
days) 
Procedures and 
assessments 
Screening 
Week -4 
Baseline 
Week 0 
Week 4 
Week 8 
Week 12 
Week 16 
Week 20 
Week 24 
Week 46 
Informed consent 
X 
 
 
 
 
 
 
 
 
Inclusion and exclusion 
criteria 
X 
X 
 
 
 
 
 
 
 
Assign 
randomization/treatment 
number 
 
X 
 
 
 
 
 
 
 
Medical and psychiatric 
history 
X 
 
 
 
 
 
 
 
 
Record demographic 
characteristics 
X 
 
 
 
 
 
 
 
 
Prior medication and 
treatment historyb 
X 
 
 
 
 
 
 
 
 
Clinical laboratory tests 
(serum chemistry, 
hematology and 
coagulation, urinalysis) 
X 
X 
X 
 
X 
X 
 
X 
 
Physical examination, 
including height and 
weightc 
X 
X 
 
 
X 
 
 
X 
 
12-Lead ECGd  
X 
X 
 
 
X 
 
 
X 
 
Vital signs measuremente, f  
X 
X 
X 
X 
X 
X 
X 
X 
X 

 
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Study period 
Pretreatment 
(incl. screening 
visit and run-in 
period) 
Double-blind treatment period 
Open-label period 
 
Follow up 
period 
Visit number 
V1 
V2a 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
Day and allowed time 
windows 
Screening 
(Days -28 to -1) 
Month 0 
(Day 0+3 
days) 
Month 1 
(Day 28±3 
days) 
Month 2 
(Day 56±3 
days) 
Month 3 
(Day 84±3 
days) 
Month 4 
(Day 112±5 
days) 
Month 5 
(Day 140±5 
days) 
End of 
Treatment/ 
Early 
termination 
(Day 168±5 
days) 
6.0 months 
after the last 
dose of IMP 
(Day 320±15 
days) 
Procedures and 
assessments 
Screening 
Week -4 
Baseline 
Week 0 
Week 4 
Week 8 
Week 12 
Week 16 
Week 20 
Week 24 
Week 46 
Serum β-HCG testg 
X 
 
 
 
 
 
 
X 
 
Urine pregnancy testg 
 
X 
X 
X 
X 
X 
X 
X 
  
FSHh 
X 
 
 
 
 
 
 
 
 
Inform patients of study 
restrictions and compliance 
requirements 
X 
 
 
 
 
 
 
 
 
Review study compliancef 
 
X 
X 
X 
X 
X 
X 
X 
 
Provide electronic 
headache diaryi 
X 
 
 
 
 
 
 
 
 
Complete electronic 
headache diary entriesj  
X 
 
 
 
 
 
 
X 
 
Review electronic headache 
diaryf 
 
X 
X 
X 
X 
X 
X 
X 
 
Return headache diary 
device 
 
 
 
 
 
 
 
X 
 
Blood samples for plasma 
concentration of IMPk 
 
X 
X 
X 
X 
X 
 
X 
 
Blood samples for serum 
ADA assessmentl 
 
X 
X 
 
X 
X 
 
X 
X 

 
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Study period 
Pretreatment 
(incl. screening 
visit and run-in 
period) 
Double-blind treatment period 
Open-label period 
 
Follow up 
period 
Visit number 
V1 
V2a 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
Day and allowed time 
windows 
Screening 
(Days -28 to -1) 
Month 0 
(Day 0+3 
days) 
Month 1 
(Day 28±3 
days) 
Month 2 
(Day 56±3 
days) 
Month 3 
(Day 84±3 
days) 
Month 4 
(Day 112±5 
days) 
Month 5 
(Day 140±5 
days) 
End of 
Treatment/ 
Early 
termination 
(Day 168±5 
days) 
6.0 months 
after the last 
dose of IMP 
(Day 320±15 
days) 
Procedures and 
assessments 
Screening 
Week -4 
Baseline 
Week 0 
Week 4 
Week 8 
Week 12 
Week 16 
Week 20 
Week 24 
Week 46 
Blood collection for serum, 
plasma, and RNA 
biomarker analysis 
 
X 
X 
 
X 
X 
 
X 
 
Urine collection for 
biomarker analysis 
 
X 
X 
 
X 
X 
 
X 
 
Saliva sample for 
biomarker analysis 
 
X 
X 
 
X 
X 
 
X 
 
Blood samples for 
pharmacogeneticsm 
 
X 
 
 
 
 
 
 
 
HIT-6 
 
X 
X 
 
X 
 
 
X 
 
MIDAS 
 
X 
X 
 
X 
 
 
X 
 
PHQ-2/PHQ-9n 
 
X 
 
 
X 
 
 
X 
 
MSQOL questionnaire 
 
X 
X 
 
X 
 
 
X 
 
EQ-5D-5L questionnaire 
 
X 
 
 
X 
 
 
X 
 
PGIC scale 
 
 
X 
 
X 
 
 
X 
 
WPAI questionnaire 
 
X 
 
 
X 
 
 
X 
 
eC-SSRSo, f 
X 
 
X 
X 
X 
X 
X 
X 
 
Adverse events f, p and 
health care resource 
utilization inquiry 
 
X 
X 
X 
X 
X 
X 
X 
X 
Administration of IMP 
 
X 
X 
X 
X 
X 
X 
 
 

 
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Study period 
Pretreatment 
(incl. screening 
visit and run-in 
period) 
Double-blind treatment period 
Open-label period 
 
Follow up 
period 
Visit number 
V1 
V2a 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
Day and allowed time 
windows 
Screening 
(Days -28 to -1) 
Month 0 
(Day 0+3 
days) 
Month 1 
(Day 28±3 
days) 
Month 2 
(Day 56±3 
days) 
Month 3 
(Day 84±3 
days) 
Month 4 
(Day 112±5 
days) 
Month 5 
(Day 140±5 
days) 
End of 
Treatment/ 
Early 
termination 
(Day 168±5 
days) 
6.0 months 
after the last 
dose of IMP 
(Day 320±15 
days) 
Procedures and 
assessments 
Screening 
Week -4 
Baseline 
Week 0 
Week 4 
Week 8 
Week 12 
Week 16 
Week 20 
Week 24 
Week 46 
Hypersensitivity/ 
Anaphylaxisq 
 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant medication 
inquiryf  
 
X 
X 
X 
X 
X 
X 
X 
X 
a  All visit 2/baseline procedures must be performed before study drug administration and health care resource utilization inquiry. Inquiries about adverse events will be made 
before and after study drug administration. Post-dose inquiries will be made before the patient leaves the study center. 
b  Collection of prior medications is limited to those medications administered within 6 months before study drug administration (visit 2) and preventive medications taken within 
10 years. 
c  Height will be measured only at the screening visit. 
d  Electrocardiograms will be performed in triplicate. Procedure will be performed before other assessments (eg, blood draws and administration of questionnaires). The ECGs 
should be performed after the patient has been supine for at least 5 minutes. 
e  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. 
f  Procedures for unscheduled visits. 
g  Women of child bearing potential only. 
h  Postmenopausal women only. 
i  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. 
j  Patients will complete electronic headache diary entries about the previous day daily beginning on day -27 through the EOT/ early termination visit. 
k  Blood samples for plasma drug concentration determination will be collected prior to dosing (as applicable) at visits 2, 3, 4, 5, 6, and 8. 
l  Blood samples for serum ADA assessment will be collected prior to dosing (as applicable) at visits 2, 3, 5, 6, 8, and 9 and will also be collected upon observation of any severe 
hypersensitivity reaction i.e., severe hypersensitivity reaction and anaphylaxis. 
m  A single blood sample for pharmacogenomic analysis will be collected at visit 2, before study drug administration from patients who consent to this procedure. A separate 
informed consent form for pharmacogenomic sampling must be signed by the patient.  
n   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. 
o  The eC-SSRS Baseline/Screening version will be completed at visit 1 and the eC-SSRS Since Last Visit version will be completed at all other visits. 
p  Inquiries about adverse events will be made before and after study drug administration. Post-dose inquiries will be made before the patient leaves the study center. 

 
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q  Patients will be assessed for severe hypersensitivity/anaphylaxis reaction during and after administration of the IMP. Oxygen saturation and respiratory rate will be measured in 
cases of suspected anaphylaxis and severe hypersensitivity. See further details in Appendix S. 
ADA=anti-drug antibodies; 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; IMP=investigational medicinal 
product; 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.  

 
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4. 
SELECTION AND WITHDRAWAL OF PATIENTS 
Prospective waivers (exceptions) from study inclusion and exclusion criteria to allow patients to 
be randomized/enrolled are not granted by Teva (Appendix C). 
4.1. 
Patient Inclusion Criteria 
Patients may be included in the study only if they meet all of the following criteria: 
a. The patient is capable of giving signed informed consent. 
b. Male or female patient aged 18 to 70 years, inclusive. 
c. The patient has a diagnosis of migraine with onset at ≤50 years of age. 
d. The patient is in good health in the opinion of the investigators as determined by 
medical history, physical examination, laboratory tests, and ECG. 
e. Body weight ≥45 kg and body mass index (BMI) within the range 17.5 to 34.9 kg/m2 
(inclusive). 
f. The patient has a history of migraine (according to ICHD-3 criteria [IHS 2013]) or 
clinical judgment suggests a migraine diagnosis (not better accounted for by another 
ICHD-3 diagnosis) for ≥12 months prior to screening. 
g. The patient fulfills the following criteria for CM or EM in prospectively collected 
baseline information during the 28-day run-in period: 
For 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 
○ ICHD-3 criteria B and C for 1.2 Migraine with aura 
○ Probable migraine (a migraine subtype where only 1 migraine criterion is 
missing) 
○ The patient used a triptan or ergot derivative to treat an established headache 
For patients with EM: 
−  Headache occurring on ≥6 days but <15 
− On ≥4 days, fulfilling any of the following: 
○ ICHD-3 diagnostic criteria C and D for 1.1 Migraine without aura 
○ ICHD-3 criteria B and C for 1.2 Migraine with aura 
○ Probable migraine (a migraine subtype where only 1 migraine criterion is 
missing) 

 
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○ The patient used a triptan or ergot derivative to treat an established headache 
h. At the time of screening, the patient must have documented inadequate response to 
2 to 4 classes of prior preventive migraine medications (as defined in Appendix H) 
within the past 10 years (in medical chart or by treating physician’s confirmation; see 
Appendix I for acceptable documentation of previous treatment failure). Inadequate 
response to prior preventive migraine medications (including valproic acid) is defined 
as: no clinically meaningful improvement per treating physician’s judgment, after at 
least 3 months of therapy at a stable dose considered appropriate for migraine 
prevention according to accepted country guidelines, or when treatment has to be 
interrupted because of adverse events that made it intolerable for the patient, or the 
medication (as defined in Appendix H) is contraindicated or unsuitable for the 
prophylactic treatment of migraine for the patient. The 3- month period does not 
apply if the drug is intolerable or contraindicated. If onabotulinumtoxinA is the 
previous preventive medication, at least 2 sets of injections and 3 months must have 
passed since the last set of injections prior to the screening visit.  
i. The patient agrees not to initiate any preventive migraine medications (as defined in 
Appendix H) during the run-in period, double-blind treatment period, and open-label 
period. At the screening visit, at least 5 half-lives of these medications must have 
passed since the patient has been on any migraine preventive medication as defined in 
Appendix H. 
j. Other prescription medications not in Appendix H must have been on stable doses for 
at least 2 months at the screening visit with no expectation to change during the 
double-blind treatment period of the study. 
k. The patient demonstrated compliance with the electronic headache diary during the 
run-in period by entry of headache data on a minimum of 24 days cumulative during 
the run-in period (~85% diary compliance). 
l. Women may be included only if they have a negative serum beta-human chorionic 
gonadotropin (β-HCG) test at screening, are sterile, or postmenopausal. Definitions of 
sterile and postmenopausal are given in Appendix E. 
m. Women of childbearing potential (WOCBP) whose male partners are potentially 
fertile (ie, no vasectomy) must use highly effective birth control methods for the 
duration of the study and the follow-up period (ie, starting at screening) and for 
6.0 months after discontinuation of IMP (for details of WOCBP, sterile, and 
postmenopausal women, see Appendix E). 
n. Men must be sterile, or if they are potentially fertile/reproductively competent (not 
surgically [eg, vasectomy] or congenitally sterile) and their female partners are of 
childbearing potential, must use, together with their female partners, acceptable birth 
control methods for the duration of the study and for 6.0 months after discontinuation 
of the IMP. 

 
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o. 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 evaluations, as specified in this protocol. 
4.2. 
Patient Exclusion Criteria 
Patients will be excluded from participating in this study if they meet any of the following 
criteria: 
a. At the time of screening visit, patient is receiving any preventive migraine 
medications, regardless of the medical indication (as defined in Appendix H) for 
more than 5 days and expects to continue with these medications.  
b. Patient has received onabotulinumtoxinA for migraine or for any medical or cosmetic 
reasons requiring injections in the head, face, or neck during the 3 months before 
screening visit.  
c. The patient uses medications containing opioids (including codeine) or barbiturates 
(including butalbital/aspirin/caffeine [Fiorinal®, Actavis plc], 
butalbital/paracetamol/caffeine [Fioricet®, Cardinal Health], or any other combination 
containing butalbital) on more than 4 days during the run-in period for the treatment 
of migraine or for any other reason. 
d. The patient has used an intervention/device (eg, scheduled nerve blocks and 
transcranial magnetic stimulation) for migraine during the 2 months prior to 
screening. 
e. The patient uses triptans/ergots as preventive therapies for migraine. 
f. Patient uses non-steroidal anti-inflammatory drugs (NSAIDs) as preventive therapy 
for migraine on nearly daily basis for other indications. Note: Low dose aspirin (eg, 
81 mg) used for cardiovascular disease prevention is allowed. 
g. The patient suffers from unremitting headaches, defined as having headaches for 
more than 80% of the time he/she is awake, and less than 4 days without headache 
per month. Daily headache is acceptable if patient has headaches 80% or less of the 
time he/she is awake on most days. 
h. The patient has a clinically significant hematological, cardiac, renal, endocrine, 
pulmonary, gastrointestinal, genitourinary, neurologic, hepatic, or ocular disease that, 
in the opinion of the investigator, could jeopardize or would compromise the patient’s 
ability to participate in this study. 
i. Evidence or medical history of clinically significant psychiatric issues that, in the 
opinion of the investigator, could jeopardize or would compromise the patient’s 
ability to participate in this study including major depression, panic disorder, or 
generalized anxiety disorder, any suicide attempt in the past or suicidal ideation with 
a specific plan the past two years prior to screening or current suicidal ideation as 
measured by eC-SSRS.  

 
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j. History of clinically significant cardiovascular disease or vascular ischemia (such as 
myocardial, neurological [e.g., 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. 
k.  History of human immunodeficiency virus, tuberculosis, or chronic hepatitis B or C 
infection. 
l. Past or current history of cancer, except for appropriately treated non-melanoma skin 
carcinoma in the last 5 years. 
m. Pregnant or lactating female patients or female patients who plan to become pregnant 
during the study. 
n. Participation in a clinical study of a new chemical entity or a prescription medicine 
within 2 months before screening (or 3 months in case of biologics if the half-life of 
the biologics is unknown) or 5 half-lives, whichever is longer, or is currently 
participating in another study of an IMP (or a medical device). 
o. Any prior exposure to a monoclonal antibody targeting the CGRP pathway (such as 
AMG 334, ALD304, LY2951742, or fremanezumab). 
p. Any finding in the baseline 12-lead ECG considered clinically significant in the 
judgment of the investigator. 
q. 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). 
r. Hepatic enzymes (alanine aminotransferase, aspartate aminotransferase, and alkaline 
phosphatase) >1.5 × the upper limit of the normal (ULN) range after confirmation in 
a repeat test or suspected hepatocellular damage that fulfills criteria for Hy’s law at 
screening. 
s. Serum creatinine >1.5 × the ULN, clinically significant proteinuria, or evidence of 
renal disease at screening. 
t. The patient has a history of alcohol abuse during the 2 years prior to screening. 
u. The patient has a history of drug abuse during the past 2 years or drug dependence 
during the past 5 years.  
v. 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 tutelage, or being 
admitted to a sanitarium or social institution 
− unable to be contacted in case of emergency 

 
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− has any other condition, which, in the opinion of the investigator, makes the 
patient inappropriate for inclusion in the study 
w. The patient is a study center or sponsor employee who is directly involved in the 
study or the relative of such an employee. 
x. The patient has been previously screen failed for the study. 
4.3. 
Withdrawal Criteria and Procedures for the Patient 
Each patient is free to withdraw from the study or discontinue from the IMP at any time, without 
prejudice to their continued care. Patients must be withdrawn from the IMP and/or study if any 
of the following events occur: 
1. Patient withdraws consent or requests discontinuation from the IMP or withdrawal from 
the study for any reason. 
2. Patient develops an illness that would interfere with his/her continued participation. 
3. Patient is noncompliant with the study procedures and assessments or administration of 
IMPs in the opinion of the investigator. 
4. Patient takes prohibited concomitant medications as defined in this protocol. 
5. A female patient has a confirmation of pregnancy during the study from a positive 
pregnancy test. 
6. The sponsor requests withdrawal of the patient. 
7. Patient experiences an adverse event or other medical condition which indicates to the 
investigator that continued participation is not in the best interest of the patient. 
Patients should be treated with standard of care after withdrawal from or termination of the study 
as appropriate. 
Investigators should attempt to obtain information on patients in the case of withdrawal from the 
study or discontinuation from IMP. Results of any evaluations and observations, together with a 
narrative describing the reason(s) for withdrawal from the study or discontinuation from IMP, 
must be recorded in the source documents. The case report form (CRF) must document the 
primary reason for withdrawal from the study or discontinuation from IMP. 
For information regarding how the study will define and address lost to follow-up patients to 
help limit the amount and impact of missing data, see Appendix F. 
If the reason for withdrawal from the study or discontinuation from IMP is an adverse event 
and/or clinically significant abnormal laboratory test result, monitoring will be continued as 
applicable (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 IMP or study 
procedure is made). The specific event or test result (including repeated test results, as 
applicable) must be recorded both on the source documentation and in the CRF; both the adverse 
events page and the relevant page of the CRF will be completed at that time. 

 
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The investigator must inform the Sponsor or delegate as soon as possible of each patient who is 
being considered for withdrawal due to adverse events. Additional reports must be provided 
when requested. 
If a patient is withdrawn from the study or discontinues IMP for multiple reasons that include 
also adverse events, the relevant 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. 
In the case of patients lost to follow-up, attempts to contact the patient must be made and 
documented in the patient’s medical records and transcribed to the CRF. 
All protocol-specified procedures/assessments should be performed at the EOT/ early withdrawal 
visit (see Table 2). Patients who withdraw from the study will be instructed to come back to the 
site for blood sample collection for the purpose of evaluating ADA 6.0 months (180 days [the 
approximate equivalent of 5 half-lives]) after their last dose of study drug. 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). 
4.4. 
Replacement of Patients 
A patient who is randomized/enrolled but does not complete the treatment period will not be 
replaced with another eligible patient. 
4.5. 
Rescreening 
A patient who is screened and does not meet study inclusion and exclusion criteria will not be 
considered for screening again. 
4.6. 
Screening Failure 
Screening failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomized/enrolled in the study. Minimal information includes but is not 
limited to demography, screening failure details, eligibility criteria, and any serious adverse 
events. 

 
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5. 
TREATMENTS 
5.1. 
Investigational Medicinal Products Used in the Study 
Investigational medicinal products are defined as the test IMP (fremanezumab) and matching 
placebo IMP. A summary of IMPs used in the study is presented in Table 3. Additional details 
may be found in the Investigator’s Brochure for fremanezumab. 
Table 3: 
Investigational Medicinal Products Used in the Study 
IMP name 
Recombinant humanized 
IgG2a/kappa mAb  
Test IMP 
Fremanezumab 
Placebo IMP 
Placebo 
Trade name and INN, if 
applicable, or 
company-assigned number 
Fremanezumab 
Known also as: TEV-48125, LBR-101, 
PF-04427429, RN307 
Placebo 
Formulation 
 
Prefilled syringes contain 1.5 mL 
solution for injection with 150 mg/mL 
(ie 225 mg total) of active ingredient 
fremanezumab 
Inactive ingredients include: 
L-histidine, sucrose, polysorbate-80, 
ethylenediaminetetraacetic 
acid (EDTA) and water for injection 
Prefilled syringes contain 1.5 mL of 
the same vehicle and excipients as 
those for active injection. 
Inactive ingredients include: 
L-histidine, sucrose, polysorbate-80, 
ethylenediaminetetraacetic 
acid (EDTA) and water for injection 
Unit dose strength(s)/Dosage 
level(s) 
225 mg/1.5 mL 
None 
Route of administration 
sc injection 
sc injection 
Dosing instructions/Dosing 
schedule/Titration 
periods/Treatment periods for 
the double-blind period 
For CM patients: A dose of 675 mg 
fremanezumab as 3 active injections 
(225 mg/1.5 mL) at visit 2 and 225 mg 
fremanezumab as 1 active injection 
(225 mg/1.5 mL) at visits 3 and 4. 
Or a dose of 675 mg fremanezumab as 
3 active injections (225 mg/1.5 mL) at 
visit 2 
No placebo injections 
 
 
 
 
Single 1.5-mL placebo injection at 
visits 3 and 4 
For EM patients: 225 mg 
fremanezumab as 1 active injection 
(225 mg/1.5 mL) at visit 2, 3, and 4 
Or a dose of 675 mg fremanezumab as 
3 active injections (225 mg/1.5 mL) at 
visit 2 
Two 1.5-mL placebo injections at 
visit 2 
 
Single 1.5-mL placebo injection at 
visits 3 and 4 
For both CM and EM patients who 
are on treatment placebo only: 
No active injections 
Three 1.5-mL placebo injections at 
visit 2 and a single 1.5-mL placebo 
injection at visits 3 and 4 

 
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IMP name 
Recombinant humanized 
IgG2a/kappa mAb  
Test IMP 
Fremanezumab 
Placebo IMP 
Placebo 
Dosing instructions/Dosing 
schedule/Titration 
periods/Treatment periods for 
the open-label period 
For all CM and EM patients:  
225 mg fremanezumab as 1 active 
injection (225 mg/1.5 mL) at visits 5, 
6, and 7 
No placebo injections 
Packaging 
A kit uniquely numbered containing 1 
prefilled syringe stored (refrigerated at 
2°C to 8°C) on site 
A kit uniquely numbered containing 
1 prefilled syringe stored 
(refrigerated at 2°C to 8°C) on site 
Manufacturer 
Drug Substance: 
Celltrion 
23, Academy-ro 
Yeonsu-gu, Incheon, 
South Korea 
 
Drug Product: 
Vetter Pharma Fertigung GmbH & Co. 
KG  
Schuetzenstrasse 87, 99-101, 
Ravensburg,  
Baden-Wuerttemberg 88212 
Germany 
Vetter Pharma Fertigung GmbH & Co. 
KG Mooswiesen 2, Ravensburg, 
Baden-Wuerttemberg 88214, Germany  
Vetter Pharma Fertigung GmbH & 
Co. KG  
Schuetzenstrasse 87, 99-101, 
Ravensburg,  
Baden-Wuerttemberg 88212 
Germany 
 
Vetter Pharma Fertigung GmbH & 
Co. KG Mooswiesen 2, Ravensburg, 
Baden-Wuerttemberg 88214, 
Germany 
CM=chronic migraine; EDTA=ethylene diamine tetra acetate; EM=episodic migraine; IMP=Investigational 
Medicinal Product; INN=international nonproprietary name; mAb=monoclonal antibody; sc=subcutaneous. 
Individual, uniquely numbered 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). 
Recommended sc injection sites follow the National Institutes of Health Patient Education 
Guidelines of June 2012 (see Appendix V). 
The suggested sites of injection are back of upper arms, lower abdomen/belly/waistline, and 
front of thighs. Each of the injections should be given in a different location (eg, not in precisely 
the same place/not on top of the previous injection site), 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 45-60 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 on the CRF for each dosing visit 
(visits 2, 3, 4, 5, 6, and 7). 

 
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5.1.1. 
Test Investigational Medicinal Product (Fremanezumab) 
5.1.1.1. 
Starting Dose and Dose Levels 
For the double-blind period, the starting dose for patients with CM will be 675 mg sc and the 
starting dose for patients with EM will be 225 mg sc or 675 mg sc. Further doses of 225 mg or 
placebo will be administered sc once monthly. The maximal dose administered sc per treatment 
will be 675 mg.  
For the open-label period, all patients will receive 225 mg fremanezumab monthly. 
5.1.1.2. 
Dose Modification and Dose Stratification 
No dose modifications were allowed. 
This is a randomized study with stratification based on CM or EM (in the double-blind period), 
gender, country, and a special treatment failure group defined as patients who must have had 
inadequate response to valproic acid. In addition, patients in the special treatment failure group 
must have had inadequate response to 2 to 3 other classes of migraine preventive medications as 
defined in Appendix H.  
The proportion of CM and EM patients in the study should be approximately 50:50 in each 
subgroup.  
The open-label period will not be randomized as all patients will receive the same monthly dose 
(225 mg fremanezumab). 
5.1.2. 
Placebo Investigational Medicinal Product 
Placebo (matching the test IMP fremanezumab) will be provided and administered as described 
in Table 3. 
5.2. 
Preparation, Handling, Labeling, Storage, and Accountability for 
IMPs 
Information pertaining to the preparation, handling, labeling, storage, and accountability for the 
IMP used in this study can be found in Appendix G. 
5.3. 
Justification for Investigational Medicinal Products 
5.3.1. 
Justification for Dose of Test Investigational Medicinal Product 
Three dose regimens of fremanezumab administered sc were tested during 2 Phase 3 pivotal 
studies in the EM and CM patient population. Chronic migraine doses were 675 mg loading 
dose/225 mg monthly or 675 mg quarterly and EM doses were 225 mg monthly or 675 mg 
quarterly.  
During the Phase 2b studies, four dose regimens (ie, EM: monthly 225 mg or 675 mg, and 
CM: monthly 675 mg followed by 225 mg or monthly 900 mg of fremanezumab sc) were tested 
and shown to be effective, safe and well tolerated at the 3 month treatment period. As it is 
considered best practice to select the lower dose for administration from two doses that show 

 
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equivalence in efficacy (to avoid higher dose than necessary) the 2 monthly dose regimens of 
225 mg monthly with 675 mg loading dose (CM) or without loading dose (EM) were used as one 
active arm in each of the Phase 3 studies. A second active arm included in both EM and CM 
studies was 675 mg fremanezumab sc administration once every 3 months. Hence, each study 
retained the lowest effective dose from Phase 2, while exploring different intervals of 
administration. Furthermore, the addition of the quarterly dose regimen, which was a shared dose 
level across the migraine continuum, enabled the exploration of the choice of treatment 
convenience and flexibility for patients and physicians, the change in preference and the 
likelihood of patients’ demand for different treatment options. 
The results of the Phase 3 studies, namely statistically significant differences, equally favoring 
monthly and quarterly fremanezumab compared with placebo for all primary and secondary 
endpoints, demonstrate the efficacy of fremanezumab as a preventive treatment for EM and CM 
in adults. In addition, all active dose regimens showed no significant difference in safety 
parameters.  
Thus, two dose regimens are included in this study: 225 mg monthly (with 675 mg loading dose 
at the start of the CM dose regimen) and 675 mg quarterly to provide patients and physicians 
convenience and flexibility on their treatment options for the preventive treatment of EM and 
CM. 
The 225 mg monthly dosing regimen selected for the open-label period is one of the phase 3 
dosing regimen that was efficacious and well tolerated. The open-label period is intended to 
provide the placebo-treated patients the opportunity to receive potential benefit from therapeutic 
doses. It also provides an opportunity to explore efficacy and tolerability beyond 3 months.  
5.3.2. 
Justification for Use of Placebo Investigational Medicinal Product 
A placebo-controlled design is appropriate given the purpose and objectives of this clinical 
study. Inclusion of a placebo control group is consistent with guidelines for controlled trials of 
prophylactic treatment of migraine in adults (Silberstein et al 2008) and the Classification 
Committee of the IHS guidelines for controlled trials of drugs in migraine, 3rd edition (Tfelt-
Hansen et al 2012). 
5.4. 
Treatment after the End of the Study 
At the end of the 24-week treatment period, it is expected that patients should return to the care 
of their treating physicians. 
Patients will return to the investigational center approximately 6.0 months following 
administration of the last dose of IMP for safety evaluation. No treatment is planned by the 
sponsor after completion of the 24-week treatment period and the study. Patients should be 
treated with standard of care after withdrawal from or termination of the 24-week treatment 
period, as appropriate. 
5.5. 
Restrictions 
Patients will be required to comply with the following restrictions: 

 
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5.5.1. 
Activity 
Patients must remain at the site, for safety observation, at least 60 minutes after injection or 
according to medical judgment.  
5.5.2. 
Blood Donation 
Patients may not donate blood while taking the IMP and for 5 half-lives (6.0 months) after the 
last dose of the IMP. 
5.5.3. 
Pregnancy 
Restrictions in regard to pregnancy and required laboratory values (ie, serum and urine β-HCG 
tests) are provided in the inclusion and exclusion criteria (Section 4.1 and Section 4.2, 
respectively). Restrictions in regard to contraception methods are reviewed in Appendix E. 
5.6. 
Prior and Concomitant Medication or Therapy 
Patients must not be on any migraine prophylactic medications (as defined in Appendix H) at the 
time of screening. At least 5 half-lives must have passed prior to the screening visit. No migraine 
prophylactic medications (as defined in Appendix H) are allowed to be initiated during the run-in 
and double-blind treatment period. Medications listed in Appendix H taken for other reason than 
migraine/headache are also disallowed during the run-in and double-blind period.  
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.  
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 listed in Appendix H that a patient took 
within 10 years before study drug administration will be recorded on the CRF. Generic or trade 
name, indication, and dosage will be recorded. In addition, medical record or treating physician’s 
affidavit (see Appendix I) or signed notes from the principal investigator (if he/she is not the 
treating physician) after interviewing the treating physician, will be required as source 
documents to corroborate patient’s report of inadequate response to 2 to 4 classes of prior 
migraine preventive medications. The sponsor will encode all therapy and medication according 
to the World Health Organization drug dictionary.  
No IMPs other than the ones used in this study or vaccine will be allowed during the study 
including follow-up period. A list of prohibited medications is given in Appendix H. Prescription 
or over the counter drugs to treat adverse events are allowed.  
At each visit at the investigational center after the screening visit, the investigator will ask 
patients whether they have taken any medications (other than IMP[s]), including 
over-the-counter medications, vitamins, or herbal or nutritional supplements, since the previous 
visit. 

 
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5.7. 
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. 
5.8. 
 Randomization and Blinding 
The sponsor, investigators, study staff (except for staff involved in bioanalytical analyses), and 
patients will be blinded to treatment assignment during the double-blind period. A computer-
generated master randomization list will be provided to drug packaging facilities. Packaging 
vendor(s) will package active drug and placebo into single-visit kits according to Good 
Manufacturing Practice procedures. Kits will be identical in appearance and contain 1 prefilled 
syringe with active drug or placebo. Adequate kit supply for upcoming study visits will be 
managed by IRT and kept (refrigerated at 2°C to 8°C) on site. 
In this randomized study, the double-blind period will be stratified based on CM or EM, gender, 
country, and a special treatment failure group defined as patients who must have had inadequate 
response to valproic acid. In addition, patients in the special treatment failure group must have 
had inadequate response to 2 to 3 other classes of migraine preventive medications as defined in 
Appendix H. 
Each patient will undergo randomization in a 1:1:1 ratio within the stratum to which he or she 
belongs to receive 1 of the 2 fremanezumab dose regimens or placebo, as assigned by the IRT. 
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). 
5.9. 
Maintenance of Randomization and Blinding 
5.9.1. 
Maintenance of Randomization 
Patient randomization codes will be maintained in a secure location at the service provider 
contracted to generate the codes. At the time of the final analysis (after the end of study), after 
receiving unblinding request from Teva statistician, the service provider will provide the 
unblinded IMP assignment according to the processes defined in the relevant Standard Operating 
Procedure (SOP). 
5.9.2. 
Blinding and Unblinding 
Blinded 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 5.8. 
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) 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 (in emergency cases) can always be 
performed by the site without prior approval by the sponsor. 
In the event that the IRT system is not functioning for emergency unblinding, the next course of 
action is to contact via phone the IRT on-call customer support helpline for manual emergency 
unblinding. Additional contact details can be found in the pharmacy manual. 
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 document. 
In this study, for adverse events that are defined as: suspected, unexpected, serious, adverse 
reaction (SUSAR) (ie, reasonable possibility; see Section 7.1.4), Global Patient Safety and 
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. 
5.9.3. 
Data Monitoring Committee 
There will be no Data Monitoring Committee in this study. 
5.10. 
Total Blood Volume 
The total blood volume to be collected for each patient in this study is approximately 180.5 mL 
for scheduled tests. Details on total blood volume are provided in Appendix J. 

 
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6. 
ASSESSMENT OF EFFICACY 
Data from any efficacy assessments performed after the specified time will not be collected on 
the CRF. However, in the event that such data are collected, these data will not be analyzed. 
A detailed description of assessments and procedures are presented in Appendix B. 
6.1. 
Assessments of Efficacy 
The primary efficacy endpoint (and secondary and exploratory efficacy endpoints as well) will 
be derived from headache variables collected daily using an electronic headache diary device. 
Eligible patients will receive comprehensive training from site personnel on 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. At least 75% compliance is needed after the 
randomization period. Site personnel will monitor patient’s compliance that at least 75% diary 
entry is met during the double-blind and open-label periods. 
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, at 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 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, then 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. 

 
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6.1.1. 
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 
has been shown to be a reliable and valid tool for assessment of headache impact in patients with 
migraine (Yang et al 2011). 
Patients will complete the HIT-6 at the time points detailed in Table 2. 
6.1.2. 
Migraine Disability Assessment 
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 will complete the MIDAS questionnaire at time points detailed in Table 2. 
6.1.3. 
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 validated measures for detecting and monitoring depression, anxiety, and somatization 
(Kroenke et al 2010). 
Patients will complete the PHQ-2 at the time points detailed in Table 2. If the PHQ-2 is positive 
(ie, a score of ≥3), patients will complete questions 3 through 9 (unique questions) of the PHQ-9. 
6.1.4. 
Migraine-Specific Quality of Life Questionnaire 
The MSQOL version 2.1 is a 14-item questionnaire that assesses 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. 
Patients will complete the MSQOL at the time points detailed in Table 2.  

 
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6.1.5. 
EuroQol-5 Dimension Questionnaire 
The EQ-5D-5L is a standardized questionnaire that assesses overall state of health. The 
EQ-5D-5L consists 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 detailed in Table 2.  
6.1.6. 
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 the time points detailed in Table 2.  
6.1.7. 
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). 
Patients will complete the WPAI questionnaire at the time points detailed in Table 2.  

 
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7. 
ASSESSMENT OF SAFETY 
In this study, safety will be assessed by qualified study personnel by evaluating reported adverse 
events, clinical laboratory test results, vital signs measurements, ECG findings, physical 
examination findings (including body weight measurements), injection site reaction/pain 
assessments, eC-SSRS scores, and use of concomitant medication. 
7.1. 
Adverse Events 
7.1.1. 
Definition of an Adverse Event 
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have to have a causal relationship with 
this treatment. 
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 fremanezumab. 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 
• drug interactions 
• events occurring during diagnostic procedures or during any washout phase 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, require medical treatment or further diagnostic work-up, or are considered by 
the investigator to be clinically significant. 
Note: Abnormal laboratory or diagnostic test results at the screening visit that 
preclude a patient from entering the study or receiving study treatment are not 
considered adverse events. 
• all events of possible drug-induced liver injury with hyperbilirubinemia (defined as 
AST or ALT ≥3 times the ULN, plus either total bilirubin ≥2 times the ULN or INR 
>1.5) or Hy’s Law events require immediate study treatment cessation and reporting 

 
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as a serious adverse event. Refer to Appendix R 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. 
Medical occurrences that begin before signing ICF will be recorded on the medical 
history/current medical conditions section of the CRF 
7.1.2. 
Recording and Reporting of Adverse Events 
For recording of adverse events, the study period is defined for each patient as the time period 
from signature of the informed consent form to the end of the follow-up period. The follow-up 
period of recording of adverse events is defined as 6.0 months after the last dose of IMP. The 
period for reporting treatment-emergent adverse events is defined as the period after the first 
dose of IMP is administered and until end of follow-up period. 
All adverse events that occur during the defined study period must be recorded on the source 
documentation and the CRF, regardless of the severity of the event or judged relationship to the 
IMP. For serious adverse events, and protocol defined adverse events of special interest (see 
Section 7.1.7) the serious and protocol defined adverse event report form must be completed and 
the serious adverse event or protocol defined adverse event of special interest must be reported 
immediately (Section 7.1.5.3). The investigator does not need to actively monitor patients for 
adverse events once the study has ended. Serious adverse events and adverse events of special 
interest occurring in 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, on the 
serious adverse event form. 
The clinical course of each adverse event will be monitored at suitable intervals until resolved, 
stabilized, or returned to baseline; or until the patient is referred for continued care to a health 
care professional; or until a determination of a cause unrelated to the IMP 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 IMP, treatment administered, and outcome for each adverse event must be 
recorded both on the source documentation and the CRF. 

 
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The relationship of each adverse event to IMP and study procedures, and the severity and 
seriousness of each adverse event, as judged by the investigator, must be recorded as described 
below. 
Further details are given in the Safety Monitoring Plan. 
7.1.3. 
Severity of an Adverse Event 
The severity of each adverse event must be recorded as 1 of the following: 
Mild: 
No limitation of usual activities 
Moderate: Some limitation of usual activities 
Severe: 
Inability to carry out usual activities 
For severity grading of local tolerability (injection site erythema, induration, ecchymosis, and 
pain), refer to Section 7.9. 
7.1.4. 
Relationship of an Adverse Event to the Investigational Medicinal Product 
The relationship of an adverse event to the IMP is characterized as described in Table 4. 

 
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Table 4: 
The Relationship of an Adverse Event to the IMP 
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 Investigational Medicinal 
Product (IMP). 
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 IMP. 
• 
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 
IMP. 
• 
It does not reappear or worsen when the IMP 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 administration of IMP 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 IMP. 
• 
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 after 
discontinuation of the IMP, yet an IMP relationship 
clearly exists. 
• 
It follows a known pattern of response to the IMP. 
7.1.5. 
Serious Adverse Events 
For recording of serious adverse event, the study period is defined for each patient as that time 
period from signature of the informed consent form to the end of the follow-up period. Serious 
adverse events occurring in a patient after the end of the follow-up 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. 
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: 
• results in death 
• is life-threatening adverse event (ie, the patient was at risk of death at the time of the 
event); it does not refer to an event which hypothetically might have caused death if it 
were more severe 

 
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• requires inpatient hospitalization or prolongation of existing hospitalization, which 
means that hospital inpatient admission 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 before the patient signed the informed consent form will 
not be considered serious adverse events, unless there was worsening of the 
preexisting condition during the patient’s participation in this study. 
• results in persistent or significant disability/incapacity (refers to a substantial 
disruption of one’s ability to conduct normal life functions) 
• is 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. 
All occurrences of possible drug-induced liver injury that meet Hy’s law criteria, defined as all 
of the below, must be reported by the investigator to the sponsor as a serious adverse event: 
• alanine aminotransferase (ALT) or aspartate aminotransferase (AST) increase of 
>3x the upper limit of normal (ULN) 
• total bilirubin increase of >2x ULN 
• absence of initial findings of cholestasis (ie, no substantial increase of alkaline 
phosphatase [ALP]) 
• no other explanation for the observed abnormalities 
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 Global Patient Safety and Pharmacovigilance Department will determine the 
expectedness for all serious adverse events. 
For the purpose of SUSAR reporting, the version of the Investigator’s Brochure at the time of 
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 that occur during the study, 
regardless of judged relationship to administration of the IMP, 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 to a patient after the last administration of IMP of that patient 
has ended 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 designee 
(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 and 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 IMP 
(no reasonable possibility, reasonable possibility) 
Additional information includes: 
• age and gender of patient 
• date of first dose of IMP 
• date and amount of last administered dose of IMP 
• action taken 
• outcome, if known 
• severity 
• explanation of assessment of relatedness 
• concomitant medication (including doses, routes of administration, 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 was related to IMP) 
− 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 IMP, study 
procedures, and to underlying disease. 
Additional information (follow-up) about any serious adverse event unavailable at the initial 
reporting should be forwarded by the investigator 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 and Pharmacovigilance Department will 
distribute the Council for International Organizations of Medical Sciences form/extensible 
markup language (XML) file to the LSO and/or CRO for submission to the regulatory 
authorities, IEC/IRBs, and investigators, according to regulations. The investigator is responsible 
for ensuring that the IEC/IRB is also informed of the event, in accordance with national and local 
regulations. 
Blinding will be maintained for people who are involved directly in the study. Therefore, in case 
of a SUSAR, only the LSO or CRO 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 IMP or study procedures, 
the sponsor will take appropriate steps to notify all investigators participating in sponsored 
clinical studies of fremanezumab and the appropriate competent authorities (and IEC/IRB, as 
appropriate). 
In addition to notifying the investigators and competent authorities (and IEC/IRB, as 
appropriate), other action may be required, including the following: 
• altering existing research by modifying the protocol 
• discontinuing or suspending the study 
• modifying the existing consent form and informing all study participants of new 
findings 
• modifying listings of expected toxicities to include adverse events newly identified as 
related to fremanezumab 
7.1.6. 
Protocol-Defined Adverse Events not for Expedited Reporting 
Not applicable. 

 
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7.1.7. 
Protocol-Defined Adverse Events of Special Interest 
For purposes of this protocol, the following treatment emergent events are considered protocol-
defined adverse events of special interest to be sent to the sponsor’s Global Patient Safety and 
Pharmacovigilance Department for evaluation:  
• ophthalmic 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), Hy’s Law events, or  
• events of anaphylaxis and severe hypersensitivity reactions.  
For guidance regarding monitoring of patients with elevated liver function tests, refer to 
Appendix R. Anaphylaxis and severe hypersensitivity 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 S). In the event of suspected anaphylaxis and severe 
hypersensitivity, vital signs, including oxygen saturation and respiration rate, will be measured. 
Other assessments will be performed at the discretion of the investigator. As a precaution, each 
site should have a resuscitation cart nearby. 
The process for reporting a protocol-defined adverse event of special interest is the same as that 
for reporting a serious adverse event (see Section 7.1.5.3). These events to be reported to the 
Global Patient Safety & Pharmacovigilance Department can be either serious or nonserious, 
according to the criteria outlined in Section 7.1.5.1.  
7.1.8. 
Protocol Deviations Because of an Adverse Event 
If a patient experiences an adverse event or medical emergency, deviations from the protocol 
may be allowed on a case-by-case basis. To ensure patient safety, after the event has stabilized or 
treatment has been administered (or both), the investigator or other physician in attendance must 
contact the physician 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. 
7.2. 
Pregnancy 
Any female subject becoming pregnant during the study will discontinue IMP. All pregnancies 
of women participating in the study and female partners of men participating in the study, that 
occur during the study, or within 6.0 months after administration of the last dose of the IMP, 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 sponsor (LSO/CRO) 
with the completed pregnancy form. The process for reporting a pregnancy is the same as that for 
reporting a serious adverse event but using the pregnancy form (Section 7.1.5.3). The 
investigator is not required to report female subjects who are found to be pregnant between 
screening and baseline, provided no protocol-related procedures were applied. 
All female subjects or female partners of men participating in the study who become pregnant 
will be monitored for the outcome of the pregnancy (including spontaneous, elective, or 

 
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voluntary abortion). Female partners of men participating in the study who become pregnant will 
be asked to sign an Informed Consent Form (ICF). 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 withdrawal from the 
study will be reported as an adverse event or serious adverse event, as appropriate. 
If the pregnancy in the woman participating in the study and/or the female partners of men 
participating in the study 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. 
7.3. 
Medication Error and Special Situations Related to the 
Investigational Medicinal Products 
Any administration of IMP that is not in accordance with the study protocol should be reported 
as an important deviation, if it meets the important deviation criteria specified in the protocol 
(Appendix C), it or as a deviation, in the patient’s source documents, regardless of whether or 
not an adverse event occurs as a result. When meeting important protocol deviation criteria, all 
instances of incorrect IMP administration should be categorized in clinical trial management 
system. 
The following are types of medication errors and special situations: 
1. Medication error: Any unintentional error in the prescribing, dispensing, or 
administration of a medicinal product while in the control of the healthcare professional, 
patient, or consumer. 
2. Overdose: Administration of a quantity of a medicinal product given per administration 
or cumulatively which is above the maximum recommended dose according to the 
authorized product information. Clinical judgment should always be applied. Any dose of 
IMP (whether the test IMP or placebo IMP), whether taken intentionally or 
unintentionally, in excess of that prescribed must be immediately reported to the sponsor. 
When the identification of the IMP is required, the investigator must follow the 
procedures for unblinding outlined in Section 5.9.2.  
3. Misuse: Situations where the IMP is intentionally and inappropriately used not in 
accordance with the authorized product information. 
4. Abuse: Persistent or sporadic, intentional excessive use of IMP which is accompanied by 
harmful physical or psychological effects. 
5. Off-label use: Situations where an IMP is intentionally used for a medical purpose not in 
accordance with the authorized product information. 

 
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6. Occupational exposure: Exposure to an IMP, as a result of one’s professional or non-
professional occupation. 
7. Breastfeeding: Suspected adverse reactions which occur in infants following exposure to 
a medicinal product from breast milk. 
7.4. 
Clinical Laboratory Tests 
All clinical laboratory test results outside of the reference range will be judged by the 
investigator as belonging to one of the following categories: 
• abnormal and not clinically significant 
• abnormal and clinically significant 
A laboratory test result that is judged by the investigator as clinically significant will be recorded 
on the source documentation and the CRF as an adverse event, and monitored as described in 
Section 7.1.2. An event may include a laboratory or diagnostic test abnormality (once confirmed 
by repeated testing) that results in the withdrawal of the patient from the study, the temporary or 
permanent withdrawal of IMP or medical treatment, or further diagnostic work-up. Note: 
abnormal laboratory or diagnostic test results at the screening visit that preclude a patient from 
entering the study or receiving IMP are not considered adverse events. 
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. 
Clinical laboratory tests (serum chemistry, hematology, coagulation, and urinalysis) will be 
performed at the time points detailed in Table 2. Clinical laboratory tests will be performed using 
the central laboratory. However, in case of abnormal coagulation during screening (run-in 
period), a local retest can be authorized by the sponsor on a case-by-case basis. Specific 
laboratory tests to be performed are provided in Appendix T. 
7.4.1. 
Other Clinical Laboratory Tests 
7.4.1.1. 
Human Chorionic Gonadotropin Test 
Serum β-HCG tests and urine β-HCG tests will be performed for all women of childbearing 
potential at time points described in Table 2. Any patient who becomes pregnant during the study 
will be withdrawn. Procedures for reporting the pregnancy are provided in Section 7.2. 
7.4.1.2. 
Follicle-Stimulating Hormone Test 
Postmenopausal women will have a follicle-stimulating hormone (FSH) test at screening 
(see Table 2). 
7.4.1.3. 
Saliva Collection 
Saliva samples (~ 1 mL) will be collected using a standardized protocol available in the 
laboratory manual at time points described in Table 2. Care should be taken to freeze at -70°C 
(or at/below -20°C if no -70°C freezer available) the properly collected saliva samples as soon as 
possible (3-5 minutes) after collection from the patient. For additional details see Appendix M. 

 
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7.5. 
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 2. A complete physical examination will 
include the following organ systems: general appearance; head, eyes, ears, nose, and throat; chest 
and lungs; heart; abdomen; musculoskeletal; skin; lymph nodes; and neurological. Any physical 
examination finding that is judged by the investigator as clinically significant (except at the 
screening visit) will be considered an adverse event, recorded on the CRF, and monitored as 
described in Section 7.1.2. 
7.6. 
Vital Signs 
Vital signs (pulse, systolic and diastolic blood pressure, oral temperature, and respiratory rate) 
will be measured at the time points detailed in Table 2. All vital signs results outside of the 
reference ranges will be judged by the investigator as belonging to one of the following 
categories: 
• abnormal and not clinically significant 
• abnormal and clinically significant 
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.  
7.7. 
Electrocardiography 
Twelve-lead ECGs will be conducted before other assessments (eg, blood draws and 
administration of questionnaires) at the time points detailed in Table 2. The ECGs should be 
performed after the patient has been supine for at least 5 minutes. The ECGs will be performed 
in triplicate, with approximately 1 to 5 minutes between recordings.  
A qualified physician at a central diagnostic center will be responsible for interpreting the ECG. 
Electrocardiograms should be performed and transmitted according to the central ECG reading 
instructions provided in the ECG user manual. Electrocardiogram equipment will be provided to 
all clinical sites.  
Although the ECG interpretation will be performed centrally, the clinical evaluation remains 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 

 
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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. 
All ECG results outside of the reference ranges will be judged by the investigator as belonging to 
one of the following categories: 
• abnormal and not clinically significant  
• abnormal and clinically significant 
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 in the CRF, and monitored as described in  Section 7.1.2. 
7.8. 
Immunogenicity 
Blood samples for serum ADA assessment will be collected at the time points detailed in 
Table 2. Only the samples from fremanezumab-treated patients will be analyzed for ADAs. 
Blood samples for ADA assessment will also be collected upon observation of any severe 
hypersensitivity reaction and anaphylaxis. Bioanalytical personnel should be made aware of 
anaphylaxis occurrence as soon as possible in case an anti-fremanezumab IgE assay is needed. 
Clinical criteria for diagnosing anaphylaxis are detailed in Appendix S. 
7.9. 
Assessment of Local Tolerability and Pain 
Spontaneous reports of injection site reactions will be recorded as AEs according to the 
following severity assessment criteria 
• Spontaneous reports of injection-site erythema, induration, and ecchymosis will be 
recorded according to measurements: 5 to ≤50 mm (mild), >50 to ≤100 mm 
(moderate), and >100 mm (severe).  
• Spontaneous report of local pain after the injection will be recorded as mild, moderate 
or severe according to patient’s self-report. 
• Appropriate treatment may be provided if necessary, in which case it must be 
recorded as concomitant medication. 
7.10. 
Assessment of Suicidality 
The study population being administered fremanezumab should be monitored appropriately and 
observed closely for suicidal ideation and behavior or any other unusual changes in behavior. 
Consideration should be given to discontinuing fremanezumab in participants who experience 
signs of suicidal ideation or behavior without relevant medical history. 
Families and caregivers of participants being treated with fremanezumab should be instructed to 
monitor participants for the emergence of unusual changes in behavior, as well as the emergence 

 
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of suicidal ideation and behavior, and to report such symptoms immediately to the study 
investigator. 
The eC-SSRS will be used to assess the patient’s suicidal ideation (severity and intensity) and 
behavior (Posner et al 2011). The time points when the eC-SSRS Baseline/Screening version and 
the eC-SSRS Since Last Visit version will be completed are detailed in Table 2. Any positive 
findings on the eC-SSRS Since Last Visit version requires evaluation by a physician or doctoral-
level psychologist. 
A positive finding will be defined as a current suicide ideation with some intent to act and no 
plan. The investigator, based on his/her medical judgment, will determine if the patient should be 
seen by a mental health specialist and if he/she should continue participating in the study. If a 
patient reports current suicide ideation with specific plan and intent, then the patient should be 
immediately discontinued from the study and seen by a mental health specialist.  
Any patient should be excluded if any suicidal behaviors are reported. 
Any patient with lifetime suicidal behaviors (actual, interrupted, and aborted attempts and 
preparatory actions) should be excluded and/or discontinued from the study. 
7.11. 
Concomitant Therapy or Medication 
Concomitant therapy or medication use will be monitored throughout the study. Details of 
prohibited medications are found in Section 5.6. 

 
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8. 
ASSESSMENT OF PHARMACOKINETICS/BIOMARKERS/ 
PHARMACOGENOMICS/IMMUNOGENICITY 
8.1. 
Pharmacokinetic Assessment 
Sampling for pharmacokinetics will be sparse. Thus, the fremanezumab pharmacokinetics 
samples may be analyzed using a population pharmacokinetics approach and if performed, this 
analysis will be reported separately to the clinical study report. 
Blood samples (approximately 4 mL) for plasma concentration measurements of fremanezumab 
will be collected via venipuncture/indwelling catheter at time points detailed in Table 2. Samples 
from patients who receive active IMP will be analyzed for concentration of fremanezumab using 
a validated method. Samples from patients who were randomized to receive placebo will not be 
analyzed (at the double-blind period only). Details on sample handling, storage, shipment, and 
analysis are given in Appendix K.  
8.2. 
Pharmacodynamics Assessment 
Pharmacodynamic parameters are not evaluated in this study. 
8.3. 
Immunogenicity Testing 
Blood samples (5 mL) for immunogenicity testing will be collected via venipuncture or 
indwelling catheter at the time points detailed in Table 2.  
Samples from patients who receive fremanezumab will be analyzed for ADA using a validated 
method. Samples from patients who receive placebo will not be analyzed. 
Details on sample handling, storage, shipment, and analysis are provided in Appendix L. 
8.4. 
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. Details on sample 
handling, storage, shipment, and analysis are provided in Appendix M.  
Based on the known biology of CGRP’s mechanism of action, biomarker assessment will 
potentially include measurement of CGRP and other potential mediators involved in migraine, as 
well as markers of bone remodeling, inflammation, and angiogenesis. Exploratory multiplex 
immunoassay panels will be applied to measure baseline levels and changes in proteins in 
various biofluids which may include urine, serum, plasma, and/or saliva. Whole blood RNA (via 
Paxgene tubes) will also be collected for future analysis. 
The planned biomarker analysis will be detailed in a separate document, which may be updated 
at a later stage prior to the analysis to allow updating with new scientific information.  

 
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8.5. 
Pharmacogenetics 
For information regarding pharmacogenomics assessments, see Appendix N. Multiple genetic 
loci have been identified that could affect the binding affinity of the CGRP-receptor-ligand 
complex, while other genetic loci have been identified as having roles in migraine and/or 
headache onset (Anttila et al 2013). To explore the potential impact of normal variations in these 
loci on parameters in this study, a blood sample (6 mL) will be collected from each patient 
(unless the patient declines testing or local regulations prohibit testing) for pharmacogenomic 
assessment during this study. Pharmacogenomic assessment potentially includes the association 
analysis of both known and unknown DNA and RNA genetic variations. 

 
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9. 
STATISTICS 
This is a multicenter, randomized, double-blind, parallel-group, placebo-controlled, study with 
an open-label period to evaluate the efficacy, safety, and tolerability of monthly and quarterly sc 
fremanezumab compared with placebo in patients with CM and EM with inadequate response to 
prior preventive treatments. Eligible patients will be randomized in a 1:1:1 ratio to receive a 
monthly dose of TEV-48125, quarterly dose of TEV-48125 at 675 mg followed by monthly 
placebo, or monthly placebo. Randomization will be stratified by gender, country, migraine 
classification (CM or EM), and special group of treatment failure (yes, no). 
9.1. 
Sample Size and Power Considerations 
In the Phase 2b study for CM (study LBR-101-021), the treatment difference between 
675/225/225 mg and placebo in change from baseline in monthly average migraine days was 
2.1 days (SD=5.2 days). In the phase 2b study for EM (study LBR-101-022), the treatment 
difference between 225 mg monthly dose and placebo in change from baseline in monthly 
average migraine days was 2.7 days (SD=4.1 days). In the Phase 3 study for CM (Study 
TV48125-CNS-30049), the treatment differences to placebo in change from baseline in monthly 
average migraine days were 1.7 days and 1.8 days for the quarterly dose and the monthly dose, 
respectively (SD=5.4 days). In the Phase 3 study for EM (Study TV48125-CNS-30050), the 
treatment differences to placebo in change from baseline in monthly average migraine days were 
1.3 days and 1.5 days for the quarterly dose and the monthly dose, respectively (SD=3.4 days). 
Combining the information above, a treatment difference of 1.8 days is used. Considering the 
patient population is different from the previous studies, a SD of 6 days is used to account for the 
complexity and uncertainty of this study. 
A sample size of 705 (235 patients per treatment group) evaluable patients completing the study 
is needed for 90% power to show a 1.8 difference in migraine days (assuming a common 
standard deviation [SD] of 6 days) at an alpha level of 0.05. Assuming a 12% discontinuation 
rate, 268 patients per treatment group will be randomized in the study. 
9.2. 
Analysis Sets 
9.2.1. 
Intent-to-Treat Analysis Set 
The intent-to-treat (ITT) analysis set will include all randomized patients. 
In the ITT analysis set, treatment will be assigned based on the treatment to which patients were 
randomized, regardless of which treatment they actually received. 
9.2.2. 
Modified Intent-to-Treat Analysis Set 
The modified intent-to-treat (mITT) analysis set is a subset of the ITT analysis set including only 
patients who receive at least 1 dose of study drug and have at least 10 days of post baseline 
efficacy assessment on the primary endpoint. 

 
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9.2.3. 
Safety Analysis Set 
The safety analysis set will include all randomized patients who receive at least 1 dose of IMP. 
In the safety analysis set, treatment will be assigned based on the treatment patients actually 
received, regardless of the treatment to which they were randomized, unless otherwise specified. 
9.2.4. 
Per-Protocol Analysis Set 
The per-protocol (PP) analysis set is a subset of the mITT analysis set including only patients 
who complete the study without important protocol deviations or any deviations/omissions of the 
study drug administration. 
In the PP analysis set, treatment will be assigned based on the treatment patients actually 
received, regardless of the treatment to which they were randomized. 
9.3. 
Data Handling Conventions 
Efficacy variables from patients who do not have diary entries completed for the entire study 
period will be imputed. The monthly average number of headache days/hours will be calculated 
based on the observed data prorated to a 28-day rate for those patients who had at least 10 days 
of post-baseline diary data. It is believed that at least 10 days of diary data should provide a 
reasonable estimate of patient’s disease status in the study while only excluding limited number 
of patients from efficacy analysis (those who had less than 10 days of diary data) to minimize 
potential bias. In calculation of a patient’s monthly number of days/hours of efficacy variables 
during the 4-week period after each dose of study drug for months 1, 2, and 3, the following 
method will be used to handle the missing data: 
• If a patient had ≥10 days of e-diary data for a month, the monthly number of 
days/hours of efficacy variables will be prorated to 28 days for that month. 
• If a patient had <10 days of e-diary data for a month, the monthly number of 
days/hours of efficacy variables will be considered as missing. 
Detailed missing data imputation rules for the headache diary data will be described in the 
statistical analysis plan. 
9.4. 
Study Population 
The ITT analysis set (Section 9.2.1) will be used for all study population summaries unless 
otherwise specified. Summaries will be presented by treatment group and for all patients. 
Summaries will be presented by treatment group and for all patients. 
9.4.1. 
Patient Disposition 
Data from patients screened, patients screened but not randomized and reason for not 
randomized, patients who are randomized, patients randomized but not treated, patients in the 
ITT, mITT, safety, and per-protocol analysis sets, patients who complete the study, and patients 
who withdraw from the study  will be summarized using descriptive statistics. Data from patients 

 
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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 therapies, and ECG findings, will be summarized using descriptive statistics. For continuous 
variables, descriptive statistics (number [n], mean, standard deviation, 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. 
Treatment groups will be compared for all continuous variables, using an analysis of variance 
(ANOVA) with treatment group as factors. The categorical variables of patient gender and race 
will be summarized using descriptive statistics for each variable category. Missing categories 
will be presented if necessary. Treatment groups will be compared for all categorical variables 
using a Pearson’s chi-square (or Fisher’s exact test if cell sizes are too small). 
9.5. 
Efficacy Analysis 
For the purpose of this study, a migraine day is endorsed when at least one of the following 
occurs: 
• a calendar day (0:00 to 23:59) demonstrating at least 4 consecutive hours of a 
headache, meeting criteria for migraine with or without aura (see Appendix U) 
• a calendar day (0:00 to 23:59) demonstrating least 4 consecutive hours of a headache 
meeting criteria for probable migraine, a migraine subtype where only 1 migraine 
criterion is missing (see Appendix U) 
• a calendar day (0:00 to 23:59) demonstrating a headache of any duration that was 
treated with migraine- specific acute medications (triptans and ergot compounds) 
A headache day of at least moderate severity is endorsed when at least 1 of the following 
situations occurs:  
• a calendar day (0:00 to 23:59) demonstrating at least 4 consecutive hours of headache 
of at least moderate severity 
• a calendar day (0:00 to 23:59) demonstrating a headache of any duration that was 
treated with migraine- specific acute medications (triptans and ergot compounds) 
9.5.1. 
Primary Endpoint 
The primary efficacy endpoint is the mean change from baseline (28-day run-in period) in the 
monthly average number of migraine days during the 12-week period after the 1st dose of 
fremanezumab. 
9.5.2. 
Secondary Endpoints 
The secondary endpoints to further demonstrate efficacy are as follows: 

 
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• proportion of patients reaching at least 50% reduction in the monthly average number 
of migraine days during the 12-week period after the 1st dose of fremanezumab 
• mean change from baseline (28-day run-in period) in the monthly average number of 
headache days of at least moderate severity during the 12-week period after the 
1st dose of fremanezumab 
• mean change from baseline (28-day run-in period) in the monthly average number of 
migraine days during the 4-week period after the 1st dose of fremanezumab 
• proportion of patients reaching at least 50% reduction in the monthly average number 
of migraine days during the 4-week period after the 1st dose of fremanezumab 
• 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 12-week period after the 
1st dose of fremanezumab 
• 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 
fremanezumab 
9.5.3. 
Exploratory Endpoints 
The exploratory objectives are as follows: 
• to further evaluate the efficacy of fremanezumab in adult migraine patients with 
inadequate response to 2 to 4 classes of prior preventive treatments  
• to evaluate immunogenicity and impact of ADA on clinical outcome 
• to explore the correlation between pharmacokinetic parameters and efficacy of 
fremanezumab 
• to explore the relationship between genetic polymorphisms, migraine onset/severity 
and efficacy and safety of fremanezumab 
• to explore the relationship between soluble exploratory biomarkers versus migraine 
response  
The exploratory endpoints for the double-blind period are as follows: 
• proportion of patients reaching at least 75% reduction in the monthly average number 
of migraine days during the 12-week period after the 1st dose of study drug  
• proportion of patients reaching total (100%) response (no headache) during the 
12-week period after the 1st dose of study drug 
• proportion of patients reaching total (100%) response (no headache) for at least one 
month during the 12-week period after the 1st dose of study drug   
• mean change from baseline (28-day run-in period) in the monthly average number of 
headache hours of at least moderate severity during the 12-week period after the 
1st dose of the study drug 

 
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• proportion of patients reaching at least 50% reduction in the number of migraine days 
during the 4-week period after the 1st dose of study drug for whom this level of effect 
is sustained throughout the 12-week period after the 1st dose of study drug 
• proportion of patients reaching at least 75% reduction in the number of migraine days 
during the 4-week period after the 1st dose of study drug for whom this level of effect 
is sustained throughout the 12-week period after the 1st dose of study drug 
• mean change from baseline (28-day run-in period) in the monthly average number of 
days with nausea or vomiting during the 12-week period after the 1st dose of study 
drug 
• mean change from baseline (28-day run-in period) in the monthly average number of 
days with photophobia and phonophobia during the 12-week period after the 1st dose 
of study drug 
• mean change from baseline (28-day run-in period) in the monthly average number of 
days of use of migraine-specific acute headache medications (triptans and ergot 
compounds) during the 12-week period after the 1st dose of study drug 
• mean change from baseline (28-day run-in period) in the number of migraine days 
during the 12-week period after the 1st dose of study drug for patients who failed 
topiramate for migraine in the past 
• mean change from baseline (28-day run-in period) in the number of migraine days 
during the 12-week period after the 1st dose of study drug for patients who failed 
onabotulinumtoxinA for migraine in the past 
• mean change from baseline (28-day run-in period) in the number of migraine days 
during the 12-week period after the 1st dose of study drug for patients who failed 
valproic acid for migraine in the past 
• mean change from baseline (28-day run-in period) in the number of migraine days 
during the 12-week period after the 1st dose of study drug for the subset of patients 
who failed  2 to 3 classes of preventive medications and valproic acid for migraine in 
the past 
• proportion of patients reaching at least 50% reduction in the monthly average number 
of migraine days during the 12-week period after the 1st dose of fremanezumab for 
the subset of  patients who failed 2 to 3 classes of preventive medications and 
valproic acid for migraine in the past 
• mean change from baseline (day 0) in disability score, as measured by the HIT-6, at 
4 weeks after administration of the 3rd dose of study drug 
• mean change from baseline (day 0) in disability score, as measured by the MIDAS 
questionnaire, at 4 weeks after the administration of the 3rd dose of study drug 
• mean change from baseline (day 0) in quality of life, as measured by the MSQOL 
questionnaire, at 4 weeks after administration of the 3rd dose of study drug 

 
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• mean change from baseline (day 0) in the health status, as measured by the 
EQ-5D-5L questionnaire at 4 weeks after administration of the 3rd dose of study drug 
• mean change from baseline (day 0) in patient depression status, as measured by the 
PHQ-2 and PHQ-9, at 4 weeks after administration of the 3rd dose of study drug 
• mean change from baseline (day 0) in patient work productivity and activity 
impairment, as measured by the WPAI questionnaire, at 4 weeks after administration 
of the 3rd dose of study drug 
• mean change from baseline (day 0) of patient satisfaction, as measured by the PGIC 
scale, at 4 weeks after the 3rd dose of study drug 
The exploratory endpoints for the open-label period are as follows: 
• mean change from baseline (28-day run-in period) in the monthly average number of 
migraine days during the 12-week period after the 4th  dose of fremanezumab 
• proportion of patients reaching at least 50% reduction from baseline (28-day run-in 
period) in the monthly average number of migraine days during the 12-week period 
after the 4th dose of fremanezumab 
• mean change from baseline (28-day run-in period) in the monthly average number of 
headache days of at least moderate severity during the 12-week period after the 4th 
dose of fremanezumab 
• 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 12-week period after the 
4th dose of fremanezumab 
• proportion of patients reaching at least 75% reduction from baseline (28-day run-in 
period) in the monthly average number of migraine days during the 12-week period 
after the 4th dose of study drug  
• proportion of patients reaching total (100%) response (no headache)  during the 
12-week period after the 4th dose of study drug 
• proportion of patients reaching total (100%) response (no headache) for at least one 
month during the 12-week period after the 4th dose of study drug   
• mean change from baseline (28-day run-in period) in the monthly average number of 
headache hours of at least moderate severity during the 12-week period after the 
4th dose of the study drug 
• proportion of patients reaching at least 50% reduction from baseline (28-day run-in 
period) in the number of migraine days during the 4-week period after the 4th dose of 
study drug for whom this level of effect is sustained throughout the 12-week period 
after the 4th dose of study drug 
• proportion of patients reaching at least 75% reduction from baseline (28-day run-in 
period) in the number of migraine days during the 4-week period after the 4th dose of 

 
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study drug for whom this level of effect is sustained throughout the 12-week period 
after the 4th dose of study drug 
• mean change from baseline (28-day run-in period) in the monthly average number of 
days with nausea or vomiting during the 12-week period after the 4th dose of study 
drug 
• mean change from baseline (28-day run-in period) in the monthly average number of 
days with photophobia and phonophobia during the 12-week period after the 4th dose 
of study drug 
• mean change from baseline (28-day run-in period) in the monthly average number of 
days of use of migraine-specific acute headache medications (triptans and ergot 
compounds) during the 12-week period after the 4th dose of study drug 
• mean change from baseline (28-day run-in period) in the number of migraine days 
during the 12-week period after the 4th dose of study drug for patients who failed 
topiramate for migraine in the past 
• mean change from baseline (28-day run-in period) in the number of migraine days 
during the 12-week period after the 4th dose of study drug for patients who failed 
onabotulinumtoxinA for migraine in the past 
• mean change from baseline (28-day run-in period) in the number of migraine days 
during the 12-week period after the 4th dose of study drug for patients who failed 
valproic acid for migraine in the past 
• mean change from baseline (28-day run-in period) in the number of migraine days 
during the 12-week period after the 4th dose of study drug for patients who failed 
2 to 3 classes of preventive medications in addition to valproic acid for migraine in 
the past 
• proportion of patients reaching at least 50% reduction from baseline (28-day run-in 
period) in the monthly average number of migraine days during the 12-week period 
after the 4th dose of fremanezumab for patients who failed 2 to 3 classes of preventive 
medications in addition to valproic acid for migraine in the past 
• mean change from baseline (day 0) in disability score, as measured by the HIT-6, at 
4 weeks after administration of the 6th dose of study drug 
• mean change from baseline (day 0) in disability score, as measured by the MIDAS 
questionnaire, at 4 weeks after the administration of the 6th dose of study drug 
• mean change from baseline (day 0) in quality of life, as measured by the MSQOL 
questionnaire, at 4 weeks after administration of the 6th dose of study drug 
• mean change from baseline (day 0) in the health status, as measured by the 
EQ-5D-5L questionnaire at 4 weeks after administration of the 6th dose of study drug 
• mean change from baseline (day 0) in patient depression status, as measured by the 
PHQ-2 and PHQ-9, at 4 weeks after administration of the 6th dose of study drug 

 
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• mean change from baseline (day 0) in patient work productivity and activity 
impairment, as measured by the WPAI questionnaire, at 4 weeks after administration 
of the 6th dose of study drug 
• mean change from baseline (day 0) of patient satisfaction, as measured by the PGIC 
scale, at 4 weeks after the last 6th dose of study drug 
The exploratory endpoints for both the double-blind and open-label periods are as follows: 
• to evaluate the immunogenicity response of fremanezumab and the impact of ADAs 
on clinical outcomes in patients exposed to sc fremanezumab.  
• to explore the relationship between genetic polymorphisms (including those within 
the calcitonin gene-related peptide (CGRP) receptor-ligand complex, in migraine-
associated susceptibility genes, and in as-yet undiscovered loci) versus migraine 
onset/severity, adverse events to medication and fremanezumab efficacy 
• to explore the relationship between  exploratory biofluid biomarkers versus 
fremanezumab concentrations, adverse events and fremanezumab efficacy 
9.5.4. 
Planned Method of Analysis 
The mITT analysis set (Section 9.2.2) will be used for all efficacy analyses. Summaries will be 
presented by treatment group. 
9.5.4.1. 
Primary Efficacy Analysis 
The primary efficacy endpoint will be analyzed using an analysis of covariance (ANCOVA) 
method. The model will include treatment, gender, region, special group of treatment failure 
(Yes or No),  migraine classification (ie, CM or EM), and treatment-by-migraine classification 
interaction as fixed effects, and baseline number of migraine days and years since onset of 
migraines as covariates. The treatment comparison between each fremanezumab treatment group 
(monthly dose and quarterly dose) and placebo for monthly average migraine days will be 
conducted under this model using the estimate statement. Ninety-five percent confidence 
intervals will be constructed for the least squares means differences between each fremanezumab 
treatment group (monthly dose and quarterly dose) and placebo. 
Note: Special treatment failure group defined as patients who must have had inadequate response 
to valproic acid. In addition, patients in the special treatment failure group must have had 
inadequate response to 2 to 3 other classes of migraine preventive medications as defined 
in Appendix H. 
9.5.4.2. 
Sensitivity Analysis 
Sensitivity analysis will be performed by imputing missing migraine days of months 1-3 using 
multiple imputation method. The average migraine days of months1-3 from each imputed data 
set will be analyzed using the same ANCOVA model as the primary efficacy analysis. Ninety-
five percent confidence intervals for the least squares means differences between each 
fremanezumab treatment groups (monthly dose and quarterly dose) and placebo will be 

 
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constructed. The detailed SAS code for imputation and analysis procedure will be provided in 
the statistical analysis plan. This sensitivity analysis will be performed on the ITT analysis set. 
Sensitivity analysis will also be performed using a mixed-effects repeated measures (MMRM) 
analysis model. If a patient is early terminated or has intermittent missing days and has fewer 
than 10 days of e-diary entries for a month, that month’s value will be considered as missing. 
The MMRM model will include  treatment, gender, region, special group of treatment failure 
(Yes or No), migraine classification (ie, CM or EM),  month, treatment-by-migraine 
classification interaction, and treatment-by-month interaction as fixed effects, baseline value and 
years since onset of migraines as covariates, and patient in the repeated statement as a random 
effect. The treatment comparison between each fremanezumab treatment group (monthly dose 
and quarterly dose) and placebo for monthly average migraine days will be conducted under this 
model using the estimate statement. Ninety-five percent confidence intervals will be constructed 
for the least squares means differences between each fremanezumab treatment group (monthly 
dose and quarterly dose) and placebo. This sensitivity analysis will be performed on the mITT 
analysis set. 
Note: Special treatment failure group defined as patients who must have had inadequate response 
to valproic acid. In addition, patients in the special treatment failure group must have had 
inadequate response to 2 to 3 other classes of migraine preventive medications as defined 
in Appendix H. 
9.5.4.3. 
Secondary Efficacy Analysis 
The continuous secondary efficacy endpoints will be analyzed similarly as the primary efficacy 
endpoint. For the proportion of responders, defined as 50% or more reduction from baseline in 
the monthly average number of migraine days, a logistic regression model will be used with the 
following effects: treatment, gender, region, special group of treatment failure (Yes or No), and 
migraine classification (ie, CM or EM). The odds ratios, 95% confidence intervals for odds 
ratios, and p-values will be presented for each fremanezumab treatment group (monthly dose and 
quarterly dose).  
9.5.4.4. 
Exploratory Efficacy Analysis 
For the double-blind period, the continuous exploratory efficacy endpoints period will be 
analyzed similarly as the primary efficacy endpoint. For the proportions of responders for the 
double-blind period, a logistic regression model will be used similarly as the secondary efficacy 
endpoint.  
For the open-label period, the exploratory efficacy endpoints will be summarized using 
descriptive statistics. 
9.5.4.5. 
Subgroup Analysis 
The ANCOVA analysis defined in Section 9.5.4.1 and MMRM analysis defined in 
Section 9.5.4.2 will also be applied for the following subgroups for the primary endpoint. 
• age group (18-45 years, >45 years) 
• sex (male, female) 

 
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• region (North America, Europe) 
• migraine classification (CM, EM) 
An exploratory analysis for the primary endpoint will also be performed by adding the 
treatment-by-region interaction to the primary analysis model to test whether treatment effects 
are homogenous across regions. 
9.6. 
Multiple Comparisons and Multiplicity 
The Hochberg’s method along with hierarchical testing procedure for multiple comparisons 
between treatment groups (2 comparisons: fremanezumab monthly dose compared with placebo 
and fremanezumab quarterly dose compared with placebo) for the primary and secondary 
endpoint analyses will be used to maintain the experiment-wise type I error of 5%. 
In the primary analysis, according to the Hochberg’s method, if the null hypothesis is rejected for 
both the fremanezumab monthly and quarterly treatment groups at an alpha level of 5%, then no 
adjustment to the alpha level will be performed and both comparisons will be declared as 
statistically significant. The secondary variables will then be tested in the order as specified in 
Section 9.5.2 for both the fremanezumab monthly and quarterly treatment groups using the same 
procedure as the primary analysis. If the null hypothesis is not rejected for 1 of the doses at an 
alpha level of 5%, then the other dose will be tested using an alpha level of 5%/2=2.5%, and the 
sequential testing will stop.  
No multiplicity adjustments will be made for exploratory efficacy analyses. 
9.7. 
Safety Analysis 
Safety analyses will be performed on the safety analysis set (Section 9.2.3). 
Safety assessments and time points are provided in Table 2. 
All adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Each patient will be counted only once in each preferred term or system organ class 
(SOC) 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 test IMP 
(i.e., reasonable possibility) (defined as related or with missing relationship) (overall and by 
severity), serious adverse events, and adverse events causing withdrawal from the study.  
Summaries will be presented by treatment group and for all patients. Patient listings of serious 
adverse events and adverse events leading to withdrawal will be presented. 
Changes in laboratory, ECG, and vital signs measurements data will be summarized 
descriptively. All values will be compared with predefined criteria to identify potentially 
clinically significant values or changes, and such values will be listed. 
Safety data will be summarized descriptively overall and by treatment group. For continuous 
variables, descriptive statistics (n, mean, standard deviation, 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. The denominator for categorical 
variables will exclude missing observations. Descriptive summaries of serious adverse events, 

 
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patient withdrawals due to adverse events, and potentially clinically significant abnormal values 
(clinical laboratory or vital signs) based on predefined criteria will be provided as well. 
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. 
Tolerability Analysis 
Local tolerability findings will be listed and summarized descriptively. 
9.9. 
Pharmacokinetic Analysis 
Pharmacokinetic plasma concentration results for fremanezumab will be tabulated descriptively 
at each planned sampling time point by treatment group and indication. 
In addition, the most appropriate population pharmacokinetic model may be developed, and 
covariates that may affect it will be tested for inclusion in the model. If performed, this analysis 
will be reported separately. 
9.10. 
Pharmacokinetic/Pharmacodynamic Analysis 
The pharmacokinetic/pharmacodynamic relationship may be estimated by compartmental 
techniques. The pharmacokinetic parameters will be based on IMP measurements. The 
pharmacodynamics analysis will be the efficacy response(s).  
The pharmacokinetic/pharmacodynamic relationship may 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. If performed, this analysis will be reported separately. 
9.11. 
Exploratory Biomarker Analysis 
Exploratory biomarker measurements will be made using appropriately validated assays. Results, 
if generated, will typically be expressed as % change from baseline and reported in a separate 
report. 
9.12. 
Pharmacogenomic Analysis 
Pharmacogenomic analysis will be conducted to correlate clinical observations 
(pharmacokinetics, safety, efficacy, or other effects) with genotypes observed in the study. 
Pharmacogenomic analysis may be conducted at a later time and will be reported in a separate 
report. 
9.13. 
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 if data allowed. This analysis will be reported separately. 

 
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9.14. 
Planned Interim Analysis 
An interim analysis is planned when the last patient has completed the double-blind period. Final 
database lock will occur following the end of the open-label period. 
The inferential analysis of efficacy variables for comparison between each fremanezumab 
treatment group (monthly dose and quarterly dose) and placebo will be done at the time of the 
first interim lock. The appropriate method for type 1 error control will be applied to the first 
interim analysis. 
Efficacy analysis for the open-label portion of this study is considered exploratory and mainly 
descriptive. This analysis will be done at the time of the final database lock. 
9.15. 
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 national, local, and 
regional requirements and regulations. 

 
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10. 
QUALITY CONTROL AND QUALITY ASSURANCE 
For information regarding quality control and quality assurance refer to Appendix C. This 
includes information about protocol amendments, deviations, responsibilities of the investigator 
to study personnel, study monitoring, and audit and inspection. 
For the definition of a clinical product complaint and investigator responsibilities in the 
management of a clinical product complaint refer to Appendix O. 
11. 
COMPLIANCE STATEMENT 
This study will be conducted in full accordance with the ICH Harmonised Tripartite Guideline, 
Guideline for Good Clinical Practice 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, Directive 2001/20/EC of the European Parliament and of the Council on the 
approximation of the laws, regulations and administrative provisions of the Member States 
relating to the implementation of good clinical practice in the conduct of clinical trials on 
medicinal products for human use). Any episode of noncompliance will be documented. 
The investigator is responsible for performing the clinical 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 
clinical study in accordance with the protocol will be documented in separate clinical study 
agreements with the sponsor and other forms as required by national competent 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 clinical study; and must ensure that trained personnel are immediately available in 
the event of a medical emergency. The investigator and the involved clinical study personnel 
must be familiar with the background and requirements of the study; and with the properties of 
the IMPs 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 clinical study at that investigational center and for contacts 
with study management, with the Independent Ethics Committee/Institutional Review Board 
(IEC/IRB), and with competent authorities. 
For the ethics expectations of informed consent competent authorities and independent ethics 
committee and institutional review board, confidentiality regarding study patients, and 
requirements for registration of the clinical study, see Appendix D. 
12. 
DATA MANAGEMENT AND RECORD KEEPING 
For information regarding data management and record keeping, see Appendix P. This includes 
direct access to source data and documents, data collection, data quality control, and archiving of 
CRFs and source documents. 

 
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13. 
FINANCING AND INSURANCE 
A separate clinical study agreement, including a study budget, will be signed between each 
principal investigator and the sponsor (or the CRO designated by the sponsor) before the IMP is 
delivered. 
The patients in this clinical study are insured in accordance with applicable legal provisions. The 
policy coverage is subject to the full policy terms, conditions, extensions, and exclusions. 
Excluded from the insurance coverage are eg, 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 Food and Drug Administration (FDA) 3454 form. 
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. 
14. 
PUBLICATION POLICY 
For information regarding the publication policy see Appendix Q. 

 
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15. 
REFERENCES 
Anttila V, Winsvold BS, Gormley P, Kurth T, Bettella F, McMahon G, et al. Genome-wide 
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 
1999;29(8):2613–24. 
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 
2012;52(3):409-21. 
Bigal ME, Dodick DW, Rapoport AM, Silberstein SD, Ma Y, Yang R, et al. Safety, tolerability, 
and efficacy of TEV-48125 for preventive treatment of high-frequency episodic migraine: a 
multicentre, randomised, double-blind, placebo-controlled, phase 2b study. Lancet Neurol 
2015a;14:1081-90. 
Bigal ME, Edvinsson L, Rapoport AM, Lipton RB, Spierings ELH, Diener H, et al. Safety, 
tolerability, and efficacy of TEV-48125 for preventive treatment of chronic migraine: a 
multicentre, randomised, double-blind, placebo-controlled, phase 2b study. Lancet Neurol 
2015b;14:1091-100. 
Bigal ME, Lipton RB. Clinical course in migraine: conceptualizing migraine transformation. 
Neurology 2008;71(11):848-55. 
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. 
Evers S, Afra J, Frese A, Goadsby PJ, Linde M, May A, et a. EFNS guideline on the drug 
treatment of migraine—revised report of an EFNS task force. Europ J Neurol 2009;16:968-81. 
Food and Drug Administration (FDA). Guidance for Industry: Drug Interaction Studies – Study 
Design, Data Analysis, Implications for Dosing, and Labeling Recommendations. 2012. 
Available at: 
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm
292362.pdf. 
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. 
Ho TW, Edvinsson L, Goadsby PJ. CGRP and its receptors provide new insights into migraine 
pathophysiology. Nat Rev Neurol 2010;6(10):573–82. 

 
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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, 
compared with zolmitriptan for acute migraine: a randomised, placebo-controlled, parallel-
treatment trial. Lancet 2008;372(9656):2115–23. 
International Headache Society. The International Classification of Headache Disorders, 3rd 
edition (beta version). Cephalalgia 2013;33(9):629-808. 
Kosinski M, Bayliss MS, Bjorner JB, Ware JE Jr, Garber WH, Batenhorst A, et al. A six-item 
short-form survey for measuring headache impact: the HIT-6. Qual Life Res 2003;12(8)963-74. 
Kroenke K, Spitzer RL, Williams JB, Löwe B. The Patient Health Questionnaire somatic, 
anxiety, and depressive symptom scales: a systematic review. Gen Hosp Psychiatry 
2010;32(4):345-59. 
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. 
Martelletti P, Katsarava Z, Lampl C, Magis D, Bendtsen L, Negro A, et al. Refractory chronic 
migraine: a Consensus Statement on clinical definition from the Europena Headache Federation. 
J Headache Pain 2014,15(47): 1-6. 
Olesen J, Diener HC, Husstedt IW, Goadsby PJ, Hall D, Meier U, et al. Calcitonin gene-related 
peptide receptor antagonist BIBN 4096 BS for the acute treatment of migraine. N Engl J Med 
2004;350(11):1104–10. 
Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, et al. The 
Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings from 
three multisite studies with adolescents and adults. Am J Psychiatry 2011;168(12):1266-77. 
Puledda F, Messina R, and Goadsby PJ. An update on migraine: current understanding and 
future directions. J Neurol 2017 Mar 20. doi: 10.1007/s00415-017-8434-y. [Epub ahead of print] 
Reilly MC, Zbrozek AS, Dukes EM. The validity and reproducibility of a work productivity and 
activity impairment instrument. PharmacoEconomics 1993; 4(5):353-65. 
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. J Allergy Clin Immunol 2006;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. 
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. 
Spitzer RL, Kroenke K, Williams JBW. Validation and utility of self-report version of 
PRIME-MD: the PHQ primary care study. JAMA 1999;282(18):1737-44. 

 
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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. 
Tfelt-Hansen P, Pascual J, Ramadan N, Dahlöf C, Domenico D, Diener H-C, et al. Guidelines for 
controlled trials of drugs in migraine: third edition. A guide for investigators. Cephalalgia 
2012;32(1):6-38. 
Yang M, Rendas-Baum R, Varon SF, Kosinski 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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16. 
SUMMARY OF CHANGES TO PROTOCOL 
16.1. 
Amendment 01 Dated 23 October 2017 
The primary reason for this amendment is to fulfill all conditions raised during Voluntary 
Harmonisation Procedure (VHP)-procedure VHP1154 (VHP2017110) in association with the 
conditional approval received on October 17th, 2017. This amendment is primarily in the 
statistical section in response to VHP request.  Clarification language about emergency 
unblinding was also added in response to VHP request. Other nonsubstantial changes have been 
made to the protocol (and protocol synopsis, as appropriate). There is no change in inclusion or 
exclusion criteria. These changes will not affect the safety or rights (physical or mental integrity) 
of the patients in this clinical study or the scientific value of the clinical study. 
Original text with changes shown 
New wording 
Reason/Justification for change 
In the footer of every page, including the title page 
 
Protocol Version 2 with 
Amendment 01, 23 October 2017 
This addition was added for 
clarification as requested by VHP 
Section 2.2 Exploratory Efficacy Objectives and Endpoints 
Other sections affected by this change: Section 9.5.3 Exploratory Endpoints, synopsis 
12-week period after the 4th 1st dose of 
study drug  
12-week period after the 1st dose of 
study drug 
Typo 
Section 4.3 Withdrawal Criteria and Procedures for the Patient  
ADA 6.0 months (180225 days 
ADA 6.0 months (180 days 
Typo; correction to reflect the 
number of days in 6 months 
Section 5.9.2 Blinding and Unblinding 
 
In the event that the IRT system is 
not functioning for emergency 
unblinding, the next course of 
action is to contact via phone the 
IRT on-call customer support 
helpline for manual emergency 
unblinding. Additional contact 
details can be found in the 
pharmacy manual. 
Text added per VHP request on 
emergency unblinding 
Section 7.6 Vital Signs 
blood pressure, body oral temperature 
blood pressure, oral temperature 
Typo; correction to align with 
secondary safety/tolerability 
endpoints 
Section 9.1 Sample Size and Power Considerations 
Other sections affected by this change: synopsis 
 
In the Phase 2b study for CM 
(Study LBR-101-021), the 
treatment difference between 
675/225/225 mg and placebo in 
Text added per VHP request on 
statistics 

 
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New wording 
Reason/Justification for change 
change from baseline in monthly 
average migraine days was 2.1 
days (SD=5.2 days). In the phase 
2b study for EM (Study LBR-101-
022), the treatment difference 
between 225 mg monthly dose and 
placebo in change from baseline in 
monthly average migraine days 
was 2.7 days (SD=4.1 days). In the 
Phase 3 study for CM (Study 
TV48125-CNS-30049), the 
treatment differences to placebo in 
change from baseline in monthly 
average migraine days were 1.7 
days and 1.8 days for the quarterly 
dose and the monthly dose, 
respectively (SD=5.4 days). In the 
Phase 3 study for EM (Study 
TV48125-CNS-30050), the 
treatment differences to placebo in 
change from baseline in monthly 
average migraine days were 1.3 
days and 1.5 days for the quarterly 
dose and the monthly dose, 
respectively (SD=3.4 days). 
Combining the information above, 
a treatment difference of 1.8 days 
is used. Considering the patient 
population is different from the 
previous studies, a SD of 6 days is 
used to account for the complexity 
and uncertainty of this study. 
Section 9.2.2 Modified Intent-to-Treat Analysis 
at least 1 10 days of post baseline  
at least 10 days of post baseline 
Typo 
Section 9.3 Data Handling Conventions 
Efficacy variables from patients who do 
not have diary entries completed for the 
entire study period will be imputed. The 
monthly average number of headache 
days/hours will be calculated based on 
the observed data prorated to a 28-day 
rate for those patients who had at least 10 
days of post-baseline diary data. It is 
believed that at least 10 days of diary 
data should provide a reasonable 
estimate of patient’s disease status in the 
study while only excluding limited 
number of patients from efficacy analysis 
Efficacy variables from patients 
who do not have diary entries 
completed for the entire study 
period will be imputed. The 
monthly average number of 
headache days/hours will be 
calculated based on the observed 
data prorated to a 28-day rate for 
those patients who had at least 10 
days of post-baseline diary data. It 
is believed that at least 10 days of 
diary data should provide a 
reasonable estimate of patient’s 
Text added per VHP request on 
statistics 

 
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New wording 
Reason/Justification for change 
(those who had less than 10 days of diary 
data) to minimize potential bias. In 
calculation of a patient’s monthly 
number of days/hours of efficacy 
variables during the 4-week period after 
each dose of study drug for months 1, 2, 
and 3, the following method will be used 
to handle the missing data: 
• 
If a patient had ≥10 days of e-
diary data for a month, the 
monthly number of days/hours of 
efficacy variables will be prorated 
to 28 days for that month. 
• 
If a patient had <10 days of e-
diary data for a month, the 
monthly number of days/hours of 
efficacy variables will be 
considered as missing. 
Detailed data imputation rules will be 
described in the statistical analysis plan. 
For all variables, the observed data from 
the patients will be used in the by visit 
summaries. 
disease status in the study while 
only excluding limited number of 
patients from efficacy analysis 
(those who had less than 10 days of 
diary data) to minimize potential 
bias. In calculation of a patient’s 
monthly number of days/hours of 
efficacy variables during the 4-
week period after each dose of 
study drug for months 1, 2, and 3, 
the following method will be used 
to handle the missing data: 
• If a patient had ≥10 days of e-
diary data for a month, the 
monthly number of 
days/hours of efficacy 
variables will be prorated to 
28 days for that month. 
If a patient had <10 days of e-diary 
data for a month, the monthly 
number of days/hours of efficacy 
variables will be considered as 
missing. 
Section 9.5.4.1 Primary Efficacy Analysis 
Other section affected by this change: synopsis 
(Yes or No), and migraine classification 
(ie, CM or EM), and treatment-by-
migraine classification interaction as 
fixed effects, and baseline number of 
migraine days and years since onset of 
migraines as covariates. The treatment 
comparison between each fremanezumab 
treatment group (monthly dose and 
quarterly dose) and placebo for monthly 
average migraine days will be conducted 
under this model using the estimate 
statement. Ninety-five percent 
confidence intervals will be constructed 
for the least squares means differences 
between each fremanezumab treatment 
group (monthly dose and quarterly dose) 
and placebo. 
(Yes or No), and migraine 
classification (ie, CM or EM), and 
treatment-by-migraine 
classification interaction as fixed 
effects, and baseline number of 
migraine days and years since 
onset of migraines as covariates. 
The treatment comparison between 
each fremanezumab treatment 
group (monthly dose and quarterly 
dose) and placebo for monthly 
average migraine days will be 
conducted under this model using 
the estimate statement. Ninety-five 
percent confidence intervals will be 
constructed for the least squares 
means differences between each 
fremanezumab treatment group 
(monthly dose and quarterly dose) 
and placebo. 
Text changed per VHP request on 
statistics 

 
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New wording 
Reason/Justification for change 
Section 9.5.4.2 Sensitivity Analysis 
Other section affected by this change: synopsis 
Sensitivity analysis willmay be 
performed by imputing missing migraine 
days of months 1-3 using multiple 
imputation method. The average 
migraine days of months 1 to 3 from 
each imputed data set will be analyzed 
using the same ANCOVA. model as the 
primary efficacy analysis. Ninety-five 
percent confidence intervals for the least 
square means differences between each 
fremaezumab treatment group (monthly 
dose and quarterly dose) and placebo will 
be constructed. The detailed SAS code 
for imputation and analysis procedure 
will be provided in the statistical analysis 
plan. This sensitivity analysis will be 
performed on the ITT analysis set. 
Sensitivity analysis will may also 
Sensitivity analysis will be 
performed by imputing missing 
migraine days of months 1-3 using 
multiple imputation method. The 
average migraine days of months 1 
to 3 from each imputed data set 
will be analyzed using the same 
ANCOVA model as the primary 
efficacy analysis. Ninety-five 
percent confidence intervals for the 
least square means differences 
between each fremaezumab 
treatment group (monthly dose and 
quarterly dose) and placebo will be 
constructed. The detailed SAS code 
for imputation and analysis 
procedure will be provided in the 
statistical analysis plan. This 
sensitivity analysis will be 
performed on the ITT analysis set. 
Sensitivity analysis will also 
Text added per VHP request on 
statistics 
The MMRM model will include, 
treatment, gender, region, special group 
of treatment failure (Yes or No), 
migraine classification (ie, CM or EM), , 
month, treatment-by-migraine 
classification interaction, and treatment-
by-month interaction as fixed effects, 
baseline value and years since onset of 
migraines as covariates, and patient in 
the repeated statement as a random 
effect. The treatment comparison 
between each fremanezumab treatment 
group (monthly dose and quarterly dose) 
and placebo for monthly average 
migraine days will be conducted under 
this model using contrast the estimate 
statement. Ninety-five percent 
confidence intervals will be constructed 
for the least squares means differences 
The MMRM model will include 
treatment, gender, region, special 
group of treatment failure (Yes or 
No), migraine classification (ie, 
CM or EM), month, treatment-by-
migraine classification interaction, 
and treatment-by-month interaction 
as fixed effects, baseline value and 
years since onset of migraines as 
covariates, and patient in the 
repeated statement as a random 
effect. The treatment comparison 
between each fremanezumab 
treatment group (monthly dose and 
quarterly dose) and placebo for 
monthly average migraine days 
will be conducted under this model 
using the estimate statement. 
Ninety-five percent confidence 
intervals will be constructed for the 
least squares means differences 
between each fremanezumab 
treatment group (monthly dose and 
quarterly dose) and placebo. This 
Text added per VHP request on 
statistics 

 
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Original text with changes shown 
New wording 
Reason/Justification for change 
between each fremanezumab treatment 
group (monthly dose and quarterly dose) 
and placebo. This sensitivity analysis 
will be performed on the mITT analysis 
set. 
Sensitivity analysis will be performed 
using the ITT analysis set. 
sensitivity analysis will be 
performed on the mITT analysis 
set. 
Section 9.5.4.3 Secondary Efficacy Analysis 
Other section affected by this change: synopsis 
a logistic regression model will be used 
with the following effects: treatment, 
gender, region, special group of 
treatment failure (Yes or No), and 
migraine classification (ie, CM or EM). 
The odds ratios, 95% confidence 
intervals for odds ratios, and p-values 
will be presented for each fremanezumab 
treatment group (monthly dose and 
quarterly dose).Cochran Mantel
Haenszel test will be used as appropriate. 
a logistic regression model will be 
used with the following effects: 
treatment, gender, region, special 
group of treatment failure (Yes or 
No), and migraine classification 
(ie, CM or EM). The odds ratios, 
95% confidence intervals for odds 
ratios, and p-values will be 
presented for each fremanezumab 
treatment group (monthly dose and 
quarterly dose). 
Text changed per VHP request on 
statistics 
Section 9.5.4.4 Exploratory Efficacy Analysis 
Other section affected by this change: synopsis 
double-blind period, the Cochran
Mantel Haenszel test a logistic 
regression model will be used similarly 
as the secondary efficacy endpoint. 
double-blind period,  a logistic 
regression model will be used 
similarly as the secondary efficacy 
endpoint. 
Text changed per VHP request on 
statistics 
Section 9.5.4.5 Subgroup Analysis 
 
9.5.4.5  Subgroup Analysis 
The ANCOVA analysis defined in 
Section 9.5.4.1 and MMRM 
analysis defined in Section 9.5.4.2 
will also be applied for the 
following subgroups for the 
primary endpoint. 
• age group (18-45 years, >45 
years) 
• sex (male, female) 
• region (North America, 
Europe) 
• migraine classification (CM, 
EM) 
An exploratory analysis for the 
Subsection added per VHP 
request on statistics 

 
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Reason/Justification for change 
primary endpoint will also be 
performed by adding the 
treatment-by-region interaction to 
the primary analysis model to test 
whether treatment effects are 
homogenous across regions. 
Section 9.14 Planned Interim Analysis 
Other section affected by this change: synopsis 
A second interim Final database lock will 
occur following the end of the open-label 
period. 
 
The inferential analysis of efficacy 
variables for comparison between each 
fremanezumab treatment group (monthly 
dose and quarterly dose) and placebo will 
be done at the time of the first interim 
lock. The appropriate method for type 1 
error control will be applied to the first 
interim analysis. 
 
Efficacy analysis for the open-label 
portion of this study is considered 
exploratory and mainly descriptive. This 
analysis will be done at the time of the 
final database lock. 
Final database lock will occur 
following the end of the open-label 
period. 
 
The inferential analysis of efficacy 
variables for comparison between 
each fremanezumab treatment 
group (monthly dose and quarterly 
dose) and placebo will be done at 
the time of the first interim lock. 
The appropriate method for type 1 
error control will be applied to the 
first interim analysis. 
 
Efficacy analysis for the open-label 
portion of this study is considered 
exploratory and mainly descriptive. 
This analysis will be done at the 
time of the final database lock. 
Text changed per VHP request on 
statistics 
Appendix J Total Blood Volume 
a A serum pregnancy test will be 
performed for women of childbearing 
potential at screening and at visit 8only. 
 
a A serum pregnancy test will be 
performed for women of 
childbearing potential at screening 
and at visit 8. 
Typo; correction to be consistent 
with associated Table 2 (Study 
Procedures and Assessments) 

 
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APPENDIX A. CLINICAL LABORATORIES AND OTHER 
DEPARTMENTS AND INSTITUTIONS 
Sponsor’s Authorized Representative 
 
  
Teva Branded Pharmaceutical Products R&D, Inc. 
 
 
 
Legal Representative of the Sponsor in the EU 
 
 
 
Teva GmbH 
 
Sponsor’s Medical Expert/Contact Point designated 
by the Sponsor for Further Information on the Study 
 
 
PRA Health Sciences 
 
 
 
Sponsor’s Representative of Global Patient Safety 
and Pharmacovigilance 
For serious adverse events: 
Send by email to the local safety officer/contract 
research organization (LSO/CRO). The email address 
will be provided in the serious adverse event report 
form. In the event of difficulty transmitting the form, 
contact the sponsor’s study personnel identified above 
for further instruction. 
 
Ratiopharm GmBH 
 
 
 
Contract Research Organization 
Pharmaceutical Research Associates, Inc. 
4130 Parklake Avenue 
Suite 400 
Raleigh, North Carolina 27612 
USA 
Central Clinical Laboratory 
Q SQUARED SOLUTIONS LLC 
1600 Terrell Mill Road  
Suite 100  
Marietta, GA 30067 
USA 
Electronic Clinical Outcome Assessment 
eResearchTechnology, Inc. 
1818 Market Street 
Philadelphia, PA 19103 
USA 

 
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Central Electrocardiogram Evaluation 
eResearchTechnology, Inc.1818 Market Street 
Suite 1000 
Philadelphia, PA 19103 
USA 
Bioanalytical Pharmacokinetics Evaluation 
 
  
Teva Branded Pharmaceuticals R&D, Inc. 
 
145 Brandywine Parkway 
West Chester, PA 19380, USA 
 
Teva Branded Pharmaceuticals R&D, Inc. 
Bioanalytical Immunogenicity Evaluation 
 
 
Teva Branded Pharmaceuticals R&D
 
 
145 Brandywine Parkway 
West Chester, PA19380 
USA 
Pharmacogenomics/Biomarker Evaluation 
Storage of samples: 
BioStorage Technologies, GmbH 
Receiving Department 
Im Leuschnerpark 1b 
64347 Griesheim Germany 
 
 
BioStorage Technologies, Inc. 
Receiving Department 
2910 Fortune Circle West, Suite E 
Indianapolis, IN 46241, USA 
 
 
Randomization and Trial Supply Management 
(RTSM) vendor 
Medidata Solutions 
350 Hudson Street 
9th Floor 
New York, NY 10014 
USA 

 
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APPENDIX B. STUDY PROCEDURES AND ASSESSMENTS BY VISIT 
1. Procedures for Screening/Run-in Period (Visit 1, Days -28 to -1 Before Visit 2) 
The screening visit (visit 1) will take place during a run-in period not more than -28 days 
before the baseline visit (visit 2). The following procedures will be performed at visit 1: 
• obtain written informed consent before any study-related procedures are performed 
• review inclusion and exclusion criteria 
• review medical and psychiatric history 
• record demographic characteristics 
• review prior medication and treatment history 
• perform clinical laboratory tests (serum chemistry, hematology and coagulation, 
urinalysis) 
• perform physical examination, including height and weight 
• perform 12-lead ECGs in triplicate 
• perform vital signs measurement 
• perform beta human chorionic gonadotropin (β-HCG) serum pregnancy test (for 
women of child-bearing potential)  
• perform FSH for postmenopausal women only 
• inform patients of study restrictions and compliance requirements 
• complete eC-SSRS 
Patients who meet all inclusion and none of the exclusion criteria will be given an 
electronic headache diary device and will be trained in its use and compliance 
requirements on the day of screening. Patients will complete electronic headache diary 
entries about the previous day daily beginning on day -27 (visit 1) through the EOT/early 
withdrawal visit (visit 8). 
2. Procedures Before Administration of Investigational Medicinal Products 
(Baseline Visit 2, Day 0+3 Days) 
Patients who meet all inclusion and none of the exclusion criteria at visit 1 will continue 
to visit 2 (week 0), when baseline assessments will be conducted. 
The following procedures will be performed at visit 2: 
• review inclusion and exclusion criteria 
• assign randomization/treatment numbers and enter in CRF 
• perform clinical laboratory tests (serum chemistry, hematology and coagulation, 
urinalysis) 

 
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• perform physical examination, including weight 
• perform 12-lead ECGs in triplicate 
• perform vital signs measurements 
• perform urine pregnancy test (women of child bearing potential only) 
• review study compliance 
• review electronic headache diary 
• obtain blood samples for plasma concentration of IMP prior to dosing 
• obtain a blood sample for serum ADA assay prior to dosing 
• obtain blood collection for serum, plasma, and RNA biomarker analysis 
• obtain urine sample for biomarker analysis 
• collect a saliva sample for biomarker analysis 
• obtain blood samples for pharmacogenetics before study drug administration from 
patients who consent to this procedure 
• complete HIT-6 
• complete the MIDAS 
• complete the PHQ-2/ PHQ-9. Patients will respond first to the PHQ-2. Patients will 
respond to questions 3 through 9 (unique questions) of the PHQ-9 only if PHQ-2 is 
positive. 
• complete the MSQOL questionnaire 
• complete the EQ-5D-5L questionnaire 
• complete the WPAI questionnaire 
• inquire about adverse events and health care resource utilization  
• inquire about concomitant medication 
3. Procedures During Administration of Investigational Medicinal Product 
(Double-Blind Period and Open-Label Period, Visits 2 Through 8, Days 0+3 
Through 168±5 Days) 
Patients will complete electronic headache diary entries about the previous day daily 
beginning on day -27 (visit 1) through the EOT/early withdrawal visit (visit 8). 
Visit 2 (baseline, day 0+3 days) 
After completion of pre-dose assessments, patients will be treated with IMP (for additional 
details regarding IMP administration, refer to Section 5.1). 
The following procedures and assessments will be performed at visit 2 (baseline) after 
dosing: 

 
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• assess hypersensitivity and anaphylaxis 
• inquire about post-dose adverse events before the patient leaves the study center 
Visit 3 (week 4, day 28±3 days) 
The following pre-dose procedures and assessments will be performed at visit 3: 
• perform clinical laboratory tests (serum chemistry, hematology and coagulation, 
urinalysis) 
• perform vital signs measurements 
• perform urine pregnancy test (women of child bearing potential only) 
• review study compliance 
• review electronic headache diary 
• obtain blood samples for plasma concentration of IMP prior to dosing 
• obtain a blood sample for serum ADA assay prior to dosing 
• obtain blood collection for serum, plasma, and RNA biomarker analysis 
• obtain urine sample for biomarker analysis 
• collect a saliva sample for biomarker analysis 
• complete HIT-6 
• complete MIDAS 
• complete MSQOL questionnaire 
• complete PGIC scale 
• complete eC-SSRS 
• inquire about adverse events and health care resource utilization inquire about 
concomitant medication 
After completing pre-dose assessments, patients will be treated with IMP (for additional 
details regarding IMP administration, refer to Section 5.1). 
The following procedures and assessments will be performed at visit 3 (week 4) after dosing: 
• assessment of hypersensitivity and anaphylaxis 
• inquire about post-dose adverse events before the patient leaves the study center 
Visit 4 (week 8, day 56±3 days) 
The following pre-dose procedures and assessments will be performed at visit 4: 
• perform vital signs measurements 
• perform urine pregnancy test (women of child bearing potential only) 
• review study compliance 

 
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• review electronic headache diary 
• obtain blood samples for plasma concentration of IMP prior to dosing 
• complete eC-SSRS 
• inquire about adverse events and health care resource utilization  
• inquire about concomitant medication 
After completing pre-dose assessments, patients will be treated with IMP (for additional 
details regarding IMP administration, refer to Section 5.1). 
The following procedures and assessments will be performed at visit 4 (week 8) after dosing: 
• assess hypersensitivity and anaphylaxis 
• inquire about post-dose adverse events before the patient leaves the study center 
Visit 5 (week 12, day 84±3 days) 
The following pre-dose procedures and assessments will be performed at visit 5: 
• assign randomization/treatment numbers and enter in CRF 
• perform clinical laboratory tests (serum chemistry, hematology and coagulation, 
urinalysis) 
• perform physical examination, including weight 
• perform 12-lead ECGs in triplicate 
• perform vital signs measurements 
• perform urine pregnancy test (women of child bearing potential only) 
• review study compliance 
• review electronic headache diary 
• obtain blood samples for plasma concentration of IMP prior to dosing 
• obtain a blood sample for serum ADA assay prior to dosing 
• obtain blood collection for serum, plasma, and RNA biomarker analysis 
• obtain urine sample for biomarker analysis 
• collect a saliva sample for biomarker analysis 
• complete HIT-6 
• complete MIDAS 
• complete PHQ-2/ PHQ-9. Patients will respond first to the PHQ-2. Patients will 
respond to questions 3 through 9 (unique questions) of the PHQ-9 only if PHQ-2 is 
positive. 
• complete the MSQOL questionnaire 

 
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• complete the EQ-5D-5L questionnaire 
• complete PGIC scale 
• complete WPAI questionnaire 
• complete eC-SSRS 
• inquire about adverse events and health care resource utilization  
• inquire about concomitant medication 
After completing pre-dose assessments, patients will be treated with IMP (for additional 
details regarding IMP administration, refer to Section 5.1). 
The following procedures and assessments will be performed at visit 5 (week 12) after 
dosing: 
• assess hypersensitivity and anaphylaxis 
• inquire about post-dose adverse events before the patient leaves the study center 
Visit 6 (week 16, day 112±5 days) 
The following pre-dose procedures and assessments will be performed at visit 6: 
• perform clinical laboratory tests (serum chemistry, hematology and coagulation, 
urinalysis) 
• perform vital signs measurements 
• perform urine pregnancy test (women of child bearing potential only) 
• review study compliance 
• review electronic headache diary 
• obtain blood samples for plasma concentration of IMP prior to dosing 
• obtain a blood sample for serum ADA assay prior to dosing 
• obtain blood collection for serum, plasma, and RNA biomarker analysis 
• obtain urine sample for biomarker analysis 
• collect a saliva sample for biomarker analysis 
• complete eC-SSRS 
• inquire about adverse events and health care resource utilization  
• inquire about concomitant medication 
After completing pre-dose assessments, patients will be treated with IMP (for additional 
details regarding IMP administration, refer to Section 5.1). 
The following procedures and assessments will be performed at visit 6 (week16) after 
dosing: 

 
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• assess hypersensitivity and anaphylaxis 
• inquire about post-dose adverse events before the patient leaves the study center 
Visit 7 (week 20, day 140±5 days) 
The following pre-dose procedures and assessments will be performed at visit 7: 
• perform vital signs measurements 
• perform urine pregnancy test (women of child bearing potential only) 
• review study compliance 
• review electronic headache diary 
• complete eC-SSRS 
• inquire about adverse events and health care resource utilization  
• inquire about concomitant medication 
After completing pre-dose assessments, patients will be treated with IMP (for additional 
details regarding IMP administration, refer to Section 5.1). 
The following procedures and assessments will be performed at visit 7 (week 20) after 
dosing: 
• assess hypersensitivity and anaphylaxis 
• inquire about post-dose adverse events before the patient leaves the study center 
4. Procedures for End-of-Treatment/Early Termination (Week 24, Visit 8, Day 168±5 
Days) 
The following procedures and assessments will be performed at the EOT visit (visit 8)/early 
withdrawal visit: 
• perform clinical laboratory tests (serum chemistry, hematology and coagulation, 
urinalysis) 
• perform physical examination, including weight 
• perform 12-lead ECGs in triplicate 
• perform vital signs measurements 
• perform β-HCG serum pregnancy test (for women of child-bearing potential) 
•  perform urine pregnancy test (women of child bearing potential only) 
• review study compliance 
• review electronic headache diary and return diary device 
• obtain blood samples for plasma concentration of IMP 
• obtain a blood sample for serum ADA assay 

 
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• obtain blood collection for serum, plasma, and RNA biomarker analysis 
• obtain urine collection for biomarker analysis 
• collect a saliva sample for biomarker analysis 
• complete HIT-6 
• complete MIDAS 
• complete PHQ-2/ PHQ-9. Patients will respond first to the PHQ-2. Patients will 
respond to questions 3 through 9 (unique questions) of the PHQ-9 only if PHQ-2 is 
positive. 
• complete MSQOL questionnaire 
• completeEQ-5D-5L questionnaire 
• complete PGIC scale 
• complete WPAI questionnaire 
• complete eC-SSRS 
• inquire about adverse events and health care resource utilization  
• inquire about concomitant medication 
• assess hypersensitivity and anaphylaxis 
5. Procedures for Follow up Period (Week 46, Visit 9, Day 320±15 Days) 
The following procedures and assessments will be performed at the follow up visit (visit 9): 
• Perform vital signs measurements 
• obtain a blood sample for serum ADA assay 
• inquire about adverse events and health care resource utilization 
• inquire about concomitant medication 
6. Procedures for Unscheduled Visits 
An unscheduled visit may be performed at any time during the study at the patient’s request 
and 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 from procedures and 
assessments. 
Procedures performed during unscheduled visits include: 
• review electronic diary data 
• review study compliance 
• perform vital signs measurements 
• inquire about adverse events and health care resource utilization  

 
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• inquire about/review concomitant medications 
• complete the eC-SSRS Since Last Visit version 
Other procedures and assessments may be performed at the discretion of the investigator. 

 
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APPENDIX C. QUALITY CONTROL AND QUALITY ASSURANCE 
Protocol Amendments and Protocol Deviations 
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. 
Important Deviations 
Any deviation from the protocol that affects, to a significant degree, (a) the safety, physical, or 
mental integrity of the patients in the study and/or (b) the scientific value of the study will be 
considered a protocol deviation. Protocol deviations may include non-adherence 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 IMP administration; 
use of prohibited medications. All protocol deviations will be reported to the responsible 
IEC/IRB, as required. 
When a protocol deviation is reported, the sponsor will determine whether to withdraw 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. 
Waivers 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 deviation. If such patient has already completed the study or has 
withdrawn early, no action will be taken but the deviation will be recorded. 
Information to Study Personnel 
The investigator is responsible for giving information about the study to all personnel 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 personnel become involved). The investigator must 
ensure that all study personnel are qualified by education, experience, and training to perform 
their specific task. These study personnel members must be listed on the investigational center 
authorization form, which includes a clear description of each personnel 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 personnel, including the 
investigator, and for ensuring they comply with the protocol. 

 
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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 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 according 
to the monitoring plan. The study monitor will be permitted to review and verify the various 
records (CRFs and other pertinent source data records, including specific electronic source 
document relating to the study) to verify adherence to the protocol and to ensure the 
completeness, consistency, and accuracy of the data being recorded. 
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 personnel must agree to cooperate with the study monitor to resolve any problems, 
errors, or possible misunderstandings concerning the findings detected during the course of these 
monitoring visits or provided in follow-up written communication. 
Audit and Inspection 
The sponsor may audit the investigational center to evaluate study conduct and compliance with 
protocols, SOPs, GCP guidelines, and applicable regulatory requirements. The sponsor’s Global 
Clinical Quality Assurance, independent of Global Specialty Development, is responsible for 
determining the need for (and timing of) an investigational center audit. 
The investigator must accept that competent authorities and sponsor representatives may conduct 
inspections and audits to verify compliance with GCP guidelines. 

 
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APPENDIX D. ETHICS 
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 oral information about the study will be provided in a language as 
nontechnical as practical to be 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 documents. 
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. The patient’s willingness to participate in the study will be 
documented in the informed 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 informed 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 participation in the study and free to 
withdraw from the study at any time without prejudice to future treatment. 
Adult patients with a legally acceptable representative should provide informed consent 
according to national and local requirements. 
Competent Authorities and Independent Ethics Committees/Institutional Review Boards 
Before this study starts, the protocol will be submitted to the national competent authority and to 
the respective IEC/IRB for review. As required, the study will not start at a given investigational 
center before the IEC/IRB and competent authority (as applicable) for the investigational center 
have given written approval or a favorable opinion. 
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 number. 
Personal medical information may be reviewed for the purpose of patient safety or for verifying 
data in the source and the CRF. This review may be conducted by the study monitor, properly 
authorized persons on behalf of the sponsor, Global Quality Assurance (GCA), or competent 
authorities. Personal medical information will always be treated as confidential. 
Registration of the Clinical Study 
In compliance with national and local regulations and in accordance with Teva standard 
procedures, this clinical study will be registered on trials registry websites. 

 
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APPENDIX E. 
BIRTH CONTROL METHODS AND PREGNANCY 
TESTING 
Assessment of likelihood of possible interaction between investigational medicinal product 
(IMP) or concomitant medications and hormonal contraception should be conducted. Hormonal 
contraception may be susceptible to interaction with the IMP, which may reduce the efficacy of 
the contraception method. 
Drug interaction studies have not been conducted with fremanezumab. Like other therapeutic 
antibodies, fremanezumab is expected to be primarily metabolized via proteolytic catabolism. 
Therefore, interaction with and impact on drug metabolizing enzymes (eg, CYP isoforms) is 
considered unlikely in humans. 
In addition, fremanezumab is not expected to indirectly influence the CYP enzymes. In general, 
protein products that are cytokine modulators have been reported to affect the metabolism or 
disposition of co-administered medication by altering CYP enzymes/transporters (FDA 2012). 
Fremanezumab is an IgG2 isotype that is directed against a non-immunologic and soluble (not 
cell bound) target. Thus, the risk of cytokine release is considered to be low in the clinical 
setting. Furthermore, fremanezumab was tested for stimulation of pro-inflammatory cytokine 
release in human whole blood (Study 111320). Fremanezumab did not elicit significant cytokine 
release (TNF-α, IL-6, INF-γ, or IL-1β) in any donor including at concentrations up to 
100 μg/mL. As such, there is no reason to suspect that fremanezumab may influence CYP 
activity. 
Women of non-childbearing potential are defined as: 
• Surgically (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy) or 
congenitally sterile 
• One year postmenopausal (stable amenorrhea for 12 months without alternative 
medical cause plus high follicle-stimulating hormone (FSH) in the postmenopausal 
range) in women not using hormonal contraception or hormonal replacement therapy 
• Women in stable post-menopause, but are taking hormone replacement therapy for 
the treatment of menopausal symptoms, may be considered eligible for the study even 
with the lower serum FSH. They do not need to use other contraception. 
Highly effective birth control methods: 
Highly effective birth control methods are methods that can achieve a failure rate of less than 
1% per year when used consistently and correctly are considered. Such methods include the 
following: 
• Combined estrogen and progestogen hormonal contraception (oral, intravaginal, or 
transdermal) associated with inhibition of ovulation; these should be initiated at least 
7 days before the first dose of IMP. 

 
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• Progestogen-only hormonal contraception (oral, injectable, or implantable) associated 
with inhibition of ovulation; these should be initiated at least 7 days before the first 
dose of IMP. 
• Intrauterine device (IUD) and intrauterine hormone-releasing system (IUS) need to be 
in place at least 2 months before screening. 
• Bilateral tubal occlusion  
• vasectomized partner provided that he is the sole sexual partner and has received 
medical assessment of the surgical process. 
• 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 patient. 
• 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 (according to Medicines and Healthcare 
Products Regulatory Agency). 
Acceptable birth control methods: 
Acceptable birth control methods that result in a failure rate of more than 1% per year include 
progestogen-only oral hormonal contraception for which the inhibition of ovulation is not the 
primary mode of action; male or female condom with or without spermicide; cap; diaphragm; or 
sponge with spermicide. The combinations of male condom with cap, diaphragm, or sponge with 
spermicide (double-barrier methods) are also considered acceptable but not highly effective 
methods of birth control. 
Unacceptable birth control methods: 
Periodic abstinence (calendar, symptothermal, or post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and lactational amenorrhea method are not acceptable methods of 
contraception. Female condom and male condom should not be used together. 
Male contraception: 
Male subjects must always use a condom. 
Vasectomy: 
Use of contraceptive methods applies also to vasectomized men. 
Pregnant female partners of male study participants: 
Male study participants must use condoms during intercourse if their female partners are 
pregnant. 

 
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APPENDIX F. LOST TO FOLLOW-UP 
A patient will be considered lost to follow-up if he/she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the investigational center. 
The following actions must be taken if a patient fails to return to the investigational center for a 
required study visit: 
• The investigational center must attempt to contact the patient and reschedule the 
missed visit as soon as possible and counsel the patient on the importance of 
maintaining the assigned visit schedule and ascertain whether or not the patient 
wishes to and/or should continue in the study. 
• In cases in which the patient is deemed lost to follow-up, the investigator or designee 
must make every effort to regain contact with the patient (where possible, 3 telephone 
calls and, if necessary, a certified letter to the patient’s last known mailing address or 
local equivalent methods). These contact attempts should be documented in the 
patient’s medical record. 
• Should the patient continue to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of ‘lost to follow-up’. 

 
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APPENDIX G. HANDLING, LABELING, STORAGE, AND 
ACCOUNTABILITY FOR INVESTIGATIONAL 
MEDICINAL PRODUCT(S) 
Storage and Security 
The investigator or designee must confirm appropriate temperature conditions have been 
maintained for all IMPs received and any discrepancies are reported and resolved before use of 
the IMPs. 
The IMPs (fremanezumab and placebo IMP must be stored refrigerated at 2°C to 8°C (36°F 
to 46°F) and protected from light. The sites should have a process for monitoring the drug 
storage temperature. 
Fremanezumab and placebo supplies must be kept in a secure area (eg, locked refrigerator) with 
access limited to the investigator and authorized staff at the investigational center. 
Diversion is considered to have occurred when the legal supply chain of prescription analgesic 
medicinal products is broken, and medicinal products are transferred from a licit to an illicit 
channel of distribution or use. 
Labeling 
Supplies of IMPs will be labeled according to the current International Council for 
Harmonisation (ICH) guidelines on Good Clinical Practice (GCP) and Good Manufacturing 
Practice and will include any locally required statements. If necessary, labels will be translated 
into the local language. 
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 materials from Teva are correctly, safely, and properly disposed of in accordance 
with local regulations. 
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. 

 
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APPENDIX H. MEDICATIONS TO EVALUATE PATIENT 
QUALIFICATION FOR INADEQUATE RESPONSE TO 
PRIOR TREATMENTAND DISALLOWED DURING THE 
RUN-IN TREATMENT PERIOD, AND FOLLOW-UP 
PERIOD  
(Martelletti et al 2014) 
The use of the medications listed below on a daily basis for other indications is disallowed for 
the duration of the study. 
• beta-blockers: propranolol, metoprolol, atenolol, and bisopropol 
• anticonvulsants:topiramate 
• tricyclics: amytriptyline 
• calcium channel blocker: flunarizine 
• angiotensin II receptor antagonist: candesartan 
• onabotulinumtoxinA 
• valproic acid 
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. 
Definition of Inadequate Response to Prior Treatment 
• Patients must have documented inadequate response (in medical chart or by treating 
physician’s confirmation) to 2 to 4 classes of prior preventive medications from the 
list above regardless of which class the medication belongs to. 
• Inadequate response is defined as: no clinically meaningful improvement per treating 
physician’s judgment, after at least 3 months of therapy at a stable dose considered 
appropriate for migraine prevention according to accepted country guidelines, or 
when treatment has to be interrupted because of adverse events that made it 
intolerable by the patient or the drug is contraindicated or not suitable for the patient. 
The 3  month period does not apply if the drug is intolerable or contraindicated or not 
suitable for the patient.  
• If onabotulinumtoxinA is a previous preventive medication, at least 2 sets of 
injections and 3 months must have passed since the last set of injections prior to the 
screening visit 
   

 
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APPENDIX I. ACCEPTABLE DOCUMENTATION OF PREVIOUS 
TREATMENT FAILURES 
Medical record with medication’s name (from Appendix H), treatment duration, dose level and 
reasons for discontinuation 
OR 
If the principal investigator is also the treating physician, the principal investigator can provide a 
dated and signed written note with the above information 
OR 
If the principal investigator is not the treating physician, the principal investigator can interview 
the treating physician to confirm the above information and document the interview with date 
and his/her signature 

 
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APPENDIX J. TOTAL BLOOD VOLUME 
Total blood volume to be collected for each patient in this study is approximately 180.5 mL. 
Total Blood Volumes 
Type of samples 
Volume per sample (mL) 
Total number of samples 
Total volume (mL) 
Serum chemistry, 
hematology, and 
coagulation 
6.5 
6 
39 
Serum β-HCG testa 
3 
2 
6 
FSHb 
3 
1 
3 
Pharmacokinetics 
4 
6 
24 
ADA 
5 
6 
30 
Biomarker 
14.5c 
5 
72.5 
Pharmacogenomicd 
6 
1 
6 
Total 
-- 
26 
180.5 
a A serum pregnancy test will be performed for women of childbearing potential at screening and at visit 8. 
b Postmenopausal women only. 
c For each 14.5 mL sample, individual volumes will be 6 mL each for serum and plasma and 2.5 mL for RNA. 
d For patients who consent to pharmacogenomics testing. 
ADA=antidrug antibody; β-HCG=beta-human chorionic gonadotropin; FSH=follicle-stimulating hormone; 
RNA=ribonucleic acid. 

 
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Appendix K. 
PHARMACOKINETICS SAMPLES 
Specimen Sampling and Handling 
For plasma collection, samples will be collected in K2EDTA anticoagulant tubes, inverted 
slowly 6 to 8 times to mix the contents, and placed on water/ice (approximately 4°C). Blood 
samples will be centrifuged (1500g, approximately 10 minutes, at 2 to 8°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 in the 2 provided labeled 2-mL polypropylene tubes 
(Sets A and B). 
Labels for samples should include study number, patient randomization number, nominal 
collection time (Visit number), Set A or B, and indication that they are pharmacokinetics 
samples. Samples will be stored at a temperature of -20°C in an upright position until they are 
shipped to the central laboratory. 
Shipment and Analysis of Samples 
Plasma samples set A for all patients will be shipped from the investigational center to the 
central laboratory, where they will be stored until shipped to the sponsor or designee for analysis. 
Plasma samples set B for all patients will be shipped from the investigational center to the central 
laboratory once the set A samples are received at the central laboratory. Samples will be stored 
in an upright position at –70ºC (or at/below -20°C if no -70°C freezer available) until shipment 
to bioanalytical laboratory. The bioanalytical laboratory will be notified before the shipment of 
the samples and will be sent the shipping information including the sample manifest when the 
samples are shipped. An electronic file containing the sample manifest  will be emailed to the 
bioanalytical laboratory and the sponsor’s representatives from bioanalytical departments for 
each shipment. 
Set A samples will be transported with a temperature data logger and frozen with dry ice 
sufficient for 4 days, by next-day courier to the central laboratory or bioanalytical laboratory. 
Set B samples will be shipped with a temperature data logger to the central laboratory and kept 
there until the end of the study unless requested by the sponsor. Instructions as to the disposition 
of the Set B samples will be provided by the sponsor. 
Sample shipments should be sent no later in the week than Wednesday morning for next-day 
delivery. Samples are not to arrive on the weekend. 
Samples will be analyzed using an appropriate validated method. Timing of the initiation of 
sample analysis will be determined by the sponsor’s representatives of bioanalytical departments 
responsible for the bioanalysis while keeping the study blinding, if any, intact. 

 
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Appendix L. 
IMMUNOGENICITY SAMPLES 
Blood Sampling and Handling 
For serum collection, samples will be collected in Vacutainer tubes containing no anticoagulant, 
and allowed to set at room temperature for between 1 and 1.5 hours to allow for serum separation 
to occur. Samples will then be centrifuged (1500 g, approximately 10 minutes, at 2 to 8°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 in the 2 
provided labeled 2-mL polypropylene tubes (Sets A and B). 
The sample vial label should include study number, patient randomization number, nominal 
collection time (Visit number), Set A or B, and indication that they are ADA samples. Serum 
samples will be stored at a temperature of -20°C in an upright position until they are shipped to 
the central laboratory. 
Shipment and Analysis of Samples 
Serum samples for set A all patients will be shipped from the investigational center to the central 
laboratory, where they will be stored until shipped to the sponsor or designee for analysis. 
Plasma samples set B for all patients will be shipped from the investigational center to the central 
laboratory once the set A samples are received at the central laboratory. Samples will be stored 
in an upright position at –70ºC (or at/below -20°C if no -70°C freezer available) until shipment 
to bioanalytical laboratory. The bioanalytical laboratory will be notified before the shipment of 
the samples and will be sent the shipping information including the sample manifest when the 
samples are shipped. An electronic file containing the sample manifest will be emailed to the 
bioanalytical laboratory and the sponsor’s representatives from bioanalytical departments for 
each shipment. 
Set A samples will be transported frozen, with a temperature data logger and with dry ice 
sufficient for 4 days, by next-day courier to the central laboratory. 
Set B samples will be shipped with a temperature data logger to the central laboratory and kept 
there until the end of the study unless requested by the sponsor. Instructions as to the disposition 
of the Set B samples will be provided by the sponsor. 
Sample shipments should be sent no later in the week than Wednesday morning for next-day 
delivery. Samples are not to arrive on the weekend. 
Samples will be analyzed using an appropriate validated method. Timing of the initiation of 
sample analysis will be determined by the sponsor’s representatives of bioanalytical departments 
responsible for the bioanalysis while keeping the study blinding, if any, intact. 

 
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Appendix M. 
EXPLORATORY BIOMARKERS SAMPLES 
Blood and Urine Samples 
Blood samples (total of 14.5 mL; 6 mL each for plasma and serum and 2.5 mL for RNA 
[PAXgene]) will be collected via venipuncture or indwelling catheter at the time points detailed 
in Table 2 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 (or a 
later visit) for DNA. Blood samples for serum and plasma should be processed within 
3-5 minutes of collection. 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 code number. Following DNA 
extraction from the pharmacogenomic sample, the sample will be labeled with a new code 
(ie, double coding), so that genetic data will not be recorded with a patient number.  
Samples will be stored for a period of up to 15 years from the last patient’s last visit in the study 
and then destroyed. 
Shipment and Analysis of Blood and Urine Samples 
Biomarker samples for serum, plasma, RNA, and urine will be stored within 3-5 minutes of 
processing at –70°C (or at/below -20°C if no -70°C freezer available) 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 the laboratory 
manual. An electronic file containing sample demographics will be emailed 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 (or 
at/below -20°C if no -70°C freezer available) 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. 
Saliva Samples 
Saliva samples should be collected using standard procedures as described in the Saliva 
Collection Handbook (SalivaBio). Briefly, saliva samples should be collected into high quality 
polypropylene tubes. Because saliva is subject to blood contamination, patients should not have 
blood in their mouth and should not have had dental procedures within 24 hours or brushed their 
teeth within the last hour prior to collection. They also should not have eaten a meal within the 
last hour prior to collection, and they should rinse their mouths with water 10 minutes before 
giving the saliva sample.  
The most optimal method for collecting is via a method known as “passive drool.” Patients 
should allow saliva to pool in their mouths for 1-2 minutes, then bring collection tube to their 

 
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mouth and allow the pooled saliva to spill into the collection tube. This should be repeated until 
sufficient volume is collected. It is important to leave approximately 15 to 20% of open air space 
in the tube to allow for expansion of saliva after freezing. Once the proper volume has been 
collected, the tube should be capped and frozen within 3-5 minutes at -70°C (or at/below -20°C 
if no -70°C freezer available) and stored at -70°C (or at/below -20°C if no -70°C freezer 
available) until it is shipped to the sample repository. 

 
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APPENDIX N. PHARMACOGENETIC ASSESSMENTS 
Blood samples (6 mL) for pharmacogenetic assessments will be collected from all patients in the 
study who signed the ICF for the pharmacogenetic assessments at the time point detailed in 
Table 2. Pharmacogenetic assessment potentially includes the association of DNA variations in 
specific genes of interest with clinical responses to test IMP (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 might be investigated will be selected at a later stage before the analysis to allow 
updating with new scientific information. Genetic analysis could also include sequencing of the 
whole genome if required. 
Pharmacogenetic assessment will be performed based on study results. Samples will be used 
only for investigations related to headache or response to fremanezumab or related 
investigational medicinal products. 
Details on processes for collection and shipment of these samples can be found in the procedural 
manual. 

 
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APPENDIX O. PRODUCT COMPLAINTS 
Clinical Product Complaints 
A clinical product complaint is defined as a problem or potential problem with the physical 
quality or characteristics of clinical IMP supplies or clinical device supplies used in a clinical 
research study sponsored by Teva. Examples of a product complaint include but are not limited 
to: 
• suspected contamination 
• questionable stability (eg, color change, flaking, crumbling, etc) 
• defective components 
• missing or extra units (eg, primary container is received at the investigational center 
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 
• 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 an IMP, all relevant samples (eg, the remainder of the patient’s IMP supply) should be 
sent back to the sponsor for investigative testing whenever possible. 
1. Product Complaint Information Needed from the Investigational Center 
In the event that the product complaint form cannot be completed, the investigator will provide 
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 
• product name and strength for open-label studies 
• patient number, bottle, and kit numbers (if applicable) for double-blind or open-label 
studies 
• product available for return Yes/No 
• product was taken or used according to protocol Yes/No 

 
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• description or nature of complaint 
• associated serious adverse event Yes/No 
• clinical supplies unblinded (for blinded studies) Yes/No 
• date and name of person receiving the complaint 
Note: Reporting a product complaint must not be delayed even if not all the required information 
can be obtained immediately. Known information must be reported immediately. The sponsor 
will collaborate with the investigator to obtain any outstanding information. 
2. Handling of Investigational Medicinal Product(s) at the Investigational Center(s) 
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 IMP. 
If it is determined that the investigational center must return all IMP, 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 
problem existing beyond the scope of the complaint may be a reason to unblind the clinical 
supplies for an affected patient. 
3. Adverse Events or Serious Adverse Events Associated with a Product Complaint 
If there is an adverse event or serious adverse event due to product complaint, the protocol 
should be followed for recording and reporting (Section 7.1.2 and Section 7.1.5.3, respectively). 
4. Documenting a Product Complaint 
The investigator will record in the source documentation a description of the product complaint, 
and 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. 
Medical device incidents, including those resulting from malfunctions of the device, must be 
detected, documented, and reported by the investigator throughout the study. 

 
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Appendix P. 
DATA MANAGEMENT AND RECORD KEEPING 
Direct Access to Source Data and Documents 
All patient data must have supportive original source documentation in the medical records, or 
equivalent, before they are transcribed to the CRF. Data may not be recorded directly on the CRF 
and considered as source data unless the sponsor provides written instructions specifying which 
data are permitted to be recorded directly to the CRF. 
If data are processed from other institutions or by other means (eg, clinical laboratory, central 
image center, or electronic diary data) the results will be sent to the investigational center, where 
they will be retained but not transcribed to the CRF, unless otherwise noted in the protocol. 
These data may also be sent electronically to the sponsor (or organization performing data 
management). 
The medical experts, study monitors, auditors, IEC/IRB, and inspectors from competent 
authority (or their agents) will be given direct access to source data and documents (eg, medical 
charts/records, laboratory test results, printouts, videotapes) for source data verification, provided 
that patient confidentiality is maintained in accordance with national and local requirements. 
The investigator must maintain the original records (ie, source documents) of each patient’s data 
at all times. The investigator must maintain a confidential patient identification list that allows 
the unambiguous identification of each patient. 
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 (USA) and documents of other concerned 
competent authorities. Before using the CDMS, it will be fully validated and 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. 
If data are processed from other sources (eg, central laboratory, bioanalytical laboratory, central 
image center, electronic diary data, electronic patient-reported outcome [ePRO] tablet), these 
data will be sent to the investigational center, where they will be retained but not transcribed to 
the CRF, unless otherwise noted in the protocol. These data may also be sent electronically to the 
sponsor (or organization performing data management). All patient data must have supportive 
original source documentation in the medical records, or equivalent, before they are transcribed 
to the CRF. Data may not be recorded directly on the CRF and considered as source data unless 
the sponsor provides written instructions specifying which data are permitted to be recorded 
directly to the CRF. 

 
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For patients who enter a study but do not meet entry criteria, at a minimum, data for screening 
failure reason, demography, and adverse events from the time of informed consent will be 
entered in the CRF. 
Data Quality Control 
Data Management is responsible for the accuracy, quality, completeness, and internal 
consistency of the data from this study. 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 contract organization, 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. 
Data will be verified by the study monitor using the data source, and reviewed by Data 
Management using both automated logical checks and manual review. Data identified as 
erroneous, or data that are missing, will be referred to the investigational center for resolution 
through data queries. 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 and any discrepancies will be queried. 
Applicable terms will be coded according to the coding conventions for this study. 
An interim database lock will occur following the end-of-double-blind treatment visit (visit 5) of 
the last patient. A second interim lock will occur following the end of the open-label period. 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. 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. 
Archiving of Case Report Forms and Source Documents 
Sponsor Responsibilities 
The original CRFs will be archived by the sponsor. Investigational center-specific CRFs will be 
provided to the respective investigational centers for archiving. 
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 national and local laws, including, but not limited to: 
• full case histories 
• signed informed consent forms 
• patient identification lists 
• case report forms for each patient on a per-visit basis 
• data from other sources (eg, central laboratory, bioanalytical laboratory, central image 
center, electronic diary) 

 
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• safety reports 
• financial disclosure reports/forms 
• reports of receipt, use, and disposition of the IMPs 
• copies of all correspondence with sponsor, the IEC/IRB, and any competent authority 
The investigator will retain all records related to the study and any additional records required, as 
indicated by the protocol and according to applicable laws and regulations, until the CRO or 
sponsor notifies the institution in writing that records may be destroyed. If, after 25 years from 
study completion, or earlier in the case of the investigational 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 60 days before any planned 
disposition of study records. After receipt of such request, the sponsor may make arrangements 
for appropriate archival or 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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APPENDIX Q. PUBLICATION POLICY 
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 results of this study may be published or presented at scientific meetings. If this is foreseen, 
the investigator agrees to submit all manuscripts or abstracts to the sponsor before submission. 
This allows the sponsor to protect proprietary information and to provide comments. 
The sponsor will comply with the requirements for publication of study results: 
“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. In accordance with standard editorial and ethical practice, 
the sponsor will generally support publication of multicenter studies only in their entirety and not 
as individual investigational center data. In this case, a coordinating investigator will be 
designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International Committee of 
Medical Journal Editors authorship requirements: 
• 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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APPENDIX R. GUIDANCE ON SAFETY MONITORING 
Guidance on Monitoring Patients with Elevated Liver Function Tests 
Liver enzymes (ALT, AST, GGT, and ALP) as well as total, direct, and indirect bilirubin will be 
measured 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, direct, or indirect 
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 IMP discontinuation in cases of elevation of either ALT or AST 
≥3 × ULN. (Note: In cases of elevation of ALT or AST ≥8 × the ULN, no confirmation is 
required prior to IMP discontinuation, but the assessments below should be performed.) The 
following procedures should be followed: 
• The 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 cell [CBC] count 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, bilirubin [total, direct, and indirect], 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 
                                                 
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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• the baseline value was above the ULN and ALT or AST is ≥2 × the baseline value 
Additional Tests/Evaluations: 
Upon confirmation of the abnormality as noted above, the following additional evaluations 
should be performed and results should be recorded in the CRF: 
• serology for hepatitis A (antibody and immunoglobulins M and G), B (core antibody 
total, core immunoglobulin M, 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 <5 × the 
ULN 
In addition to the above procedures required for any elevation to levels >3 × the ULN: 
• Alanine aminotransferase, AST, GGT, ALP, total bilirubin, direct bilirubin, indirect 
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 bilirubin, direct bilirubin, 
indirect bilirubin should be sent to the central laboratory at least once a month. 
ALT or AST ≥5 × but <8 × the ULN 
In addition to the above procedures required for any elevation to levels >3 × the ULN: 
• Alanine aminotransferase, AST, GGT, ALP, total bilirubin, direct bilirubin, indirect 
bilirubin, CBC and differential count (to assess for eosinophilia), and INR should be 
monitored twice a week. 

 
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• 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: 
• The IMP 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 IMP will be discontinued immediately: 
• any increase in ALT or AST to ≥3 × the ULN, combined with INR >1.5 × the ULN 
or total bilirubin >2 × the ULN 
• any increase in ALT or AST to ≥3 × the ULN, which is accompanied by symptoms 
clearly associated with impaired liver function (eg, vomiting, nausea, fever, rash, and 
eosinophilia) and not deemed related to other diseases (eg, vomiting or nausea 
triggered by cluster headache) 
• any increase in ALT or AST to levels ≥5 but <8 × the ULN, which is persistent for 
≥2 weeks of repeated measurements 
• any increase in ALT or AST to levels ≥8 × the ULN 
• in any case where monitoring of liver enzymes cannot be performed according to the 
protocol guidance 
Follow-Up of Liver Enzymes After Stopping Rules Are Met 
• A patient who meets the above criteria for discontinuation of the IMP should be 
invited to the investigational site to return the IMP. 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 S. CLINICAL CRITERIA FOR DIAGNOSING 
ANAPHYLAXIS 
As detailed by Sampson et al 2006, anaphylaxis is broadly defined as, “a serious allergic reaction 
that is rapid in onset and may cause death.” Diagnostic criteria defined by the National Institute 
of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network during the second 
symposium on the definition and management of anaphylaxis, modified from Sampson et al 
2006, are as follows: 
Anaphylaxis is highly likely when any 1 of the following 3 criteria is fulfilled: 
5. 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 1 of the following: 
a. respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced peak 
expiratory flow [PEF], hypoxemia) 
b. reduced blood pressure or associated symptoms of end-organ dysfunction 
(eg, hypotonia [collapse], syncope, incontinence) 
6. Two or more of the following that occur rapidly after exposure to a likely allergen for 
that patient (minutes to several hours): 
a. involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, swollen 
lips-tongue-uvula) 
b. respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia) 
c. reduced blood pressure or associated symptoms (eg, hypotonia [collapse], syncope, 
incontinence) 
d. persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting) 
7. Reduced blood pressure after exposure to known allergen for that patient (minutes to 
several hours): 
a. adults: systolic blood pressure of <90 mm Hg or >30% decrease from that person’s 
baseline 
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. 
As a precaution, each investigational site should have a resuscitation cart nearby. 

 
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APPENDIX T. CLINICAL LABORATORY TESTS 
Clinical Laboratory Tests 
Serum Chemistry 
Hematology and Coagulation 
Urinalysis 
Calcium 
Phosphate 
Sodium 
Potassium 
Chloride 
Creatinine 
Glucose 
Blood urea nitrogen (BUN) 
Low density lipoprotein (LDL) 
High density lipoprotein (HDL) 
Triglycerides 
Urate 
Alanine aminotransferase (ALT) 
Aspartate aminotransferase (AST) 
Lactate dehydrogenase (LDH) 
Gamma-glutamyl transpeptidase (GGT) 
Alkaline phosphatase 
Bicarbonate 
Carbon dioxide 
Protein 
Albumin 
Bilirubin 
Direct bilirubin 
Hemoglobin 
Hematocrit 
Erythrocytes 
Platelets 
Leucocytes 
− Neutrophils 
− Lymphocytes 
− Eosinophils 
− Monocytes 
− Basophils 
Lymphocytes atypical 
Prothrombin International Normalized 
Ratio (INR) 
Protein 
Glucose 
Ketones 
Hemoglobin 
pH 
Specific gravity 
Microscopic tests 
− Bacteria 
− Erythrocytes 
− Leucocytes 
− Crystals 
− Casts 

 
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APPENDIX U. ICHD-3 DIAGNOSTIC CRITERIA 
For further details, refer to IHS 2013. 
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. e. not better accounted for by another ICHD-3 diagnosis 
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 V. INJECTION INSTRUCTIONS 
 

 
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