Clinical trial NCT05458011
Conditions: Migraine
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc.
Start date: 2022-09-30; Completion date: 2024-06-13
Enrollment: 365 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Primary Objective:

To demonstrate the efficacy of fremanezumab administered as monthly and quarterly subcutaneous (sc) injections to adult Chinese participants with migraine.

Secondary Objectives:

* To further demonstrate the efficacy of fremanezumab administered as monthly and quarterly sc injections.
* To evaluate the safety and tolerability of fremanezumab administered as monthly and quarterly sc injections.

Detailed description:
The total study duration for participants is planned to be approximately 9 months. The study will consist of a screening visit, a baseline period (4 weeks), a 12-week double-blind treatment period, a 12-week open-label treatment period, and a follow-up period lasting approximately 3 months after the last dose of treatment.

Arms: arm 1: Double Blind (DB) Period: Participants will receive fremanezumab once a month (approximately every 4 weeks). Participants will receive a single injection of fremanezumab and two placebo injections on Day 1, and a single injection of fremanezumab on Days 29 and 57.

Open Label (OL) Period: Participants will receive fremanezumab once a month (approximately every 4 weeks) administered as a single injection on Days 85, 113, and 141. arm 2: DB Period: Participants will receive fremanezumab once a quarter (once at the beginning of the 12-week double-blind treatment period). Participants will receive 3 injections of fremanezumab on Day 1, and a single placebo injection on Days 29 and 57.

OL Period: Participants will receive fremanezumab once a month (approximately every 4 weeks) administered as a single injection on Days 85, 113, and 141. arm 3: DB Period: Participants will receive placebo once a month (approximately every 4 weeks). Participants will receive 3 placebo injections on Day 1, and a single injection of placebo on Days 29 and 57.

OL Period: Participants will receive fremanezumab once a month (approximately every 4 weeks) administered as a single injection on Days 85, 113, and 141.
Interventions: intervention 1: Fremanezumab intervention 2: Placebo
Intervention descriptions: intervention 1: Pharmaceutical form: solution for injection

Route of administration: subcutaneous injection intervention 2: Pharmaceutical form: solution for injection

Route of administration: subcutaneous injection

Protocol documents:
Prot_000.pdf: 
Clinical Study Protocol 
A Randomized, Double-Blind, Placebo-Controlled Study with an Open-Label 
Period on Efficacy and Safety of Fremanezumab in Chinese Adults with Migraine 
Study Number TV48125-CNS-30088 
NCT05458011 
Protocol with Amendment 02 Approval Date: 08 March 2023 


 
Placebo-Controlled Study–Migraine 
Clinical Study Protocol with Amendment 02 with Revision 01 
Study TV48125-CNS-30088 
 
1 
 
  
Clinical Study Protocol with Amendment 02 with Revision 01 
Study Number TV48125-CNS-30088 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Efficacy and Safety Study 
with an Open-Label Treatment Period of Fremanezumab Administered Subcutaneously 
Monthly or Quarterly for the Preventive Treatment of Migraine in Adult Chinese Patients  
A Randomized, Double-Blind, Placebo-Controlled Study with an Open-Label Period on 
Efficacy and Safety of Fremanezumab in Chinese Adults with Migraine 
A Study to Test if Fremanezumab is Effective in Relieving Migraine 
Efficacy and Safety Study (Phase 3) 
IND number: Not applicable; NDA number: Not applicable;  BLA number: Not 
applicable; 
EudraCT number: Not applicable 
EMA Decision number of Pediatric Investigation Plan: P/0411/2019 
Article 45 or 46 of 1901/2006 does not apply 
 
Protocol with Amendment 02 with Revision 01 Version Date: 08 March 2023 
Sponsor 
Teva Branded Pharmaceutical Products R&D, Inc. 
145 Brandywine Parkway 
West Chester, Pennsylvania 19380 
United States of America 
 
Information regarding clinical laboratories and other departments and institutions is 
found in Appendix A 
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; current GCP as directed by China 
National Medical Products Administration and National Health Commission; United States Code of 
Federal Regulations and European Union Directives and Regulations (as applicable in the region of the 
study); national country legislation; and the sponsor’s Standard Operating Procedures. 
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. 
© 2023 Teva Branded Pharmaceutical Products R&D, Inc. All rights reserved. 
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AMENDMENT HISTORY  
The protocol for Study TV48125-CNS-30088 (original protocol dated 11 November 2020) has 
been amended and reissued as follows: 
Amendment 02 with Revision 01 
08 March 2023 
22 patients randomized/enrolled to date 
Amendment 02 
14 February 2023 
20 patients randomized/enrolled to date 
Administrative Letter 01 
26 July 2022 
Amendment 01 
15 September 2021 
0 patients randomized/enrolled to date 
Revision 01 
01 April 2021 
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. 
 
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INVESTIGATOR AGREEMENT  
Clinical Study Protocol with Amendment 02 with Revision 01 Version Date: 08 March 2023 
IND number: Not applicable; NDA number: Not applicable;  BLA number: Not 
applicable; 
EudraCT number: Not applicable 
 
EMA Decision number of Pediatric Investigation Plan: P/0411/2019 
Article 45 or 46 of 1901/2006 does not apply 
 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Efficacy and Safety Study 
with an Open-Label Treatment Period of Fremanezumab Administered Subcutaneously 
Monthly or Quarterly for the Preventive Treatment of Migraine in Adult Chinese Patients 
Principal Investigator:   
Title: 
 
Address of Investigational Center: 
 
 
 
Tel: 
 
I have read the protocol with amendment 02 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, 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 
Executed signature pages are maintained within the Investigator Site File and Trial Master File. 
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SPONSOR PROTOCOL APPROVAL 
Sponsor’s Authorized 
Representative 
 
 
 
Signature 
Date 
Executed signature pages are maintained within the Trial Master File. 
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CLINICAL STUDY PROTOCOL SYNOPSIS  
with Amendment 02 with Revision 01 
Study TV48125-CNS-30088 
Title of Study: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Efficacy and 
Safety Study with an Open-Label Treatment Period of Fremanezumab Administered 
Subcutaneously Monthly or Quarterly for the Preventive Treatment of Migraine in Adult Chinese 
Patients 
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc. 
Investigational New Drug (IND) Number: Not applicable; 
New Drug Application (NDA) 
Number: Not applicable; Biological License Application (BLA) Number: Not applicable;
 
EudraCT Number: Not applicable 
EMA Decision number of Pediatric Investigation Plan: P/0411/2019; Article 45 or 46 of 
1901/2006 does not apply 
Name of Test Investigational Medicinal Product (IMP): Fremanezumab 
EudraVigilance (EV) code for the IMP, if applicable: SUB181665 
Type of the Study: Efficacy and Safety Study (Phase 3) 
Indication: Fremanezumab is intended for the preventive treatment of migraine in adults. 
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 30 investigational centers in China. 
Countries Planned: The study is planned to be conducted in China. 
Planned Study Period: approximately quarter 3 (Q3) 2022 to approximately quarter 2 
(Q2) 2024 
Number of Patients Planned (total): Approximately 372 patients (93 patients in each active 
treatment group and 186 patients in the placebo group) are planned to be enrolled in this study to 
have approximately 328 patients who complete the study (82 patients in each active treatment 
group and 164 patients in the placebo group); a 12% discontinuation rate is anticipated. The 
primary efficacy analysis will consider all fremanezumab-treated patients as 1 group. 
Study Population: The study population will be composed of female and male patients, 18 to 
70 years of age, inclusive, with a history of migraine (as defined by International Classification 
of Headache Disorders, 3rd revision [ICHD-3] criteria [IHS 2018, CMAPS 2016]) for at least 
12 months prior to screening and a prospectively documented diagnosis of migraine confirmed 
via a review of headache data recorded daily in an electronic headache diary device during a 
28-day baseline period. Guidelines consider preventive therapies as the standard for the 
treatment of migraine because of the frequency of headaches and high degree of disability. 
Accordingly, up to 30% of patients will be allowed to continue on a stable dose regimen of 
1 migraine preventive medication listed in Appendix K for migraine or for other chronic 
conditions, which lists medications with reasonable efficacy for migraine prevention. 
Medications that may be used for migraine prevention that are not in this appendix are 
considered to have questionable efficacy and are therefore allowed for all patients but will not be 
counted toward the 30% limit. Patients must have been taking a stable dose of a medication for at 
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least 2 months of consecutive use prior to screening and do not expect to change dosing regimens 
or to change to another medication during the treatment phase of the study. Acute medications 
for breakthrough migraine are allowed. This study will include both patients with episodic 
migraine (EM) and patients with chronic migraine (CM), as in previous studies (eg, the global 
HALO studies and the pivotal studies for Japan [Dodick et al 2018b, Silberstein et al 2017, Sakai 
et al 2021a, 2021b]) that demonstrated similar effect size across efficacy and safety endpoints for 
both populations. Nevertheless, the enrollment minimum of either migraine type will be 30% to 
ensure a reasonable number of patients from migraine type. In addition, primary efficacy 
analysis will be stratified by EM and CM, and subgroup analysis for EM and CM will be 
conducted.  
Primary and Secondary Objectives and Endpoints: 
The primary and secondary study objectives and endpoints are presented in Table 1. Note that, 
for endpoints that are based on a monthly average, “baseline” refers to the monthly average value 
during the 28-day baseline period. 
Table 1: 
Primary and Secondary Study Objectives and Endpoints  
Objectives 
Endpoints 
The primary objective of the 
study is to demonstrate the 
efficacy of fremanezumab 
administered as monthly and 
quarterly sc injections to adult 
Chinese patients with migraine. 
The primary efficacy analysis will 
consider all 
fremanezumab-treated patients as 
1 group. 
The primary endpoint is the mean change from baseline in the 
monthly average number of migraine days during the 12-week 
period after the 1st dose of IMP. 
The secondary objective of the 
study is to further demonstrate the 
efficacy of fremanezumab 
administered as monthly and 
quarterly sc injections to adult 
Chinese patients with migraine. 
The secondary efficacy analyses 
will consider all 
fremanezumab-treated patients as 
1 group. 
The secondary endpoints are as follows: 
• 
mean change from baseline in the number of migraine 
days during the 4-week period after the 1st dose of IMP 
• 
mean change from baseline in the monthly average 
number of days that any acute headache medications were 
used during the 12-week period after the 1st dose of IMP 
• 
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 IMP  
• 
mean change from baseline in the monthly average 
number of days with headache of at least moderate 
severity during the 12-week period after the 1st dose of 
IMP 
A secondary objective of the 
study is to evaluate the safety and 
tolerability of fremanezumab 
The safety/tolerability endpoints are as follows: 
• 
occurrence of adverse events throughout the study 
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Objectives 
Endpoints 
administered as monthly and 
quarterly sc injections to adult 
Chinese patients with migraine. 
• 
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: 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 
• 
assessment of the immunogenicity of fremanezumab and 
the impact of ADAs on clinical outcomes in patients 
exposed to sc fremanezumab 
• 
assessment of the ADA incidence and characteristics (eg, 
titer, kinetics, and neutralizing activities) 
ADA=antidrug antibody; ECG=electrocardiogram; IMP=investigational medicinal product; sc=subcutaneous. 
Pharmacokinetic and Other Objectives and Endpoints 
Pharmacokinetic and other endpoints to address the objective to further characterize 
fremanezumab safety, efficacy, and pharmacokinetics are as follows:  
• assessment of plasma concentration of fremanezumab during the 12-week period after the 
1st dose of IMP and at the follow-up visit using a population pharmacokinetic modeling 
approach 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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General Study Design: This is a multicenter, randomized, double-blind, placebo-controlled 
study with an open-label treatment period to evaluate the efficacy, safety, and tolerability of 
monthly and quarterly subcutaneous (sc) fremanezumab for the preventive treatment of migraine 
in adults. 
The study will consist of a screening visit, a baseline period (4 weeks), a 12-week double-blind 
treatment period, a 12-week open-label treatment period, and a follow-up period lasting 
approximately 3 months after the last dose of IMP (ie, 2 months after the end of treatment 
[EOT]/early termination [ET] visit). 
Randomization using electronic interactive response technology (IRT) will be stratified based on 
preventive medication use and migraine type (EM or CM) to ensure balance. 
Patients will be randomized to receive treatment with 1 of the following regimens: 
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• fremanezumab 225 mg sc once a month (approximately every 4 weeks [28 days]), for a 
total of 3 doses; one 225-mg injection and 2 placebo injections at visit 2 and one 225-mg 
injection at visits 3 and 4 
• fremanezumab 675 mg sc once a quarter (once at the beginning of the 12-week 
double-blind treatment period), for a total of 1 dose; three 225-mg injections at visit 2 and 
1 placebo injection at visits 3 and 4 or  
• placebo sc once a month (approximately every 4 weeks [28 days]), for a total of 3 doses; 
3 placebo injections at visit 2 and 1 placebo injection at visits 3 and 4  
Patients must return to the study center after visit 2, visit 3, or visit 4 for 2 additional blood 
sampling visits to measure plasma fremanezumab concentration. Additional details on these 
visits are provided in the protocol. 
During the 12-week open-label treatment period, patients will receive fremanezumab 225 mg sc 
once a month (approximately every 4 weeks) for a total of 3 doses (one 225-mg injection at 
visits 5, 6, and 7).  
At the end of the open-label treatment period (4 weeks after the last dose), an EOT study visit 
(visit 8) will be scheduled. Patients should return to the care of their treating physicians after 
visit 8. Patients should be treated with standard of care after withdrawal from or termination of 
the 24-week treatment period/study, as appropriate. 
Follow-up visits for ADA sample collection will occur approximately 1 month and 3 months 
after the last dose of study drug (visit 7), at the EOT/ET visit (visit 8) and at the end of study 
(EOS) visit (visit 9), respectively. The EOS is defined as the last visit of the last patient (follow-
up visit, visit 9). Two interim analyses are planned. A first 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 (visit 5). A second interim database lock will occur following the end of 
the open-label period (visit 8). Final database lock will occur following the end of the follow-up 
period.  
The schedule of study procedures and assessments is shown in Table 3. 
Brief Summary of Study Design for the Trial Registry(s): 
The purpose of the study is to confirm the efficacy and safety of fremanezumab in adult Chinese 
patients with the diagnosis of migraine in China. Patients with migraine who successfully 
complete a 4-week baseline period and meet the eligibility criteria will be included in the study. 
At their 2nd visit, patients will be given either fremanezumab (the study drug) at 1 of 2 dosing 
regimens or placebo (looks like the study drug but has no medicine in it); they will also receive 
either fremanezumab or placebo at the 3rd and 4th study visits. At the 5th, 6th, and 7th visits, all 
patients in the study will receive the same dose of fremanezumab. Comparing fremanezumab and 
placebo will show if fremanezumab works or if it is the same as not having any treatment at all. 
The study staff will track patients’ health and migraine symptoms during the treatment period. 
During the first 12-week treatment period (the 2nd, 3rd, and 4th visits), no one will know who got 
fremanezumab or placebo. This is called a “blind” and helps keep the results more accurate. 
During the second 12-week treatment period (the 5th, 6th, and 7th visits), the study staff and 
patients will know that all the patients got fremanezumab. 
Following the treatment period, patients will go back to their regular physicians. 
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Method of Randomization and Blinding: This is a randomized, double-blind, 
placebo-controlled study with stratification based on preventive medication use and migraine 
type (CM vs EM). For treatment during the double-blind period, patients will be randomized in a 
1:1:2 ratio within the appropriate stratum to receive fremanezumab monthly, fremanezumab 
quarterly, or placebo, respectively, as assigned by the IRT. Additionally, the IRT will manage 
initial drug supply, maintenance of adequate IMP supplies at each study center, and study 
randomization centrally. At the time of each study visit when the study drug is administered 
during the double-blind treatment period, the IRT will be queried, and the site personnel will 
retrieve and administer a 1.5 mL-volume from each syringe contained in the appropriately 
numbered kit(s). 
The open-label treatment period will not be randomized as all patients will receive the same 
monthly dosing regimen (225 mg fremanezumab). 
IMPs: Dose, Pharmaceutical Form, Route of Administration, and Administration Rate 
The dosing regimens of fremanezumab to be evaluated in the double-blind treatment period of 
this study (225 mg once a month [approximately every 4 weeks, monthly] and 675 mg once 
every 3 months [approximately every 12 weeks, quarterly]) have been approved in the United 
States (US), the European Union, Japan, Korea, Australia, Canada, Israel, and many other 
countries and are commercially available in these countries. Inclusion of a placebo control group 
is consistent with guidelines for controlled studies of preventive treatment of migraine in adults 
(Silberstein et al 2008) and the Classification Committee of the International Headache Society 
guidelines for controlled trials of drugs in migraine, 3rd edition (Tfelt-Hansen et al 2012). 
Prefilled syringes (active or placebo) will be contained in uniquely numbered kits and stored 
(refrigerated at 2°C to 8°C) on site. Active prefilled syringes will contain 225 mg of 
fremanezumab in 1.5-mL solution, and placebo prefilled syringes will contain the same vehicle 
and excipients as those for active injections. Each kit will contain 1 prefilled syringe. 
Adequate kit supply for upcoming study visits will be managed by the IRT and kept on-site. 
Treatment (active or placebo) will be administered at visit 2, visit 3, and visit 4. Active treatment 
will be administered to all patients at visit 5, visit 6, and visit 7. Final treatment evaluation will 
be performed at visit 8 (EOT), approximately 4 weeks after administration of the last dose of 
study drug. 
The IMP is defined as the test IMP (fremanezumab) and matching placebo IMP. Fremanezumab 
and placebo are characterized in Table 2. 
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Table 2: 
Investigational Medicinal Products Used in the Study  
IMP name 
Fremanezumab, a fully humanized 
IgG2Δa/kappa mAb 
Placebo 
Trade name and INN, if 
applicable, or 
company-assigned number 
AJOVY 
Fremanezumab 
TEV-48125 
Placebo 
Formulation 
Prefilled syringes containing 150 mg/mL 
of active ingredient: fremanezumab 
Inactive ingredients include L-histidine, 
L-histidine hydrochloride monohydrate, 
sucrose, polysorbate-80, disodium 
EDTA dihydrate, and water for injection 
Prefilled syringes containing 1.5 mL of 
the same inactive vehicle and excipients 
that are in the active injections 
Inactive ingredients include L-histidine, 
L-histidine hydrochloride monohydrate, 
sucrose, polysorbate-80, disodium 
EDTA dihydrate, and water for injection 
Unit dose strength(s)/ 
Dosage level(s) 
225 mg 
None 
Route of administration 
sc injection 
sc injection 
Dosing instructions 
Quarterly: fremanezumab 675 mg as 
3 injections (225 mg/1.5 mL) at visit 2; 
1 placebo (1.5 mL) injection at visits 3 
and 4 
Monthly: fremanezumab 225 mg 
as 1 injection (225 mg/1.5 mL) and 
2 placebo (1.5 mL) injections at visit 2; 
fremanezumab 225 mg as 1 injection 
(225 mg/1.5 mL) at visits 3 and 4 
3 placebo (1.5 mL) injections at visit 2; 
1 placebo (1.5 mL) injection at visits 3 
and 4 
Packaging 
A uniquely numbered kit containing 
1 prefilled syringe stored (refrigerated at 
2°C to 8°C) on site 
A uniquely numbered kit containing 
1 prefilled syringe stored (refrigerated at 
2°C to 8°C) on site 
Manufacturer 
Drug substance: 
 
 
 
 
Drug product: 
 
  
  
  
 
 
  
  
  
 
EDTA=ethylenediaminetetraacetic acid; IgG2Δa=immunoglobulin G2Δa; IMP=investigational medicinal product; 
INN=international nonproprietary name; mAb=monoclonal antibody; sc=subcutaneous. 
The recommended sc injection sites follow the Instructions for Use in the US-approved AJOVY 
Prescribing Information (2020). Appropriate injection sites are back of upper arms, stomach area 
(abdomen), and front of thighs. Fremanezumab should not be injected into an area that is tender, 
red, bruised, callused, tattooed, or hard; that has scars; or that has stretch marks. 
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Study drug should be removed from the refrigerator and allowed to equilibrate at room 
temperature for 30 minutes before administration of the study drug. The total number of sc 
injections and their injection site locations will be recorded on the case report form for each 
dosing visit (visits 2 through 7).  
Test IMP: Fremanezumab 
Reference IMP: Not applicable. 
Placebo IMP: Matching placebo for fremanezumab 
Duration of Patient Participation and Maximal Exposure to IMP: The total duration of 
patient participation in the study is planned to be approximately 9 months (including a screening 
visit, a 28-day baseline period, a 12-week double-blind treatment period, a 12-week open-label 
treatment period, and a follow-up period lasting approximately 3 months after the last dose of 
IMP (ie, 2 months after the EOT/ET visit). 
The maximal exposure to IMP is 675 mg of fremanezumab, administered either once a month 
(ie, 1 dose of 225 mg approximately every 4 weeks) or once a quarter (ie, 3 doses of 225 mg 
during a single visit) during the 12-week double-blind treatment period. During the 12-week 
open-label treatment period, all patients will receive 1 dose of 225 mg approximately every 
4 weeks. 
Study Duration: Approximately 2 years and from approximately Q3 2022 to approximately Q2 
2024 
End of Study: EOS is defined as the last visit of the last patient. 
Plans for Treatment or Care after the Patient Has Ended Participation in the Study: After 
the EOT visit (visit 8), patients will return to the care of their primary physician(s) for migraine 
management. 
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 as described in Appendix D, 
which includes compliance with the requirements and restrictions listed in this 
protocol. 
b. The patient is a man or woman 18 to 70 years of age, 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 evaluation, including medical and psychiatric history, physical examination, 
laboratory tests, and cardiac monitoring. 
e. The patient has a body weight 45 kg and body mass index within the range 17.5 to 
34.9 kg/m2 (inclusive). 
f. The patient has a history of migraine (according to the ICHD-3 criteria [IHS 2018, 
CMAPS 2016, Appendix J]), or clinical judgment suggests a migraine diagnosis (not 
better accounted for by another ICHD-3 diagnosis) for ≥12 months prior to screening 
(visit 1). 
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g. The patient has a clinical history of migraine that is confirmed during a prospectively 
recorded 28-day baseline period with the following characteristics: 
− Patient has 4 or more migraine days consistent with the characteristics of migraine 
(Appendix J) or probable migraine (a migraine subtype where only 1 migraine 
criterion is missing) or used a triptan or ergot derivative to treat an ongoing 
headache. 
− Patient has 2 or more days per month that are completely free of migraine 
headache or associated migraine symptoms. 
h. The patient agrees not to initiate any preventive migraine medications during the 
28-day baseline and double-blind treatment period. Up to 30% of patients are allowed 
to continue on 1 migraine preventive medication listed in Appendix K. However, 
patients must have been taking a stable dose of these medications for at least 
2 months of consecutive use prior to screening (visit 1) with no expectation to change 
dosing regimen or change to another migraine preventive medications during the 
treatment phase of the study. 
i. [Revision 1] Other concomitant medications (including herbal medicine) and 
acupuncture for migraine or other conditions are allowed for all patients, provided 
that the patient has been on a stable dose regimen for at least 2 months of consecutive 
use prior to screening (visit 1) with no expectation to change dosing regimen or 
change to another medication during the treatment phase of the study. 
j. The patient demonstrated compliance with the electronic headache diary device 
during the baseline period by entry of headache data on a minimum of 21 days during 
the baseline period and throughout the treatment period (approximately 75% diary 
compliance during each period). 
k. Women may be included only if they have either a negative serum beta-human 
chorionic gonadotropin test at screening (visit 1), are sterile, or are postmenopausal. 
Definitions of sterile and postmenopausal are given in Appendix E. 
l. Women of childbearing potential whose male partners are potentially fertile (ie, no 
vasectomy) must use highly effective birth control methods for the duration of the 
study (ie, starting at screening [visit 1]) and for 6 months after discontinuation of the 
IMP. Further details are included in Appendix E. 
m. Men must be sterile or, if they are potentially fertile/reproductively competent (not 
congenitally sterile) and their female partners are of childbearing potential, should use 
highly effective birth control for the duration of the study. Definitions of women of 
non-childbearing potential, sterile, and postmenopausal women; male contraception; 
and highly effective birth control methods, including examples, are given in 
Appendix E. 
n. 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 further visits, as applicable, and the follow-up evaluations, as specified in this 
protocol. 
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Exclusion Criteria: Patients will be excluded from participating in this study if they meet any of 
the following criteria: 
a. Uses medications containing opioids (including codeine), barbiturates (including 
butalbital), or any combination product containing opioids or barbiturates (including 
butalbital) on more than 4 days during the screening period for the treatment of 
migraine or for any other reason. 
b. Has used an intervention/device (eg, scheduled nerve blocks or transcranial magnetic 
stimulation) for migraine, or in the head or neck area, during the 2 months prior to 
screening (visit 1). 
c. Clinically significant hematological, cardiac, renal, endocrine, pulmonary, 
gastrointestinal, genitourinary, neurologic, hepatic, ocular disease, or complications 
of an infection that, in the opinion of the investigator, could interfere with the normal 
completion of study activities. 
d. 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, 
generalized anxiety disorder, any suicide attempt in the past, suicidal ideation with a 
specific plan in the past 2 years prior to screening (visit 1), or current suicidal 
ideation. 
e. History of clinically significant cardiovascular disease or vascular ischemia (such as 
myocardial, neurological [eg, cerebral ischemia], or peripheral extremity ischemia or 
other ischemic event) or thromboembolic events (arterial or venous thrombotic or 
embolic events), such as cerebrovascular accident (including transient ischemic 
attacks), deep vein thrombosis, or pulmonary embolism. 
f. [Revision 1] Known current infection or any history of infection with human 
immunodeficiency virus, tuberculosis, or Lyme disease, or a known or suspected 
active infection of coronavirus disease 2019 (COVID-19). 
g. Past or current history of cancer in the past 5 years, except for appropriately treated 
non-melanoma skin carcinoma. 
h. Pregnant or nursing females or females who plan to become pregnant during the 
study. 
i. History of hypersensitivity reactions to injected proteins, including monoclonal 
antibodies (mAbs), or a history of Stevens-Johnson Syndrome or toxic epidermal 
necrolysis syndrome, or the patient is concomitantly using lamotrigine. 
j. Participation in a clinical study of a new chemical entity or a prescription medicine 
within 2 months before screening (visit 1) (or 3 months in the case of a biologic if the 
half-life of the biologic is unknown) or 5 half-lives, whichever is longer, or is 
currently participating in another study of an IMP or medical device. 
k. Any prior exposure to a mAb targeting the calcitonin gene–related peptide pathway 
(erenumab, eptinezumab, galcanezumab, or fremanezumab) during the 6 months 
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before the screening visit (visit 1), or exposure to gepants for less than 5 half-lives 
before screening. 
l. Any finding in the baseline 12-lead electrocardiogram (ECG) considered clinically 
significant in the judgment of the investigator. 
m. Any finding that, in the judgment of the investigator, is a clinically significant 
abnormality, including physical examination findings, and serum chemistry, 
hematology, coagulation, and urinalysis test values (abnormal test results may be 
repeated for confirmation). 
n. Hepatic enzymes (alanine aminotransferase, aspartate aminotransferase, and alkaline 
phosphatase) >2× the upper limit of normal (ULN) after confirmation in a repeat test 
or suspected hepatocellular damage that fulfills criteria for Hy’s law at screening 
(visit 1). 
o. Serum creatinine >1.5× ULN, clinically significant proteinuria, or evidence of renal 
disease at screening (visit 1). 
p. Any clinically significant uncontrolled medical condition (treated or untreated). 
q. History of alcohol or drug abuse during the past 2 years or drug dependence during 
the past 5 years. 
r. The patient cannot participate or successfully complete the study, in the opinion of 
his/her 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 that, in the opinion of the investigator, makes the patient 
inappropriate for inclusion in the study 
s. The patient is a study center or sponsor employee who is directly involved in the 
study or the relative of such an employee. 
t. The patient has any disorder that may interfere with the absorption, distribution, 
metabolism, or excretion of the IMP. 
u. Vulnerable patients (eg, members of a group with a hierarchical structure [such as 
medical, pharmacy, dental, and nursing students], subordinate hospital and laboratory 
personnel, employees of the pharmaceutical industry, members of the armed forces, 
persons kept in detention, patients with incurable diseases, persons in nursing homes, 
unemployed or impoverished persons, patients in emergency situations, ethnic 
minority groups, homeless persons, nomads, refugees, minors, and those incapable of 
giving consent). 
v. The patient has previously participated in this study or has been assigned previously 
to a study with the IMP. 
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w. [New Criterion] Known current infection or history of infection in the past 6 months 
with hepatitis B or C viruses. 
Statistical Considerations 
Sample Size Rationale: Using study data from 2 completed Phase 3 US pivotal studies in 
migraine, it is estimated that 163 completers per treatment group (ie, combined fremanezumab 
groups and placebo group) will provide at least 90% power to detect the assumed treatment 
difference at a significance level of 0.05. Assuming a 12% discontinuation rate, approximately 
372 patients will be randomized in this study (93 patients in each fremanezumab treatment group 
and 186 patients in the placebo group). The primary efficacy analysis will consider all 
fremanezumab-treated patients including both patients with EM and with CM, both monthly and 
quarterly dosing, as 1 group, since similar effect size has been observed across these subgroups 
from previous studies (Sakai et al 2021a, 2021b, Dodick et al 2018b, Silberstein et al 2017). 
 
 
 
 
 
 
 
 
 
Primary Efficacy Analysis: The primary comparison will be made between the combined 
fremanezumab groups versus the placebo group in the primary efficacy variable: mean change 
from baseline in the monthly average number of migraine days during the 12-week double-blind 
treatment period after the 1st dose of IMP. The primary efficacy analysis will consider all 
fremanezumab-treated patients as 1 group. 
An estimand in general includes the following 4 interrelated attributes: population of interest, 
variable (endpoint) of interest, intercurrent events (ICEs) along with the strategy for handling 
ICEs, and population-level summary for the endpoint.  
The estimand selected for the primary analysis will assess the 12-week monthly average number 
of migraine days as initially randomized in the modified intent-to-treat analysis set.  
The ICEs that may affect the efficacy endpoint will include instances where a patient early 
terminates from the IMP, receives the wrong IMP due to medication errors, or receives a rescue 
medication due to worsening symptoms. If observations are collected after the occurrences of the 
ICEs, the observations will be included in the calculation of the primary endpoint for the primary 
analysis. 
The population-level summaries would be the adjusted mean changes from baseline in monthly 
average number of migraine days for the treatment groups and corresponding 95% confidence 
intervals. 
An analysis of covariance will be performed, including treatment and stratification factors of 
migraine type (CM vs EM) and preventive medication use as fixed factors, as well as baseline 
number of migraine days as a covariate in the model. A 95% confidence interval for the 
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treatment difference between the combined fremanezumab groups versus the placebo group will 
be derived through an appropriate contrast, and p-values for the comparison will be presented. 
Further details will be presented in the statistical analysis plan.  
Sensitivity Analysis: A sensitivity analysis may be performed to assess the primary estimand 
using mixed-effects model for repeated measures (MMRM) as a different missing data handling 
approach. The MMRM model will include treatment and stratification factors of migraine type 
(CM vs EM) and preventive medication use as fixed factors, as well as treatment-by-month 
interaction effects, and baseline number of migraine days as a covariate with an unstructured 
covariance matrix. The 12-week monthly average number of migraine days will be estimated by 
the least squares means of the overall treatment effect over 3 months.  
An additional sensitivity analysis may be conducted to assess a different estimand, ie, treatment 
effects due to initially randomized treatment as actually taken. For patients who early terminate 
from study drugs in the monthly dosing regimen group or start a rescue medication, observations 
collected more than 4 weeks after the last dose or after starting a rescue medication will be 
treated as missing and will not be used in the calculation of monthly average number of migraine 
days. 
Finally, the primary analysis will be repeated in the intent-to-treat analysis set (in case there is a 
10% difference in patient count in any treatment group) and per-protocol analysis set.  
Secondary Efficacy Analysis: Comparisons of secondary endpoints will be made between the 
combined fremanezumab groups versus the placebo group. Analysis of the continuous secondary 
endpoints (monthly average number of days of efficacy endpoints) will be similar to the analysis 
of the primary efficacy endpoint. The responder endpoints will be analyzed using logistic 
regression, including treatment and stratification factors of migraine type (CM vs EM), 
preventive medication use as fixed factors, as well as baseline number of migraine days as a 
covariate in the model. The secondary efficacy analyses will consider all fremanezumab-treated 
patients as 1 group. Further details will be presented in the statistical analysis plan. 
A fixed-sequence, hierarchical testing procedure will be implemented to control the type 1 error 
rate at 0.05 for formal hypothesis testing of the secondary endpoints. Upon the success of the 
primary analysis, the first secondary endpoint in the sequence will be tested at a significance 
level of 0.05, and a p-value ≤0.05 will be interpreted inferentially. The process will continue 
following the order of the sequence until a point when the test for the efficacy endpoint fails, ie, 
2-sided p-value >0.05. Subsequently, no further test results will be interpreted inferentially. The 
sequence of testing will follow the order specified for secondary endpoints in Section 9.5.2. 
Multiple Comparisons and Multiplicity: The type 1 error will be controlled at a significance 
level of 0.05 using the appropriate method for the analysis of the primary efficacy endpoint, 
which is conducted by pooling the fremanezumab patients in the 2 dosing regimens. 
A fixed-sequence, hierarchical testing procedure will be implemented upon achieving the success 
of the primary analysis to control the type 1 error rate at 0.05 for formal hypothesis testing of the 
secondary endpoints. The sequence of testing will follow the order specified for secondary 
endpoints in Section 9.5.2. 
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Analysis of Other Efficacy Endpoints: 
 
 
 
 
 
 
Safety Analysis: Safety analyses will be performed on the safety analysis set. 
Safety assessments and time points are provided in Table 3. 
All adverse events will be coded using the Medical Dictionary for Regulatory Activities. Each 
patient will be counted only once in each preferred term or system organ class category for the 
analyses of safety. Summaries will be presented for all adverse events (overall and by severity), 
adverse events determined by the investigator to be related to the test IMP (ie, reasonable 
possibility; defined as related or with missing relationship [overall and by severity]), serious 
adverse events, and adverse events leading to discontinuation from the study. Summaries will be 
presented by treatment group. Patient listings of serious adverse events and adverse events 
leading to discontinuation will be presented. 
Changes in clinical 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. 
The use of concomitant medications will be summarized by therapeutic class using descriptive 
statistics. Concomitant medications will include all medications taken while the patient is treated 
with the IMP. 
Safety data will be summarized descriptively by treatment group. For continuous variables, 
descriptive statistics (n, mean, SD, median, minimum, and maximum) will be provided for actual 
values and changes from baseline to each time point. For categorical variables, patient counts 
and percentages will be provided. Descriptive summaries of serious adverse events, patient 
discontinuations 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. 
Tolerability Analysis: Spontaneously reported 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. 
The pharmacokinetic data from this study will be pooled with the data from other fremanezumab 
studies and assessed for comparability. Summary statistics of fremanezumab pharmacokinetic 
parameters model-based predictions of weight-adjusted exposures will be compared and will be 
reported separately. 
Immunogenicity Analysis: Summary of immunogenicity results will be provided, and the 
incidence of immunogenicity will be calculated. This analysis will be reported separately. 
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Planned Interim Analysis: Two interim analyses are planned. The first interim analysis is 
planned when the last patient has completed the double-blind period (visit 5). A second interim 
analysis is planned following the end of the open-label period (visit 8). 
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 second database lock. 
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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
AMENDMENT HISTORY .............................................................................................................2 
INVESTIGATOR AGREEMENT...................................................................................................3 
CLINICAL STUDY PROTOCOL SYNOPSIS...............................................................................5 
LIST OF ABBREVIATIONS ........................................................................................................28 
1. 
INTRODUCTION AND BACKGROUND INFORMATION ..................................31 
1.1. 
Introduction .................................................................................................................31 
1.2. 
Findings from Nonclinical and Clinical Studies .........................................................33 
1.2.1. 
Nonclinical Studies .....................................................................................................33 
1.2.2. 
Clinical Studies ...........................................................................................................34 
1.2.2.1. 
Pharmacokinetics ........................................................................................................34 
1.2.2.2. 
Clinical Safety and Efficacy Studies ..........................................................................36 
1.3. 
Known and Potential Benefits and Risks to Patients ..................................................38 
1.3.1. 
Known and Potential Benefits and Risks of the Test Investigational 
Medicinal Product(s) ..................................................................................................38 
1.3.1.1. 
Identified Risks ...........................................................................................................38 
1.3.1.2. 
Potential Risks ............................................................................................................39 
1.3.2. 
Overall Benefit and Risk Assessment for This Study ................................................40 
2. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................41 
2.1. 
Primary and Secondary Study Objectives and Endpoints ..........................................41 
2.2. 
Pharmacokinetic and Other Objectives and Endpoints ..............................................42 
3. 
STUDY DESIGN .......................................................................................................45 
3.1. 
General Study Design and Study Schematic Diagram ...............................................45 
3.2. 
Planned Number of Patients and Countries ................................................................49 
3.3. 
Justification for Study Design and Selection of Population .......................................49 
3.4. 
Stopping Rules for the Study ......................................................................................50 
3.5. 
Schedule of Study Procedures and Assessments ........................................................51 
4. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................56 
4.1. 
Patient Inclusion Criteria ............................................................................................56 
4.2. 
Patient Exclusion Criteria ...........................................................................................57 
4.3. 
Withdrawal Criteria and Procedures for the Patient ...................................................59 
4.4. 
Replacement of Patients .............................................................................................60 
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4.5. 
Rescreening .................................................................................................................60 
4.6. 
Screening Failure ........................................................................................................61 
5. 
TREATMENTS ..........................................................................................................62 
5.1. 
Investigational Medicinal Products Used in the Study ...............................................62 
5.1.1. 
Test Investigational Medicinal Product ......................................................................63 
5.1.1.1. 
Starting Dose and Dose Levels ...................................................................................63 
5.1.1.2. 
Dose Modification ......................................................................................................63 
5.1.2. 
Placebo Investigational Medicinal Product ................................................................63 
5.2. 
Preparation, Handling, Labeling, Storage, and Accountability for 
Investigational Medicinal Products ............................................................................64 
5.2.1. 
Storage and Security ...................................................................................................64 
5.2.2. 
Labeling ......................................................................................................................64 
5.2.3. 
Accountability .............................................................................................................64 
5.3. 
Justification for Investigational Medicinal Products ..................................................65 
5.3.1. 
Justification for Dose of Test Investigational Medicinal Product ..............................65 
5.3.2. 
Justification for Use of Placebo Investigational Medicinal Product ..........................65 
5.4. 
Treatment after the End of the Study ..........................................................................66 
5.5. 
Restrictions .................................................................................................................66 
5.5.1. 
Activity .......................................................................................................................66 
5.5.2. 
Blood Donation ...........................................................................................................66 
5.6. 
Prior and Concomitant Medication or Therapy ..........................................................66 
5.7. 
Procedures for Monitoring Patient Compliance .........................................................67 
5.8. 
Randomization and Blinding ......................................................................................67 
5.9. 
Maintenance of Randomization and Blinding ............................................................68 
5.9.1. 
Maintenance of Randomization ..................................................................................68 
5.9.2. 
Blinding and Unblinding ............................................................................................68 
5.9.3. 
Data Monitoring Committee .......................................................................................69 
5.10. 
Total Blood Volume ...................................................................................................69 
6. 
ASSESSMENT OF EFFICACY ................................................................................70 
6.1. 
Assessments of Efficacy .............................................................................................70 
6.1.1. 
Electronic Headache Diary Device .............................................................................70 
6.1.2. 
Patient Global Impression of Change .........................................................................71 
7. 
ASSESSMENT OF SAFETY .....................................................................................72 
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7.1. 
Adverse Events ...........................................................................................................72 
7.1.1. 
Definition of an Adverse Event ..................................................................................72 
7.1.2. 
Recording and Reporting of Adverse Events .............................................................73 
7.1.3. 
Severity of an Adverse Event .....................................................................................74 
7.1.4. 
Relationship of an Adverse Event to the Investigational Medicinal Product .............74 
7.1.5. 
Serious Adverse Events ..............................................................................................74 
7.1.5.1. 
Definition of a Serious Adverse Event .......................................................................75 
7.1.5.2. 
Expectedness ...............................................................................................................75 
7.1.5.3. 
Reporting a Serious Adverse Event ............................................................................76 
7.1.6. 
Protocol-Defined Adverse Events of Special Interest ................................................77 
7.1.7. 
Protocol Deviations Because of an Adverse Event ....................................................78 
7.2. 
Pregnancy ...................................................................................................................78 
7.3. 
Medication Error and Special Situations Related to the Investigational 
Medicinal Products .....................................................................................................79 
7.4. 
Clinical Laboratory Tests ...........................................................................................79 
7.4.1. 
Serum Chemistry, Hematology, and Urinalysis .........................................................81 
7.4.2. 
Other Clinical Laboratory Tests .................................................................................81 
7.4.2.1. 
Human Chorionic Gonadotropin Tests .......................................................................81 
7.4.2.2. 
Follicle-Stimulating Hormone Tests ...........................................................................81 
7.5. 
Physical Examinations ................................................................................................81 
7.6. 
Vital Signs ..................................................................................................................81 
7.7. 
Electrocardiography ....................................................................................................82 
7.8. 
Immunogenicity ..........................................................................................................82 
7.9. 
Assessment of Local Tolerability and Pain ................................................................82 
7.10. 
Assessment of Suicidality ...........................................................................................83 
8. 
ASSESSMENT OF PHARMACOKINETICS/IMMUNOGENICITY ......................84 
8.1. 
Pharmacokinetic Assessment ......................................................................................84 
8.2. 
Pharmacodynamic Assessment ...................................................................................84 
8.3. 
Immunogenicity Testing .............................................................................................84 
8.4. 
Assessment of Exploratory Biomarkers .....................................................................84 
9. 
STATISTICS ..............................................................................................................85 
9.1. 
Sample Size and Power Considerations .....................................................................85 
9.2. 
Analysis Sets ...............................................................................................................85 
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9.2.1. 
Intent-to-Treat Analysis Set ........................................................................................85 
9.2.2. 
Modified Intent-to-Treat Analysis Set ........................................................................85 
9.2.3. 
Safety Analysis Set .....................................................................................................86 
9.2.4. 
Per-Protocol Analysis Set ...........................................................................................86 
9.3. 
Data Handling Conventions ........................................................................................86 
9.3.1. 
Handling Withdrawals and Missing Data ...................................................................86 
9.4. 
Study Population .........................................................................................................86 
9.4.1. 
Patient Disposition ......................................................................................................86 
9.4.2. 
Demographic and Baseline Characteristics ................................................................86 
9.5. 
Efficacy Analysis ........................................................................................................86 
9.5.1. 
Primary Endpoint ........................................................................................................88 
9.5.2. 
Secondary Endpoints ..................................................................................................88 
9.5.3. 
Other Efficacy Endpoints ...........................................................................................88 
9.5.4. 
Planned Method of Analysis .......................................................................................90 
9.5.4.1. 
Primary Efficacy Analysis ..........................................................................................91 
9.5.4.2. 
Sensitivity Analysis ....................................................................................................91 
9.5.4.3. 
Secondary Efficacy Analysis ......................................................................................92 
9.5.4.4. 
Other Efficacy Analysis ..............................................................................................92 
9.6. 
Multiple Comparisons and Multiplicity......................................................................92 
9.7. 
Safety Analysis ...........................................................................................................92 
9.8. 
Tolerability Analysis ..................................................................................................93 
9.9. 
Pharmacokinetic Analysis ..........................................................................................93 
9.10. 
Immunogenicity Analysis ...........................................................................................93 
9.11. 
Planned Interim Analysis ............................................................................................93 
9.12. 
Reporting Deviations from the Statistical Plan ..........................................................94 
10. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................95 
11. 
COMPLIANCE STATEMENT ..................................................................................95 
12. 
DATA MANAGEMENT AND RECORD KEEPING ..............................................95 
13. 
FINANCING AND INSURANCE .............................................................................96 
14. 
PUBLICATION POLICY ..........................................................................................96 
15. 
REFERENCES ...........................................................................................................97 
16. 
SUMMARY OF CHANGES TO PROTOCOL .......................................................100 
16.1. 
Amendment 02 with Revision 01 Dated 08 March 2023 .........................................100 
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16.2. 
Amendment 02 Dated 14 February 2023 ..................................................................101 
16.3. 
Administrative Letter 01 Dated 26 July 2022...........................................................108 
16.4. 
Amendment 01 Dated 15 September 2021 ...............................................................110 
16.5. 
Revision 01 Dated 01 April 2021 .............................................................................123 
APPENDIX A. CLINICAL LABORATORIES AND OTHER DEPARTMENTS AND 
INSTITUTIONS .......................................................................................................124 
APPENDIX B. STUDY PROCEDURES AND ASSESSMENTS BY VISIT .........................125 
APPENDIX C. QUALITY CONTROL AND QUALITY ASSURANCE ..............................131 
APPENDIX D. ETHICS ...........................................................................................................133 
APPENDIX E. BIRTH CONTROL METHODS AND PREGNANCY TESTING .................134 
APPENDIX F. LOST TO FOLLOW-UP .................................................................................136 
APPENDIX G. PRODUCT COMPLAINTS ............................................................................137 
APPENDIX H. DATA MANAGEMENT AND RECORD KEEPING ...................................139 
APPENDIX I. PUBLICATION POLICY .................................................................................142 
APPENDIX J. INTERNATIONAL CLASSIFICATION OF HEADACHE 
DISORDERS, 3RD REVISION, DIAGNOSTIC CRITERIA ...................................143 
APPENDIX K. PREVENTIVE MIGRAINE MEDICATIONS ALLOWED FOR 30% 
OF THE STUDY POPULATION FOR THE DURATION OF THE STUDY .......145 
APPENDIX L. CLINICAL CRITERIA FOR DIAGNOSING ANAPHYLAXIS ...................146 
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LIST OF TABLES 
Table 1: 
Primary and Secondary Study Objectives and Endpoints ............................................6 
Table 2: 
Investigational Medicinal Products Used in the Study ...............................................12 
Table 3: 
Study Procedures and Assessments ............................................................................52 
Table 4: 
Investigational Medicinal Products Used in the Study ...............................................62 
Table 5: 
The Relationship of an Adverse Event to the Investigational Medicinal 
Product ........................................................................................................................74 
Table 6: 
Clinical Laboratory Tests ...........................................................................................80 
 
 
 
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LIST OF FIGURES 
Figure 1: 
Overall Study Schematic Diagram .............................................................................48 
 
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LIST OF ABBREVIATIONS  
Abbreviation 
Term 
21CFR 
Title 21 Code of Federal Regulations 
β-HCG 
beta-human chorionic gonadotropin 
ADA 
antidrug antibody 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
AUC 
area under the plasma drug concentration-time curve 
BA 
bioavailability 
CDE 
Center for Drug Evaluation 
CDMS 
clinical data management system  
CGRP 
calcitonin gene–related peptide 
CH 
cluster headache 
CIOMS 
Council for International Organizations of Medical Sciences 
CL 
clearance 
CM 
chronic migraine 
CNS 
central nervous system 
COVID-19 
coronavirus disease 2019 
CRF 
case report form (refers to any media used to collect study data [ie, paper or electronic]) 
CRO 
contract research organization 
CSR 
clinical study report 
CV 
coefficient of variation 
CYP 
cytochrome P450 
ECG 
electrocardiography/electrocardiogram 
eCRF 
electronic case report form 
EM 
episodic migraine 
EOT 
end of treatment (visit) 
EOS 
end of study 
ET 
early termination 
EU 
European Union 
FDA 
Food and Drug Administration 
FM 
fibromyalgia 
GCP 
Good Clinical Practice 
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Abbreviation 
Term 
GLP 
Good Laboratory Practice 
GPSP 
Global Patient Safety and Pharmacovigilance 
IB 
Investigator’s Brochure 
ICE 
intercurrent event 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
ICHD-3 
International Classification of Headache Disorders, 3rd revision 
IEC 
Independent Ethics Committee 
IHS 
International Headache Society 
IMP 
investigational medicinal product 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
iv 
intravenous(ly) 
IRT 
interactive response technology 
LS 
least square 
LSO 
local safety officer 
mAb 
monoclonal antibody 
mITT 
modified intent-to-treat 
MMRM 
mixed-effects model for repeated measures 
NOAEL 
no-observed-adverse-effect level 
NSAIDs 
non-steroidal anti-inflammatory drugs 
PEF 
peak expiratory flow 
PGIC 
Patient Global Impression of Change 
PP 
per-protocol 
PPK 
population pharmacokinetic 
PRN 
taken as needed 
PTH 
posttraumatic headache 
Q2 
quarter 2 
Q3 
quarter 3 
RBC 
red blood cell 
RSI 
reference safety information 
sc 
subcutaneous(ly) 
SD 
standard deviation 
SOP 
standard operating procedure 
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Abbreviation 
Term 
SUSAR 
suspected unexpected serious adverse reaction 
t½ 
terminal elimination half-life 
ULN 
upper limit of normal 
US 
United States  
XML 
extensible markup language 
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1. 
INTRODUCTION AND BACKGROUND INFORMATION  
1.1. 
Introduction  
Migraine is a prevalent disease characterized by attacks of headache and associated symptoms 
(such as nausea, vomiting, photophobia, or phonophobia). The most common form of migraine 
occurs on less than 15 days per month and is referred to as episodic migraine (EM) (Lipton et al 
2007). However, 3% to 6% of individuals with EM evolve, in any given year, to a significantly 
more disabling form of the disease 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, face considerable disability (Bigal and Lipton 2008). 
The goals of migraine treatment are to relieve pain, restore function, reduce headache frequency, 
and prevent progression of EM to CM. Pharmacological interventions for migraine treatment 
include acute (symptomatic) treatments and preventive medications. 
Preventive medications may be appropriate in several instances, including when the frequency of 
attacks per month is 2 or higher or when a patient’s quality of life is significantly impaired 
(Evers et al 2009). Several drugs from different pharmacological categories (eg, beta-blockers 
and anticonvulsants) have been approved for migraine prevention or have class A evidence to 
support their use. However, adherence to and persistence on these medications can be poor, and 
there is a need for preventive medications that 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 that is implicated in both 
central and peripheral processes underlying the pathophysiology of migraine (Eftekhari and 
Edvinsson 2010). Jugular levels of CGRP are increased during migraine attacks, and 
intravenous (iv) CGRP administration induces migraine-like headache in most individuals with 
migraine (Ashina et al 2000, Hansen et al 2010). CGRP is thought to be involved in the 
pathophysiology of migraine at all levels, peripherally (eg, neuronal sensitization, 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 
(Bigal et al 2015a, Dodick et al 2018a, Dodick et al 2018b, Reuter et al 2018) and CM (Bigal et 
al 2015b, Silberstein et al 2017). 
Fremanezumab (TEV-48125 [formerly LBR-101, PF-04427429, and RN-307]) is a fully 
humanized immunoglobulin G 2(delta)a/kappa monoclonal antibody (mAb), which has been 
developed for administration by the subcutaneous (sc) route in monthly or quarterly doses for the 
preventive treatment of migraine. Fremanezumab was approved for use in adults in the United 
States (US) on 14 September 2018 and was approved by the European Medicines Agency 
(EMA) in March 2019, and marketing authorization applications have been submitted and 
approved in several countries worldwide, including Canada, Australia, Korea, and Japan. Pivotal 
studies leading to these approvals have been published (Sakai et al 2021a, 2021b, Dodick et al 
2018b, Silberstein et al 2017). Fremanezumab potently and selectively binds to both CGRP 
isoforms (α- and β-CGRP) to prevent them from binding to the CGRP receptor. Fremanezumab 
is specific for CGRP and does not bind to other closely related neuropeptides (eg, amylin, 
calcitonin, intermedin, and adrenomedullin). Two mutations were introduced into the constant 
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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 efficacy and tolerability profiles of fremanezumab have been confirmed in the Phase 3 
development program (HALO studies; monthly sc doses of 225 mg and quarterly sc doses of 
675 mg). 
In addition to migraine prevention from fremanezumab, more than half of total patients who had 
participated in the fremanezumab HALO long-term study who were surveyed about their 
treatment response reported that the treatment satisfactorily reduced related migraine-associated 
symptoms (55%), pain intensity (55%), migraine-associated disability (60%), and attack duration 
(69%; Lipton et al 2019). Pain intensity and migraine symptoms are 2 of the strongly correlated 
factors in disability due to migraine (Park et al 2008). 
The purpose of the study is to confirm the efficacy and safety of fremanezumab in adult Chinese 
patients with the diagnosis of migraine in China. The epidemiology and treatment guidelines in 
China are similar to those in the US and the European Union (EU) and are summarized here. The 
1-year prevalence of migraine in China was estimated to range from 9.3% to 10.5%, with 
incidences of 1.5% and 1.1%, respectively (GBD 2016 Disease and Injury Incidence and 
Prevalence Collaborators 2017). In China, there are a large number of acute medications used for 
the treatment of migraine, although there is a lack of preventive treatment and excessive use of 
analgesic drugs (Liu et al 2013). Migraine treatment guidelines in China recommend the use of 
preventive treatment when the patient’s quality of life, work, and study are seriously impaired, 
the migraine frequency is more than 2 times per month, acute treatment is ineffective or not 
tolerable, the patient experiences prolonged or extremely uncomfortable aura, acute treatment is 
used more than 6 to 8 times a month (continuously for at least 2 months), or the migraine attacks 
last for more than 72 hours. Treatment recommendations from the Chinese guidelines include 
nonsteroidal anti-inflammatory drugs (naproxen or aspirin), magnesium, riboflavin, or coenzyme 
Q10. Other medication recommendations include antiepileptics (topiramate and valproic acid), 
beta blockers (propranolol and metoprolol), and antidepressants (amitriptyline and venlafaxine) 
(CMAPS 2016). Of note, none of these molecules were developed for migraine based on 
attempts to target the biological dysfunction underlying the disease. They are all registered for 
another primary indication; efficacy of these drugs in migraine prevention was detected by 
serendipity and not by pathophysiological considerations. Furthermore, these drugs require 
titration, daily use, or multiple uses per day and are often associated with notable adverse events 
that reduce compliance with long-term use and prompt many patients to discontinue treatment 
(D’Amico and Tepper 2008, Tfelt-Hansen and Olesen 2012). Thus, there remains a significant 
need for safe and effective preventive migraine medications that are mechanism-based. 
Refer to the locally approved prescribing information (for countries where fremanezumab is 
approved for the preventive treatment of migraine) or the current Investigator’s Brochure (IB) 
(for countries where fremanezumab is not yet approved) for detailed information on the 
background, pharmaceutical particulars, nonclinical experience, and clinical experience with 
fremanezumab. 
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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 IB. 
1.2.1. 
Nonclinical Studies  
In vivo pharmacology studies of fremanezumab in animal models demonstrated 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 capsaicin-induced 
skin flare response in cynomolgus monkeys. In addition, efficacy was demonstrated in 2 rat 
models relevant for visceral/chronic pain. 
Safety pharmacology parameters of fremanezumab were assessed in the pivotal toxicology 
studies in cynomolgus monkeys and a separate cardiovascular safety pharmacology study in 
male cynomolgus monkeys. There were no treatment-related changes in electrocardiograms 
(ECGs) or heart rates in the 1- and 3-month toxicity studies, and a single iv dose of 
fremanezumab 100 mg/kg did not result in changes in cardiovascular parameters or body 
temperature in monkeys. Moreover, no concern for fremanezumab to cause any biologically 
significant changes in the respiratory system and central nervous system of rats was identified in 
safety pharmacology studies after administration of sc doses of fremanezumab up to 300 mg/kg. 
In the general toxicology studies conducted in rats and monkeys, no target organ toxicity was 
identified. In the chronic repeat-dose studies, the no-observed-adverse-effect level (NOAEL) 
ranged from 100 to 300 mg/kg/week administered either iv or sc (the highest doses tested in the 
studies). 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 considered to be the 
result of an incidental immune-mediated reaction and of doubtful relevance. No similar finding 
was noted in the 1- or 6-month studies in monkeys after administration of fremanezumab up to 
300 mg/kg/week iv or sc and after high exposures. 
Fremanezumab was administered to rats and monkeys by the iv or sc route for up to 3 months in 
duration and was found to be well tolerated. In addition, weekly sc administration 
of fremanezumab was well tolerated in a 6-month chronic toxicology study in monkeys. 
In the pivotal 6-month chronic toxicity study in monkeys, no fremanezumab-related 
abnormalities were noted. No target organs were identified after microscopic evaluation, and no 
apparent adverse injection site reactions were recorded. The NOAEL of this study was 
considered to be at least the highest dose tested (ie, 300 mg/kg/week). At this dose, the 
calculated safety margins (based on area under the plasma drug concentration-time curve [AUC]) 
were at least 158-fold higher than the expected clinical exposure for the migraine indication, 
where the clinical dose was 225 mg sc once monthly. 
Additionally, pivotal reproductive and developmental toxicity studies in animals with 
fremanezumab were completed. 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. In addition, a pre-and postnatal development 
study in rats was completed, and no treatment-related effects were noted. 
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Good Laboratory Practice (GLP) juvenile toxicity studies in rats and a non-GLP dose 
range-finding study in juvenile rats were conducted. No toxicological findings were noted 
following weekly sc administration of fremanezumab (starting from postnatal day 28) at dose 
levels up to 450 mg/kg/week. 
In a standalone local tolerance study in rabbits, no injection site reactions were observed after 
administration of fremanezumab at 150 mg/mL when compared to vehicle control via 5 alternate 
routes of administration (iv, sc, intramuscular, paravenous, and intra-arterial). 
The pharmacokinetics of fremanezumab in animals (rats and monkeys) is typical of a humanized 
IgG2 molecule, with low mean plasma clearance (CL), low volume of distribution at steady 
state, and a long terminal elimination half-life (t½). Exposure, as defined by the maximum 
observed plasma drug concentration and the AUC, increased linearly across doses after single 
and repeated once-weekly dosing. No sex differences in exposure were observed in rats or 
monkeys. 
After sc administration, mean systemic exposure values (calculated using AUC from time 0 to 
168 hours after study drug administration) were 65% to 67% and 81% to 92% of the equivalent 
iv doses for rats (300 mg/kg dose) and monkey (100 and 300 mg/kg dose levels), respectively, 
demonstrating reasonably high sc bioavailability (BA). After multiple dosing in the 2 species, 
both iv and sc administration showed accumulation due to the long t½ of the drug (longer than 
the period between dosing intervals). 
Further details may be found in the current IB.  
1.2.2. 
Clinical Studies  
As of 30 August 2019, fremanezumab has been studied in a total of 24 completed, terminated, or 
ongoing clinical studies (9 in healthy subjects, 9 in adult patients with migraine, 1 in pediatric 
patients with migraine, 3 in patients with cluster headache [CH], 1 in patients with posttraumatic 
headache [PTH], and 1 in patients with fibromyalgia [FM]). As of 30 August 2019, a cumulative 
total of 5804 subjects and patients (536 healthy subjects, 4741 adult patients with migraine, 
15 pediatric patients with migraine, 428 patients with CH, 77 patients with PTH, and 7 patients 
with FM) have been enrolled in the fremanezumab clinical studies. Of the enrolled subjects and 
patients, approximately 4972 patients (474 healthy subjects, 4062 adult patients with migraine, 
15 pediatric patients with migraine, 380 patients with CH, 37 patients with PTH, and an 
estimated 4 patients with FM) have received at least 1 dose of fremanezumab. 
A brief summary of clinical pharmacology and clinical safety and efficacy studies of 
fremanezumab follows. Further details may be found in the current IB.  
1.2.2.1. 
Pharmacokinetics  
Absorption 
After single sc administrations of 225 and 675 mg of fremanezumab, the median time to 
maximum observed concentration in healthy subjects was 5 to 7 days. The estimated absolute 
BA of fremanezumab after sc administrations of 225 and 900 mg in healthy subjects was 55% to 
66%, respectively. Dose proportionality, based on population pharmacokinetics, was observed 
between 225 and 900 mg. Steady state was approached by 3 months of dosing and was expected 
to be achieved by approximately 168 days (about 6 months) following 225-mg monthly and 
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675-mg quarterly dosing regimens. The median accumulation ratio, based on once-monthly and 
once-quarterly dosing regimens, was approximately 2.4 and 1.2, respectively. The 
pharmacokinetics of fremanezumab demonstrated bioequivalence when delivered sc via a 
prefilled syringe versus via an AI. 
Distribution 
Assuming the model-derived estimated BA of 66%, the volume of distribution for a typical 
patient was 3.6 L (35.1% coefficient of variation [CV]) following sc administrations of 225, 675, 
and 900 mg of fremanezumab. 
Biotransformation 
Similar to other mAbs, fremanezumab is expected to be degraded by enzymatic proteolysis into 
small peptides and amino acids. 
Elimination 
Assuming the model-derived estimated BA of 66%, the central CL for a typical patient was 
0.09 L/day (23.4% CV) following sc administrations of 225, 675, and 900 mg of fremanezumab. 
Fremanezumab has an estimated terminal elimination half-life of 30 days. 
Drug Interactions 
No formal clinical drug interaction studies have been performed with fremanezumab. No 
pharmacokinetic drug interactions are expected based on the characteristics of fremanezumab. 
Furthermore, concomitant use of acute migraine treatments (specifically analgesics, ergots, and 
triptans) and preventive migraine medicinal products during the clinical studies did not affect the 
pharmacokinetics of fremanezumab. 
Special Populations 
A population pharmacokinetic analysis looking at age, race, sex, and weight was conducted on 
data from 2546 subjects. Approximately twice as much exposure is expected in the lowest body 
weight quartile (43.5 to 60.5 kg) compared to the highest body weight quartile (84.4 to 131.8 
kg). However, body weight did not have an observed effect on the clinical efficacy based on the 
exposure-response analyses in patients with EM and CM. No dose adjustments are required for 
fremanezumab for migraine. 
Renal or Hepatic Impairment 
As mAbs are not known to be eliminated via renal pathways or to be metabolized in the liver, 
renal and hepatic impairments are not expected to impact the pharmacokinetics of 
fremanezumab. Patients with severe renal impairment (estimated glomerular filtration rate 
<30 mL/min/1.73 m2) have not been studied. A population pharmacokinetic analysis of 
integrated data from the fremanezumab clinical studies did not reveal a difference in the 
pharmacokinetics of fremanezumab in patients with mild to moderate renal impairment or 
hepatic impairment relative to those with normal renal or hepatic function. 
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1.2.2.2. 
Clinical Safety and Efficacy Studies  
Fremanezumab was well tolerated with a favorable safety profile across the 8 completed Phase 1 
studies in healthy subjects and the 2 completed Phase 2b studies and 2 completed Phase 3 studies 
in patients with migraine. 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 CM and EM patients (Studies TV48125-CNS-30049 and 
TV48125-CNS-30050, respectively) confirmed the efficacy findings in Phase 2. 
Study TV48125-CNS-30049 (Silberstein et al 2017) 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 675 mg fremanezumab 
[675 mg/placebo/placebo; N=379] and a starting dose of 675 mg fremanezumab followed by 
monthly 225 mg fremanezumab [675/225/225 mg; N=376]) 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 (visit 1), a baseline 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 was -4.2 and -4.5 (mean reduction of 4.7 and 4.9 days) versus -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 versus the placebo group, 
respectively. The least square (LS) mean difference from placebo was 1.8 days for the 
675 mg/placebo/placebo treatment group and 2.1 days for the 675/225/225 mg treatment group. 
Statistically significant improvements (p<0.0001 for both comparisons versus placebo) were 
evident as early as month 1 (secondary endpoint), 
 
 (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 the use of acute headache medication, and 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 
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events were mild to moderate. Injection site–related adverse events were the most frequent 
treatment-related adverse events and were overall comparable across all treatment groups. 
Study TV48125-CNS-30050 (Dodick et al 2018b) 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 dose of 675 mg fremanezumab 
[675 mg/placebo/placebo; N=291] and monthly doses of 225 mg fremanezumab 
[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 (visit 1), a baseline 
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, 
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) versus -2.7 days (mean reduction 
2.6 days) for the 675 mg/placebo/placebo and 225/225/225 mg treatment groups versus the 
placebo group, respectively. The LS mean difference from placebo was 1.3 days for the 
675 mg/placebo/placebo treatment group and 1.5 days for the 225/225/225 mg treatment group. 
Statistically significant improvements (p<0.0001 for both comparisons versus placebo) were 
evident as early as month 1 (secondary endpoint), 
 
 (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 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. 
Three Otsuka-sponsored studies in Japanese and Korean patients with EM and CM to evaluate 
the efficacy and safety of fremanezumab have been completed. These studies are 2 Phase 2b/3 
double-blind, placebo-controlled studies in approximately 900 patients (406-102-00001 and 406-
102-00002; Sakai et al 2021a, 2021b) and 1 long-term study in 50 patients (406-102-00003; 
manuscript accepted by Drug Safety as of 31 August 2021). The study designs of the Otsuka 
studies are the same as those of the HALO studies. Efficacy results demonstrated that treatment 
with fremanezumab monthly and quarterly was associated with statistically significant and 
clinically meaningful improvements on all primary and secondary efficacy measures. The safety 
profile observed in these studies was found to be consistent with that seen in the global pivotal 
efficacy studies; no safety signals were identified. These studies, together with the global HALO 
studies, led to marketing authorization in Japan and Korea in 2021. 
Fremanezumab at the doses tested was generally safe and well tolerated for 3 months in patients 
with migraine. Serious adverse events and adverse events leading to discontinuation from the 
study occurred infrequently and with similar frequency across the treatment groups. Injection 
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site–related adverse events were the most frequent treatment-related adverse events and were 
comparable across all treatment groups. 
One Phase 3 study (Study TV48125-CNS-30051) was conducted to further evaluate the 
long-term efficacy, safety, and tolerability of various dose regimens of fremanezumab in the 
preventive treatment of migraine (CM and EM). For the placebo rollover and the new patients, 
the efficacy profile during the first 3 months was similar to what was seen in 
Studies TV48125-CNS-30049 and TV48125-CNS-30050 for patients treated with 
fremanezumab. For all patients, efficacy was sustained for over 12 months in the long-term 
treatment period when patients received fremanezumab without interruption. 
One additional placebo-controlled study followed by an open-label and follow-up period 
Phase 3b study (Study TV48125-CNS-30068 [Ferrari et al 2019]) was conducted to evaluate the 
efficacy, safety, and tolerability of monthly and quarterly fremanezumab compared with placebo 
in patients with CM and EM with documented inadequate response to 2 to 4 prior preventive 
migraine medications. The results of this study demonstrate that sc administration of 
fremanezumab via quarterly or monthly dosing over 3 months was effective and well tolerated in 
patients with CM and EM with documented prior failure of 2 to 4 classes of preventive migraine 
medications. Improvements were sustained throughout the 3-month duration of the double-blind 
portion of the study. 
No clinically relevant changes in clinical laboratory values, vital signs measurements, or ECG 
findings have been observed in any of the studies to date. 
The safety, tolerability, and efficacy of fremanezumab have also been evaluated in 2 completed 
Phase 2b studies (Studies LBR-101-021 and LBR-101-022) in patients with migraine 
(Bigal et al 2015a, 2015b). The results of both studies showed fremanezumab to be superior to 
placebo for primary and secondary endpoints (benefit at 3 months of therapy). 
One Phase 4 study (Study TV48125-MH-40142) was conducted (last patient last visit: 31 August 
2021) to evaluate the efficacy and safety of fremanezumab in adult patients with migraine and 
comorbid major depressive disorder. The main objective of this study was to determine whether 
fremanezumab is effective in the preventive treatment of migraine in patients who also have 
major depressive disorder given the significant number of people afflicted by both diseases. 
1.3. 
Known and Potential Benefits and Risks to Patients  
1.3.1. 
Known and Potential Benefits and Risks of the Test Investigational Medicinal 
Product(s)  
Additional information regarding benefits and risks to patients may be found in the IB or 
approved Product Information or Summary of Product Characteristics applicable. 
1.3.1.1. 
Identified Risks  
1.3.1.1.1. General Disorders and Administrative Conditions  
Reports of transient administration site reactions, including injection site bruising, injection site 
swelling, injection site pain, injection site pruritus, injection site induration, injection site 
erythema, injection site inflammation, injection site warmth, injection site dermatitis, injection 
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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. 
Among these events, the following have been identified as adverse drug reactions (identified 
risks): injection site erythema, injection site induration, injection site pruritus, injection site pain, 
and injection site rash. None of the identified risks were considered important risks. 
1.3.1.1.2. Injury, Poisoning, and Procedural Complications/Immune System Disorders  
Type I hypersensitivity or allergic reactions (eg, shortness of breath, urticaria, anaphylaxis, and 
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, and angioedema, and, if untreated and severe, can 
progress to glomerulonephritis. Type III hypersensitivity reactions were not observed in clinical 
trials with fremanezumab. 
Drug hypersensitivity reactions have occurred rarely with fremanezumab. In all patients in the 
placebo-controlled studies, drug hypersensitivity occurred in 2 patients (<1%) who received 
placebo and 2 patients (<1%) who received fremanezumab (1 moderate event and 1 mild event). 
Among all fremanezumab-treated patients, 3 additional patients who received fremanezumab had 
adverse events of drug hypersensitivity (2 moderate events and 1 mild event). 
While no severe hypersensitivity or anaphylactic reactions related to fremanezumab 
administration occurred in the clinical development program for migraine, a small number of 
severe hypersensitivity reactions, including anaphylaxis, have been reported in the postmarketing 
period. One patient, who was taking multiple concomitant medications including lamotrigine and 
treated with fremanezumab, was reported to have Stevens-Johnson Syndrome. This reaction has 
also been rarely reported to occur in patients taking other mAbs targeting the CGRP pathway, 
along with concomitant medications including lamotrigine. 
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 mAb 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, there is a theoretical risk of unfavorable cardiovascular effects 
with CGRP inhibition. Extensive research conducted with the CGRP ligand antagonists has not 
identified relevant safety cardiovascular concerns in humans. Dedicated studies conducted in 
monkeys and humans using fremanezumab have not identified clinically relevant changes in 
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heart rate, blood pressure, or other cardiovascular parameters. No cardiovascular safety signals 
have been detected in the completed studies or in the postmarketing period. 
1.3.2. 
Overall Benefit and Risk Assessment for This Study  
In summary, the benefit and risk assessment for fremanezumab is favorable following review of 
the available safety and efficacy data. 
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2. 
STUDY OBJECTIVES AND ENDPOINTS  
2.1. 
Primary and Secondary Study Objectives and Endpoints  
Note that, for endpoints that are based on a monthly average, “baseline” refers to the monthly 
average value during the 28-day baseline period. 
The primary endpoint was chosen based on the International Headache Society (IHS) guidelines 
for studies 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). 
The primary and secondary study objectives and endpoints are the following: 
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 Chinese patients 
with migraine. The primary efficacy 
analysis will consider all 
fremanezumab-treated patients as 
1 group. 
The primary endpoint is the mean change from baseline in 
the monthly average number of migraine days during the 
12-week period after the 1st dose of investigational medicinal 
product (IMP). 
The secondary objective of the study 
is to further demonstrate the efficacy of 
fremanezumab administered as 
monthly and quarterly sc injections to 
adult Chinese patients with migraine. 
The secondary efficacy analyses will 
consider all fremanezumab-treated 
patients as 1 group. 
The secondary endpoints are as follows: 
• 
mean change from baseline in the number of 
migraine days during the 4-week period after the 1st 
dose of IMP 
• 
mean change from baseline in the monthly average 
number of days that any acute headache medications 
were used during the 12-week period after the 1st 
dose of IMP 
• 
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 IMP  
• 
mean change from baseline in the monthly average 
number of days with headache of at least moderate 
severity during the 12-week period after the 1st dose 
of IMP  
A secondary objective of the study is 
to evaluate the safety and tolerability 
of fremanezumab administered as 
monthly and quarterly sc injections to 
adult Chinese patients with migraine. 
The safety/tolerability endpoints are as follows: 
• 
occurrence of adverse events throughout the study 
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Objectives 
Endpoints 
• 
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: Oxygen saturation and respiratory rate 
will be measured in cases of suspected anaphylaxis 
and severe hypersensitivity.) 
• 
12-lead electrocardiogram (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 
• 
assessment of the immunogenicity of fremanezumab 
and the impact of antidrug antibodies (ADAs) on 
clinical outcomes in patients exposed to sc 
fremanezumab 
• 
assessment of the ADA incidence and characteristics 
(eg, titer, kinetics, and neutralizing activities) 
ADA=antidrug antibody; ECG=electrocardiogram; IMP=investigational medicinal product; sc=subcutaneous. 
2.2. 
Pharmacokinetic and Other Objectives and Endpoints  
Pharmacokinetic and other endpoints for the double-blind treatment period to address the 
objective to further characterize fremanezumab safety, efficacy, and pharmacokinetics are as 
follows:  
• assessment of plasma concentration of fremanezumab during the 12-week period after the 
1st dose of investigational medicinal product (IMP) and at the follow-up visit using a 
population pharmacokinetic modeling approach 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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3. 
STUDY DESIGN  
3.1. 
General Study Design and Study Schematic Diagram  
This is a multicenter, randomized, double-blind, placebo-controlled study with an open-label 
treatment period to evaluate the efficacy, safety, and tolerability of monthly and quarterly sc 
fremanezumab for the preventive treatment of migraine in adults. The study will consist of a 
screening visit, a baseline period (4 weeks), a 12-week double-blind treatment period, a 12-week 
open-label treatment period, and a follow-up period lasting approximately 3 months after the last 
dose of IMP (ie, 2 months after the end of treatment [EOT]/early termination [ET] visit). A 
follow-up visit 3 months after the last dose of fremanezumab will occur for ADA blood sample 
collection. 
The total duration of patient participation in the study is planned to be approximately 9 months. 
This study will include female and male patients, aged 18 to 70 years, inclusive, with a history of 
migraine (as defined by the International Classification of Headache Disorders, 3rd revision 
[ICHD-3] criteria [IHS 2018, CMAPS 2016]) for at least 12 months prior to screening and a 
prospectively documented diagnosis of migraine confirmed via a review of headache data 
recorded daily in an electronic headache diary device during a 28-day baseline period. 
Up to 30% of patients will be allowed to continue on a stable dose of 1 preventive migraine 
medication listed in Appendix K for migraine prevention or for other chronic conditions that they 
were using before screening (patients must have been taking a stable dose of these medications 
for at least 2 months of consecutive use prior to screening and do not expect to change dosing 
regimens or to change to another medication during the treatment phase of the study). Patients 
will be allowed to use acute medications to treat breakthrough migraines as needed, with the 
exception of medications containing opioids and barbiturates, which cannot be used on more 
than 4 days during the screening period for the treatment of migraine or for any other reason. 
Traditional Chinese therapy (including herbal medicine) and acupuncture are allowed if the patient 
is on a stable dose/regimen for at least 2 months (consecutive) before screening. 
After completing the informed consent process (screening visit [visit 1]), patients will be 
screened for eligibility. Eligible patients will enter a 28-day baseline period. Headache 
information will be captured daily during the screening/baseline period and treatment period 
using an electronic headache diary device. 
After completing the baseline period, patients will be asked to return to the study center on day 1 
(visit 2). Patients who have confirmed migraine and meet all other eligibility criteria (including 
electronic headache diary device compliance criteria during the 28-day baseline period) will be 
randomly assigned in a 1:1:2 ratio to 1 of 3 treatment groups: 
• fremanezumab 225 mg sc once a month (approximately every 4 weeks [28 days]), for a 
total of 3 doses; one 225-mg injection and 2 placebo injections at visit 2 and one 225-mg 
injection at visits 3 and 4 
• fremanezumab 675 mg sc once a quarter (once at the beginning of the 12-week 
double-blind treatment period), for a total of 1 dose; three 225-mg injections at visit 2 and 
1 placebo injection at visits 3 and 4 or  
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• placebo sc once a month (approximately every 4 weeks [28 days]), for a total of 3 doses; 
3 placebo injections at visit 2 and 1 placebo injection at visits 3 and 4  
Patients must return to the study center after visit 2, visit 3, or visit 4 for 2 additional blood 
sampling visits to measure plasma fremanezumab concentration. Additional details on these 
visits are provided in Section 8.1. 
During the 12-week open-label treatment period, patients will receive fremanezumab 225 mg sc 
once a month (approximately every 4 weeks) for a total of 3 doses (one 225-mg injection at 
visits 5, 6, and 7). 
At the end of the open-label treatment period (4 weeks after the last dose), an EOT study visit 
(visit 8) will be scheduled. Patients should return to the care of their treating physicians after 
visit 8. Patients should be treated with standard of care after withdrawal from or termination of 
the 24-week treatment period/study, as appropriate. 
Randomization using electronic interactive response technology (IRT) will be stratified based on 
migraine type (CM vs EM) and preventive medication use to ensure balance. Blinded treatment 
will be administered sc once monthly (ie, approximately every 4 weeks), for a total of 3 doses. 
First treatment administration will occur at visit 2 (day 1), and additional doses will be 
administered at visits 3 and 4. 
The Patient Global Impression of Change (PGIC) scale, safety evaluations, and blood draws for 
pharmacokinetic and immunogenicity analysis will be performed throughout the study according 
to the schedule of study procedures and assessments (Table 3).  
Patients will have treatment evaluations performed at visit 8 (EOT visit), approximately 4 weeks 
after administration of the final dose of study drug. 
Follow-up visits for ADA sample collection will occur approximately 1 month and 3 months 
after the last dose of study drug (visit 7), at the EOT/ET visit (visit 8) and at the end of study 
(EOS) visit (visit 9), respectively. 
Patients who discontinue treatment prematurely should be encouraged to continue to attend the 
regular scheduled visits and complete the prescribed safety and efficacy evaluations through the 
EOT/ET visit and the follow-up visit, if at all possible. 
Patients who both discontinue treatment and also withdraw from the study should have EOT/ET 
visit procedures/assessments (Table 3) performed on the last day that the patient receives the 
IMP or as soon as possible thereafter. The patient should also return for the follow-up visit 
approximately 3 months after the last dose IMP if at all possible. 
The EOS is defined as the last visit of the last patient (follow-up visit, visit 9). Two interim 
analyses are planned. The first 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 (visit 5). A 
second interim database lock will occur following the end of the open-label period (visit 8). Final 
database lock will occur following the end of the follow-up period. 
The study duration will be approximately 2 years, from approximately quarter 3 (Q3) 2022 to 
approximately quarter 2 (Q2) 2024. 
The study schematic diagram is presented in Figure 1. 
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In the event of an emergency situation (eg, pandemic or potential pandemic), the investigational 
center will inform the patient of the safeguards being taken and will discuss their willingness or 
feasibility to come to the site for upcoming visits. If an ongoing patient cannot go to the site, the 
Medical Monitor will be notified to discuss further plans for that patient. 
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Figure 1: 
Overall Study Schematic Diagram  
 
ADA=antidrug antibody; IMP=investigational medicinal product; N=planned number of patients in the study population; sc=subcutaneous; V=visit. 
Note: Blood samples for plasma drug concentration will be collected at visits 2, 3, and 4. Patients will be asked to return to the study center after visit 2, visit 3, 
or visit 4 for 2 additional blood sampling visits to measure plasma fremanezumab concentration (one being 3 to 10 days after either visit 2, visit 3, or visit 4 and 
the other being 15 to 20 days after either visit 2, visit 3, or visit 4). If 2 additional visits are not possible for the patient, then the patient must return for only 
1 additional pharmacokinetic blood sampling at either of the aforementioned time points. When patients return to the study center for additional blood sampling, 
then inquiries about adverse events and concomitant medications will be performed. 
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3.2. 
Planned Number of Patients and Countries  
Approximately 372 patients (93 patients in each active treatment group and 186 patients in the 
placebo group) are planned to be enrolled in this study to have approximately 328 patients who 
complete the study (82 patients in each active treatment group and 164 patients in the placebo 
group); a 12% discontinuation rate is anticipated. 
The study is planned to be conducted in China in approximately 30 investigational centers. The 
study is expected to start in approximately Q3 2022 and last until approximately Q2 2024. 
3.3. 
Justification for Study Design and Selection of Population  
Efficacy has been demonstrated in patients in North America, Europe, Japan, and Korea in the 
fremanezumab pivotal studies, the HALO studies, which led to its approval in the US, the EU, 
Australia, Canada, Taiwan, Hong Kong, Brazil, Mexico, Israel, and several other countries. 
(Section 1.2.2). Additional double-blind, placebo-controlled studies have been completed in 
Japan and South Korea and have demonstrated consistent efficacy and safety profiles. Those 
studies, together with the HALO studies, led to approval in Japan and Korea (Dodick et al 
2018b, Silberstein et al 2017, Sakai et al 2021a, 2021b). The pharmacokinetic and 
safety/tolerability profiles of fremanezumab are consistent among non-Japanese and Japanese 
patients (as well as Korean patients), as demonstrated in the pharmacokinetic bridging study in 
western and Japanese populations, and as observed in an independently executed and completed 
study by Otsuka. In the population pharmacokinetic analysis, race was not found to be a 
significant covariate. No ethnic differences are expected or observed in the safety or efficacy of 
fremanezumab used for the preventive treatment of migraine.  
This study is intended to confirm the efficacy and safety of fremanezumab in adult Chinese 
patients with the diagnosis of migraine in China. Study design elements, including treatment 
duration; dosing regimen; inclusion/exclusion criteria; and efficacy, safety, and pharmacokinetic 
assessments, are consistent with the global pivotal HALO studies and studies for Japanese and 
Korean patients with migraine. The sample size calculation is based on the observed effect size 
from these completed global efficacy studies. More specifically, all patients with migraine 
meeting the Chinese preventive migraine treatment guidelines will be eligible for screening and 
will, in general, be allowed to continue their current acute migraine management regimen. Up to 
30% of patients will also be allowed to continue their current preventive migraine regimen. 
Patients in the study will be randomized to double-blind treatment in a 1:1:2 ratio to receive 
225 mg fremanezumab once a month (approximately every 4 weeks, monthly), 675 mg 
fremanezumab once every 3 months (approximately every 12 weeks, quarterly), or placebo 
monthly for 3 months, respectively. After 12 weeks of double-blind treatment, all patients will 
receive fremanezumab 225 mg sc once a month (approximately every 4 weeks, monthly). Both 
fremanezumab dosing regimens are approved in the US, the EU, Japan, Korea, Australia, 
Canada, Israel, and several additional countries. 
Study design elements, including the duration of the double-blind and open-label treatment 
periods; dosing regimen; inclusion/exclusion criteria; and efficacy, safety and pharmacokinetic 
assessments are consistent with the pivotal HALO studies and all fremanezumab migraine 
efficacy studies completed so far.  
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Throughout the global fremanezumab clinical program, patients with the full range of clinical 
severities, from the episodic to chronic subtypes of migraine, both separately and combined, 
have consistently demonstrated similar efficacy and safety with fremanezumab treatment by the 
same measures. Therefore, in this study, the primary analysis will consider patients representing 
the entire disease spectrum of migraine as a single study population stratified by EM and CM. 
Moreover, this study population is fully consistent with the currently approved indication for 
migraine in the US, Canada, EU, and other countries, and fully reflects the intended population 
for use in Chinese patients. In order to provide added granularity to the migraine subtypes, data 
for patients with EM and CM will be provided as subgroup analyses. Pharmacokinetic samples 
will be collected during the treatment and follow-up periods and analyzed using a population 
pharmacokinetic (PPK) modeling approach. Pharmacokinetic plasma concentration results for 
fremanezumab will be tabulated descriptively at each planned sampling time point by treatment 
group. The pharmacokinetic data from this study will be compared with the general migraine 
population data in order to demonstrate comparability. Anti-drug antibody samples will be 
collected and analyzed during and after the treatment period. 
Primary efficacy will be measured by the change from baseline in the monthly average number 
of migraine days during the 12 weeks after the 1st dose of IMP. This primary efficacy endpoint is 
widely accepted by the US Food and Drug Administration (FDA) and the EMA for preventive 
migraine medication studies. This endpoint was used in the Phase 3 HALO studies that were 
pivotal for FDA and EMA approval. It was also used in the Otsuka-sponsored Phase 3 
fremanezumab studies in Japanese patients that were deemed pivotal for approval by the 
Pharmaceuticals and Medical Devices Agency in Japan. All aforementioned Phase 3 
fremanezumab studies have demonstrated similar efficacy and safety profiles across regions, 
races, sexes, and ages. In addition, PGIC will be recorded. Pharmacokinetic samples will be 
collected during the double-blind treatment period and the follow-up period and will be analyzed 
using a population pharmacokinetic approach. ADAs will be evaluated according to established 
validated methods during the double-blind treatment period and approximately 3 months 
(3 half-lives) after the last dose of study drug. 
3.4. 
Stopping Rules for the Study  
There are no formal rules for ET of this study. During the conduct of the study, serious adverse 
events will be reviewed (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 that invalidate the earlier 
positive benefit-risk assessment 
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). 
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3.5. 
Schedule of Study Procedures and Assessments  
Study procedures and assessments with their time points are presented in Table 3. 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 
immunogenicity assessments). Study procedures and assessments by visit are listed in 
Appendix B. 
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Table 3: 
Study Procedures and Assessments  
Study period 
Pretreatment 
(screening 
visit and 
baseline 
period) 
Double-blind treatment period 
Open-label treatment period 
Follow-up period 
Visit number 
V1 
V2a   
V3 
V4 
V5 
V6 
V7 
V8 
V9b 
Time point 
Week -4 
Week 0 
Week 4 
Week 8 
Week 
12 
Week 16 
Week 20 
Week 24 
Approximately 
3 months after 
the last dose of 
IMP (2 months 
after V8) 
Day and allowed time 
windowsc   
Day -28 to -1 
Day 1 
+3 days 
Day 29 
±3 days 
Day 57 
±3 days 
Day 85 
±5 days 
Day 113 ±5 days 
Day 141 
±5 days 
Day 169 
±5 days 
Day 225 
±15 days 
Procedures and assessments 
Screening 
Baseline 
 
 
 
 
 
EOT/ET 
EOS 
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 
historyd   
X 
 
 
 
 
 
 
 
 
Clinical laboratory tests (serum 
chemistry, hematology, 
coagulation, and urinalysis)e   
X 
X 
 
X 
X 
 
 
X 
Xf 
Blood samples for plasma 
concentration of the IMPg   
 
X 
X 
X 
 
 
 
X 
 
Blood samples for serum ADA 
assessmenth   
 
X 
 
X 
 
 
 
X 
X 
Physical examination, including 
height and weighti   
X 
X 
X 
X 
X 
 
 
X 
X 
12-Lead ECGj   
X 
X 
 
X 
 
 
 
X 
Xf 
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Study period 
Pretreatment 
(screening 
visit and 
baseline 
period) 
Double-blind treatment period 
Open-label treatment period 
Follow-up period 
Visit number 
V1 
V2a   
V3 
V4 
V5 
V6 
V7 
V8 
V9b 
Time point 
Week -4 
Week 0 
Week 4 
Week 8 
Week 
12 
Week 16 
Week 20 
Week 24 
Approximately 
3 months after 
the last dose of 
IMP (2 months 
after V8) 
Day and allowed time 
windowsc   
Day -28 to -1 
Day 1 
+3 days 
Day 29 
±3 days 
Day 57 
±3 days 
Day 85 
±5 days 
Day 113 ±5 days 
Day 141 
±5 days 
Day 169 
±5 days 
Day 225 
±15 days 
Procedures and assessments 
Screening 
Baseline 
 
 
 
 
 
EOT/ET 
EOS 
Vital signs measurementk,l   
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum β-HCG testm   
X 
 
 
 
 
 
 
X 
 
Urine pregnancy testm 
 
X 
X 
X 
X 
X 
X 
X 
 
FSHn   
X 
 
 
 
 
 
 
 
 
Inform patients of study 
restrictions and compliance 
requirements 
X 
 
 
 
 
 
 
 
 
Review study compliancel 
 
X 
X 
X 
X 
X 
X 
X 
 
Provide the electronic headache 
diary deviceo   
X 
 
 
 
 
 
 
 
 
Complete electronic headache 
diary entriesp   
X 
 
 
 
 
 
 
X 
 
Review the electronic headache 
diaryl 
 
X 
X 
X 
X 
X 
X 
X 
 
Return the electronic headache 
diary device 
 
 
 
 
 
 
 
X 
 
PGIC scale 
 
 
 
 
X 
 
 
X 
 
Adverse eventsl q   
 
X 
X 
X 
X 
X 
X 
X 
X 
Administration of IMP 
 
X 
X 
X 
X 
X 
X 
 
 
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Study period 
Pretreatment 
(screening 
visit and 
baseline 
period) 
Double-blind treatment period 
Open-label treatment period 
Follow-up period 
Visit number 
V1 
V2a   
V3 
V4 
V5 
V6 
V7 
V8 
V9b 
Time point 
Week -4 
Week 0 
Week 4 
Week 8 
Week 
12 
Week 16 
Week 20 
Week 24 
Approximately 
3 months after 
the last dose of 
IMP (2 months 
after V8) 
Day and allowed time 
windowsc   
Day -28 to -1 
Day 1 
+3 days 
Day 29 
±3 days 
Day 57 
±3 days 
Day 85 
±5 days 
Day 113 ±5 days 
Day 141 
±5 days 
Day 169 
±5 days 
Day 225 
±15 days 
Procedures and assessments 
Screening 
Baseline 
 
 
 
 
 
EOT/ET 
EOS 
Hypersensitivity/anaphylaxisr   
 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant medication inquiryl 
 
X 
X 
X 
X 
X 
X 
X 
X 
a All visit 2/baseline procedures must be performed before IMP administration. Inquiries about adverse events will be made before and after IMP administration. 
Postdose inquiries will be made before the patient leaves the study center. 
b The EOS is defined as the last visit of the last patient. Each patient attends his/her follow-up visit approximately 3 months after the last dose of IMP 
(approximately 2 months after the EOT/ET visit [visit 8]). 
c In case of an emergency situation (eg, pandemic or potential pandemic), visit windows for post baseline visits may be extended to 14 calendar days, except for 
visit 2. The window for visit 2 may only be extended to 7 calendar days in case of an emergency situation (eg, pandemic or potential pandemic). In case of an 
out-of-window visit, the date of the next visit will be calculated based on the actual date of the last administration of study drug.  
d Collection of prior medications is limited to those medications administered within 6 months before IMP administration (visit 2) and preventive medications 
taken within 10 years. 
e At visits where IMP is administered, clinical laboratory tests should be performed predose. 
f To be performed at visit 9 (follow-up) if assessment at visit 8 (EOT/ET) shows abnormality. 
g Blood samples for plasma drug concentration determination will be collected prior to dosing (as appropriate). Patients will be asked to return to the study center 
after visit 2, visit 3, or visit 4 for 2 additional blood sampling visits to measure plasma fremanezumab concentration (one being 3 to 10 days after either visit 2, 
visit 3, or visit 4 and the other being 15 to 20 days after either visit 2, visit 3, or visit 4). If 2 additional visits are not possible for the patient, then the patient 
must return for only 1 additional pharmacokinetic blood sampling at either of the aforementioned time points. When patients return to the study center for 
additional blood sampling, then inquiries about adverse events and concomitant medications will be performed. 
h Blood samples for serum ADA assessment will be collected prior to dosing (as appropriate). 
i Height will be measured only at the screening visit. 
j A single ECG will be performed predose. The ECG should be performed after the patient has been supine for at least 5 minutes. If results are abnormal, the 
ECG will be repeated 1 time. 
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k 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. 
l Procedures for unscheduled visits. 
m Women of childbearing potential only. At visits where IMP is administered, serum/urine β-HCG tests should be performed predose (see Appendix E). 
n Postmenopausal women only (see Appendix E). 
o 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. 
p Patients will complete electronic headache diary entries about the previous day daily beginning on day -27 through the EOT/ET visit. 
q Inquiries about adverse events will be made before and after IMP administration. Postdose inquiries will be made before the patient leaves the study center. 
r 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. 
β-HCG=beta human chorionic gonadotropin; ADA=antidrug antibody; ECG=electrocardiogram; EOS=end of study; EOT=end of treatment; ET=early 
termination; FSH=follicle-stimulating hormone; IMP=investigational medicinal product; PGIC=Patient Global Impression of Change; V=visit. 
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4. 
SELECTION AND WITHDRAWAL OF PATIENTS  
Prospective waivers (exceptions) from the 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 randomized/enrolled in this study only if they meet all of the following criteria: 
a. The patient is capable of giving signed informed consent as described in Appendix D, 
which includes compliance with the requirements and restrictions listed in this 
protocol. 
b. The patient is a man or woman 18 to 70 years of age, 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 evaluation, including medical and psychiatric history, physical examination, 
laboratory tests, and cardiac monitoring. 
e. The patient has a body weight 45 kg and body mass index within the range 17.5 to 
34.9 kg/m2 (inclusive). 
f. The patient has a history of migraine (according to the ICHD-3 criteria [IHS 2018, 
CMAPS 2016, Appendix J]), or clinical judgment suggests a migraine diagnosis (not 
better accounted for by another ICHD-3 diagnosis) for ≥12 months prior to screening 
(visit 1). 
g. [Revision 1] The patient has a clinical history of migraine that is confirmed during a 
prospectively recorded 28-day baseline period with the following characteristics: 
− Patient has 4 or more migraine days consistent with the characteristics of migraine 
(Appendix J) or probable migraine (a migraine subtype where only 1 migraine 
criterion is missing) or used a triptan or ergot derivative to treat an ongoing 
headache. 
− Patient has 2 or more days per month that are completely free of migraine 
headache or associated migraine symptoms. 
h. The patient agrees not to initiate any preventive migraine medications during the 
28-day baseline and double-blind treatment period. Up to 30% of patients are allowed 
to continue on 1 migraine preventive medication listed in Appendix K. However, 
patients must have been taking a stable dose of these medications for at least 
2 months of consecutive use prior to screening (visit 1) with no expectation to change 
dosing regimen or change to another migraine preventive medications during the 
treatment phase of the study. 
i. [Revision 1] Other concomitant medications (including herbal medicine) and 
acupuncture for migraine or other conditions are allowed for all patients, provided 
that the patient has been on a stable dose regimen for at least 2 months of consecutive 
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use prior to screening (visit 1) with no expectation to change dosing regimen or 
change to another medication during the treatment phase of the study. 
j. The patient demonstrated compliance with the electronic headache diary device 
during the baseline period by entry of headache data on a minimum of 21 days during 
the baseline period and throughout the treatment period (approximately 75% diary 
compliance during each period). 
k. Women may be included only if they have either a negative serum beta-human 
chorionic gonadotropin (β-HCG) test at screening (visit 1), are sterile, or are 
postmenopausal. Definitions of sterile and postmenopausal are given in Appendix E. 
l. 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 (ie, starting at screening [visit 1]) and for 6 months after 
discontinuation of the IMP. Further details are included in Appendix E. 
m. Men must be sterile or, if they are potentially fertile/reproductively competent (not 
congenitally sterile) and their female partners are of childbearing potential, should use 
highly effective birth control for the duration of the study. Definitions of women of 
non-childbearing potential, sterile, and postmenopausal women; male contraception; 
and highly effective birth control methods, including examples, are given in 
Appendix E. 
n. 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 further visits, as applicable, and the follow-up evaluations, as specified in this 
protocol. 
4.2. 
Patient Exclusion Criteria  
Patients will not be randomized/enrolled in this study if they meet any of the following criteria: 
a. Uses medications containing opioids (including codeine), barbiturates (including 
butalbital), or any combination product containing opioids or barbiturates (including 
butalbital) on more than 4 days during the screening period for the treatment of 
migraine or for any other reason. 
b. Has used an intervention/device (eg, scheduled nerve blocks or transcranial magnetic 
stimulation) for migraine, or in the head or neck area, during the 2 months prior to 
screening (visit 1). 
c. Clinically significant hematological, cardiac, renal, endocrine, pulmonary, 
gastrointestinal, genitourinary, neurologic, hepatic, ocular disease, or complications 
of an infection that, in the opinion of the investigator, could interfere with the normal 
completion of study activities. 
d. 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, 
generalized anxiety disorder, any suicide attempt in the past, suicidal ideation with a 
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specific plan in the past 2 years prior to screening (visit 1), or current suicidal 
ideation. 
e. History of clinically significant cardiovascular disease or vascular ischemia (such as 
myocardial, neurological [eg, cerebral ischemia], or peripheral extremity ischemia or 
other ischemic event) or thromboembolic events (arterial or venous thrombotic or 
embolic events), such as cerebrovascular accident (including transient ischemic 
attacks), deep vein thrombosis, or pulmonary embolism. 
f. [Revision 1] Known current infection or any history of infection with human 
immunodeficiency virus, tuberculosis, or Lyme disease, or a known or suspected 
active infection of coronavirus disease 2019 (COVID-19). 
g. Past or current history of cancer in the past 5 years, except for appropriately treated 
non-melanoma skin carcinoma. 
h. Pregnant or nursing females or females who plan to become pregnant during the 
study. 
i. History of hypersensitivity reactions to injected proteins, including mAbs, or a history 
of Stevens-Johnson Syndrome or toxic epidermal necrolysis syndrome, or the patient 
is concomitantly using lamotrigine. 
j. Participation in a clinical study of a new chemical entity or a prescription medicine 
within 2 months before screening (visit 1) (or 3 months in the case of a biologic if the 
half-life of the biologic is unknown) or 5 half-lives, whichever is longer, or is 
currently participating in another study of an IMP or medical device. 
k. Any prior exposure to a mAb targeting the CGRP pathway (erenumab, eptinezumab, 
galcanezumab, or fremanezumab) during the 6 months before the screening visit 
(visit 1), or exposure to gepants for less than 5 half-lives before screening. 
l. Any finding in the baseline 12-lead ECG considered clinically significant in the 
judgment of the investigator. 
m. Any finding that, in the judgment of the investigator, is a clinically significant 
abnormality, including physical examination findings, and serum chemistry, 
hematology, coagulation, and urinalysis test values (abnormal test results may be 
repeated for confirmation). 
n. Hepatic enzymes (alanine aminotransferase [ALT], aspartate aminotransferase [AST], 
and alkaline phosphatase [ALP]) >2× the upper limit of normal (ULN) after 
confirmation in a repeat test or suspected hepatocellular damage that fulfills criteria 
for Hy’s law at screening (visit 1). 
o. Serum creatinine >1.5× ULN, clinically significant proteinuria, or evidence of renal 
disease at screening (visit 1). 
p. Any clinically significant uncontrolled medical condition (treated or untreated). 
q. History of alcohol or drug abuse during the past 2 years or drug dependence during 
the past 5 years. 
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r. The patient cannot participate or successfully complete the study, in the opinion of 
his/her 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 that, in the opinion of the investigator, makes the patient 
inappropriate for inclusion in the study 
s. The patient is a study center or sponsor employee who is directly involved in the 
study or the relative of such an employee. 
t. The patient has any disorder that may interfere with the absorption, distribution, 
metabolism, or excretion of the IMP. 
u. Vulnerable patients (eg, members of a group with a hierarchical structure [such as 
medical, pharmacy, dental, and nursing students], subordinate hospital and laboratory 
personnel, employees of the pharmaceutical industry, members of the armed forces, 
persons kept in detention, patients with incurable diseases, persons in nursing homes, 
unemployed or impoverished persons, patients in emergency situations, ethnic 
minority groups, homeless persons, nomads, refugees, minors, and those incapable of 
giving consent). 
v. The patient has previously participated in this study or has been assigned previously 
to a study with the IMP. 
w. [New criterion] Known current infection or history of infection in the past 6 months 
with hepatitis B or C viruses. 
4.3. 
Withdrawal Criteria and Procedures for the Patient  
Each patient is free to withdraw from the study or discontinue from IMP at any time (but may 
continue with study assessments), without prejudice to their continued care. Patients must be 
withdrawn from the IMP 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. 
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7. Patient experiences an adverse event or other medical condition that 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. 
See Appendix F 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. 
If the reason for withdrawal from the study or discontinuation from the 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 or until the patient is referred to the care 
of a health care professional). The specific event or test result (including repeated test results, as 
applicable) must be recorded on the source documents and in the CRF as applicable. 
If a patient is withdrawn from the study or discontinues IMP for multiple reasons that also 
include adverse events, the relevant page of the CRF should indicate that the 
withdrawal/discontinuation 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 
“Other,” specifying the details as “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. 
4.4. 
Replacement of Patients  
Generally, a patient who is randomized but does not complete the treatment period will not be 
replaced.  
ET rate and screen failures due to an emergency situation (eg, pandemic or potential pandemic) 
will be monitored during the study. In order to maintain study power, an excess loss of patients 
will be replaced (eg, if there are >5% patients lost due to an emergency situation [eg, pandemic 
or potential pandemic], additional patients may be recruited). 
4.5. 
Rescreening  
A patient who is screened but not randomized (eg, because study eligibility criteria were not met 
[inclusion criteria not met or exclusion criteria met]) due to any of the following reasons: 
technical issues (eg, diary malfunction), out of visit 2 window due to an emergency situation (eg, 
pandemic or potential pandemic), a change in the patient’s medical background, a modification 
of study inclusion and exclusion criteria, or upon the sponsor’s discretion on a case-by-case 
basis, may be considered for rescreening 1 time.  
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Patients may be rescreened once if the repeated values for the laboratory, vital sign, or ECG 
screening criteria are within acceptable limits as judged by the investigator or if repeated values 
show normalization of the out-of-range values, but their initial baseline period has expired. 
If the patient is rescreened, an informed consent form (ICF) will need to be re-signed, and a new 
screening number will be assigned. 
4.6. 
Screening Failure  
Screening failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomized 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  
Treatment (active or placebo) will be administered at visit 2, visit 3, and visit 4. Active treatment 
will be administered to all patients at visit 5, visit 6, and visit 7. Final treatment evaluation will 
be performed at visit 8 (EOT), approximately 4 weeks after administration of the last dose of 
study drug. 
IMP is defined as the test IMP (fremanezumab) and matching placebo IMP. A summary of IMPs 
is presented in Table 4. Additional details may be found in the IB for fremanezumab. 
Table 4: 
Investigational Medicinal Products Used in the Study  
IMP name 
Fremanezumab, a fully humanized 
IgG2Δa/kappa mAb 
Placebo 
Trade name and INN, if 
applicable, or 
company- assigned 
number 
AJOVY 
Fremanezumab 
TEV-48125 
Placebo 
Formulation 
Prefilled syringes containing 150 mg/mL of 
active ingredient: fremanezumab 
Inactive ingredients include L-histidine, 
L-histidine hydrochloride monohydrate, 
sucrose, polysorbate-80, disodium EDTA 
dihydrate, and water for injection 
Prefilled syringes containing 1.5 mL of 
the same inactive vehicle and excipients 
that are in the active injections 
Inactive ingredients include L-histidine, 
L-histidine hydrochloride monohydrate, 
sucrose, polysorbate-80, disodium 
EDTA dihydrate, and water for injection 
Unit dose strength(s)/ 
Dosage level(s) 
225 mg 
None 
Route of administration sc injection 
sc injection 
Dosing instructions 
Quarterly: fremanezumab 675 mg as 
3 injections (225 mg/1.5 mL) at visit 2; 
1 placebo (1.5 mL) injection at visits 3 and 4 
Monthly: fremanezumab 225 mg as 1 injection 
(225 mg/1.5 mL) and 2 placebo (1.5 mL) 
injections at visit 2; fremanezumab 225 mg as 
1 injection (225 mg/1.5 mL) at visits 3 and 4 
3 placebo (1.5 mL) injections at visit 2; 
1 placebo (1.5 mL) injection at visits 3 
and 4 
Packaging 
A uniquely numbered kit containing 1 prefilled 
syringe stored (refrigerated at 2°C to 8°C) on 
site 
A uniquely numbered kit containing 
1 prefilled syringe stored (refrigerated at 
2°C to 8°C) on site 
Manufacturer 
Drug substance: 
 
 
 
 
Drug product: 
  
  
  
 
 
  
  
  
 
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EDTA=ethylenediaminetetraacetic acid; IgG2Δa=immunoglobulin G2Δa; IMP=investigational medicinal product; 
INN=international nonproprietary name; mAb=monoclonal antibody; sc=subcutaneous. 
Three individual, uniquely numbered visit kits each containing 1 prefilled syringe will be 
provided. 
At the time of each dosing visit, the IRT will be queried, and site staff will retrieve and 
administer 1.5 mL from each prefilled syringe contained in the appropriately numbered kits.  
The recommended sc injection sites follow the Instructions for Use in the US-approved AJOVY 
Prescribing Information (2020). Appropriate injection sites are back of upper arms, stomach area 
(abdomen), and front of thighs. Fremanezumab should not be injected into an area that is tender, 
red, bruised, callused, tattooed, or hard; that has scars; or that has stretch marks. 
Study drug should be removed from the refrigerator and allowed to equilibrate at room 
temperature for 30 minutes before administration of the study drug. The total number of sc 
injections and their injection site locations will be recorded on the CRF for each dosing visit.  
5.1.1. 
Test Investigational Medicinal Product  
Refer to the Pharmacy Manual for full instructions for the preparation and administration of the 
test IMP and placebo IMP. 
Prefilled syringes (active or placebo) will be contained in uniquely numbered kits and stored 
(refrigerated at 2°C to 8°C) on site. Active prefilled syringes will contain 225 mg of 
fremanezumab in 1.5-mL solution, and placebo prefilled syringes will contain the same vehicle 
and excipients as those for active injections. Each kit will contain 1 prefilled syringe. 
Adequate kit supply for upcoming study visits will be managed by the IRT and kept on-site. 
5.1.1.1. 
Starting Dose and Dose Levels  
The starting dose of fremanezumab will be either 675 mg or 225 mg at visit 2 (day 1), depending 
on the treatment group. 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 double-blind 
period and 225 mg for the open-label treatment period. 
5.1.1.2. 
Dose Modification  
No dose modifications are allowed. 
5.1.2. 
Placebo Investigational Medicinal Product  
Placebo (matching the test IMP fremanezumab) will be provided and administered as described 
in Table 4. 
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5.2. 
Preparation, Handling, Labeling, Storage, and Accountability for 
Investigational Medicinal Products  
5.2.1. 
Storage and Security  
The investigator or designee must confirm that 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, protected 
from the light. The investigational center must have a process for monitoring IMP storage 
temperature. 
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. 
5.2.2. 
Labeling  
Supplies of IMPs will be labeled according to the current China National Medical Products 
Administration (NMPA) and National Health Commission (NHC) guidelines on Good Clinical 
Practice (China GCP), International Council for Harmonisation (ICH) guidelines on Good 
Clinical Practice (GCP) and Good Manufacturing Practice, and will include any locally required 
statements. Labels will be translated into the local language. 
5.2.3. 
Accountability  
Each IMP shipment will include a packing slip listing the contents of the shipment, return 
instructions, and any applicable forms. 
The investigator is responsible for ensuring that deliveries of IMPs and other study materials 
from the sponsor are correctly received, recorded, handled, and stored safely and properly in 
accordance with the national and local regulations and used in accordance with this protocol. 
Only patients randomized in the study may receive IMPs, and only authorized site staff at the 
investigational center may supply and administer IMPs. All IMPs must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labeled storage conditions or appropriate instructions, with access limited to the investigator and 
authorized site staff at the investigational center. 
The investigator, the institution, or the head of the medical institution (where applicable) is 
responsible for IMP accountability, reconciliation, and record maintenance (ie, receipt, 
reconciliation, and final disposal of records). 
A record of IMP accountability (ie, IMP and other study 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. Prefilled syringes should never be used partially. 
Empty syringes should be destroyed at the investigational center after reconciliation is 
performed. If the investigational center does not have the capability to destroy the empty 
syringes, they should be sent back to the sponsor. Unused prefilled syringes of the IMP will be 
returned to the sponsor or designee. 
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5.3. 
Justification for Investigational Medicinal Products  
5.3.1. 
Justification for Dose of Test Investigational Medicinal Product  
The 2 dosing regimens for this study have been approved in the US, the EU, Japan, Korea, and in 
all other countries in which AJOVY received approval. Three dose regimens of fremanezumab 
administered sc were tested during two Phase 3 pivotal studies in the CM and EM patient 
populations (Studies TV48125-CNS-30049 and TV48125-CNS-30050, respectively). CM dosing 
regimens were 675-mg starting dose/monthly 225 mg or quarterly 675 mg, and EM dosing 
regimens were monthly 225 mg or quarterly 675 mg. Post hoc analysis demonstrated that the 
starting dose of 675 mg is not necessary, which led to the 2 approved dosing regimen for both 
EM and CM patients. 
During the Phase 2b studies, 4 dose regimens of fremanezumab (ie, EM: monthly 225 mg or 
675 mg; CM: monthly 675 mg, followed by 225 mg or monthly 900 mg sc) were tested and 
shown to be effective, safe, and well tolerated during the 3-month treatment period. Because it is 
considered best practice to select the lower dose for administration from 2 doses that show 
equivalence in efficacy (to avoid higher dose than necessary), the 2 monthly dose regimens of 
225 mg with the 675-mg starting dose (CM) or without starting dose (EM) were used as 1 active 
arm in each of the global Phase 3 studies and Otsuka Japanese and Korean studies. A 2nd active 
arm included in both the EM and CM studies was 675 mg sc fremanezumab 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 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 different 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 
migraine in adults. In addition, all active dose regimens showed no significant difference in 
efficacy and safety parameters. 
The quarterly 675-mg and monthly 225-mg sc doses of fremanezumab were selected for this 
study. These 2 dosing regimen have been approved for migraine prevention in all countries Teva 
received approval, including US, EU, Japan, Korea, Canada, Australia, Israel, and many other 
countries. 
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 studies of 
preventive 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). In addition, acute (rescue) medications are allowed for breakthrough 
migraine episodes. 
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5.4. 
Treatment after the End of the Study  
After the EOT visit (visit 8), patients will return to the care of their primary physician(s) for 
migraine management. 
5.5. 
Restrictions  
Patients will be required to comply with the following restrictions. 
5.5.1. 
Activity  
Patients must remain at the site, for safety observation, at least 30 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 months) after the last 
dose of the IMP. 
5.6. 
Prior and Concomitant Medication or Therapy  
Any prior or concomitant therapy, medication, or procedure (ie, procedures for the treatment of 
migraine [eg, nerve blocks]) 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 (preventive medications taken 
within 10 years will be recorded). Generic or trade name, indication, and dosage will be 
recorded. The sponsor will encode all therapy and medication according to the World Health 
Organization Drug Dictionary. 
Details regarding excluded prior medications, including preventive migraine treatments, are 
described in the exclusion criteria (Section 4.2). 
Up to 30% of patients will be allowed to remain on stable doses of no more than 1 preventive 
migraine medication presented in Appendix K (in addition to other medications not listed in 
Appendix K) for the duration of the study. Patients on preventive medication must be on a stable 
dose for at least 2 months of consecutive use prior to screening with no expectation to change 
dosing regimen or change to another migraine preventive medications during the treatment phase 
of the study. 
Patients will be allowed to use acute medication to treat breakthrough migraines as needed, with 
the exception of medications containing opioids and barbiturates, which cannot be used on more 
than 4 days during the screening period. Traditional Chinese therapy (including herbal medicine) 
and acupuncture are allowed if the patient is on a stable dosing regimen for at least 2 months 
(consecutive) before screening. 
Use of concomitant therapies for indications other than migraine prevention is allowed 
throughout the course of the study, provided patients have been on a stable dose for at least 
2 consecutive months prior to screening and do not expect to change dosing regimen or to 
change to another medication during the treatment phase of the study. 
All concomitant medications or treatments taken during the study, including over-the-counter 
medications, vitamins, nutritional supplements, or acupuncture, must be recorded with the 
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indication, daily dose, and start and stop dates of administration. All patients will be asked about 
concomitant medication use at each visit. 
After the EOT visit (visit 8), patients will return to the care of their primary physician(s) for 
migraine management. 
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 Independent 
Ethics Committee/Institutional Review Board (IEC/IRB) should be notified. 
5.8. 
Randomization and Blinding  
After the 28-day baseline period, the next 12 weeks of the study will be double blind. Patients 
and investigators will remain blinded to IMP assignment during this double-blind period. 
A computer-generated master randomization list will be provided to drug packaging facilities. 
The packaging vendor(s) will package the active IMP and placebo each into single-visit kits 
according to Good Manufacturing Practice procedures. Kits will be identical in appearance, and 
each will contain 1 prefilled syringe with either active IMP or placebo. Kits will be administered 
at each dosing visit according to Table 3. 
Patients will be stratified based on migraine type (CM vs EM) and preventive medication use. 
Patients will be randomly assigned to treatment groups by means of a computer-generated 
randomization list using electronic IRT. This system is used to ensure a balance across treatment 
groups. The specifications for randomization will be under the responsibility and oversight of 
Teva Global Statistics. 
At visit 2 (day 1), patients will be randomized in a 1:1:2 ratio within the appropriate stratum to 
1 of 3 treatment groups, as assigned by the IRT: 
• fremanezumab 225 mg sc once a month (approximately every 4 weeks), for a total of 
3 doses; one 225-mg injection and 2 placebo injections at visit 2 and one 225 mg 
injection at visits 3 and 4  
• fremanezumab 675 mg sc once a quarter (once at the beginning of the 12-week double-
blind treatment period), for a total of 1 dose; three 225-mg injections at visit 2 and 
1 placebo injection at visits 3 and 4 or  
• placebo sc once a month (approximately every 4 weeks), for a total of 3 doses; 3 placebo 
injections at visit 2 and 1 placebo injection at visits 3 and 4  
The placebo will contain the same vehicle and excipients as those for the active injection. 
The IRT will manage the initial drug supply, maintenance of adequate study drug supplies on 
site, and study randomization centrally. At the time of each study visit when the study drug is 
administered, the IRT will be queried, and the site personnel will retrieve the study drug from 
refrigerated storage and will administer a 1.5-mL volume from each syringe contained in the 
appropriately numbered kit(s). 
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The sponsor’s clinical personnel (and delegates) involved in the study will be blinded to the 
identity of the IMPs until the database is locked for analysis and the IMP assignment is known.  
In the event of an emergency, it will be possible to determine to which treatment group the 
patient has been allocated by accessing the IRT system. All investigational centers will be 
provided with details on how to access the system for code breaking at the start of the study. The 
medical monitor or equivalent should be notified following unblinding. Any unblinding of the 
IMP performed by the investigator must be recorded in the source documents. 
The randomization list will be assigned to the relevant treatment groups through a qualified 
service provider, eg, via the IRT system. The generation of the randomization list and the 
management of the IRT system will be done by a qualified service provider under the oversight 
of the responsible function at Teva. 
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 first interim analysis, after receiving the 
unblinding request from the Teva statistician, the service provider will provide the unblinded 
IMP assignment according to the processes defined in the relevant standard operating procedure. 
5.9.2. 
Blinding and Unblinding  
Blinded pharmacokinetic data may be assessed during the study. For patients who have 
pharmacokinetic sample bioanalysis or data analysis conducted, the individuals responsible for 
sample bioanalysis and other responsible personnel will know who received the test IMP and 
who received the placebo IMP during the study (of those patients only). Personnel responsible 
for bioanalysis will be provided with the randomization code to facilitate the analysis. However, 
the personnel responsible for bioanalysis and pharmacokinetic data analysis will not have access 
to clinical safety and efficacy data and will provide concentration data to other personnel in a 
manner that will not identify individual patients (ie, a dummy patient identifier will be linked to 
the concentration data of an individual patient). 
In case of a serious adverse event or a pregnancy or when knowledge of the IMP assignment is 
needed to make treatment decisions, the investigator may unblind the patient’s IMP assignment 
as deemed necessary, mainly in emergency situations, through specialized access in the IRT 
system. Breaking of the treatment code can always be performed by the investigator without 
prior approval by the sponsor; however, the sponsor should be notified that the code was broken, 
but the patient treatment assignment should not be revealed to the sponsor. 
When a blind is broken, the patient will be withdrawn from the study, and the event will be 
recorded on 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 documents. Assignment 
of IMP should not be recorded in any study documents or source documents. 
In blinded studies, for an adverse event defined as a suspected unexpected serious adverse 
reaction (SUSAR) (ie, reasonable possibility; see Section 7.1.4), Global Patient Safety and 
Pharmacovigilance (GPSP) may independently request that the blind code be broken (on a 
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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 of the study and the analysis and 
reporting of the data. 
5.9.3. 
Data Monitoring Committee  
There will be no Data Monitoring Committee/Data and Safety Monitoring Board in this study. 
5.10. 
Total Blood Volume  
The total blood volume to be collected for each patient in this study is approximately 110 mL. 
Details are provided in the Laboratory Manual. 
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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; in the event, however, that such data are collected, these data will not be analyzed. 
6.1. 
Assessments of Efficacy  
6.1.1. 
Electronic Headache Diary Device  
The primary efficacy endpoint (and secondary and other efficacy endpoints) will be derived from 
headache variables collected daily using an electronic headache diary device (Table 3). 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 headache diary. Approximately 75% compliance is needed 
during the baseline (ie, entry of headache data on a minimum of 21 days) and treatment 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 device 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 headache diary, 
provided no more than 48 hours has elapsed since completion of that day. If more than 48 hours 
has 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 the duration of headache for each day will be completed in the 
electronic headache 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 acute migraine medications (the name of the drug, the number of 
tablets/capsules, and the dose in milligrams per tablet/capsule) taken on each day. These acute 
medications are opioids, barbiturates, triptans, ergots, non-steroidal anti-inflammatory drugs 
(NSAIDs), acetaminophen and their combination products. 
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6.1.2. 
Patient Global Impression of Change  
The PGIC scale is a validated generic tool for the 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 3. 
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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 height and weight measurements), use of concomitant 
medication, local tolerability and pain, immunogenicity, and occurrence of severe 
hypersensitivity/anaphylactic reactions. 
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 
Note: A condition recorded as pre-existing that is intermittently symptomatic 
(eg, headache) and that occurs during this study should be recorded as an adverse 
event. 
• drug interactions 
• events occurring during diagnostic procedures or during any follow-up period of this 
study 
• laboratory or diagnostic test abnormalities that result in the withdrawal of the patient 
from the study, are associated with clinical signs and symptoms or a serious adverse 
event, 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. 
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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 the 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 the recording of adverse events, the study period is defined for each patient as the time 
period from signature of the ICF to the end of the follow-up period. The follow-up period of the 
recording of adverse events is defined as 3 months after the last dose of IMP. The period for 
reporting treatment-emergent adverse events is defined as the period after the 1st dose of IMP is 
administered and until the end of the follow-up period. 
All adverse events that occur during the defined study period must be recorded both on the 
source documents and the CRF, regardless of the severity of the event or judged relationship to 
the IMP. For serious adverse events, the serious adverse event form must be completed, and the 
serious adverse event must be reported immediately (Section 7.1.5.3.1). The investigator does 
not need to actively monitor patients for adverse events after the defined period. Serious adverse 
events and adverse events of special interest (Section 7.1.6) occurring 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. 
The onset and end dates, duration (in case of an adverse event, duration of less than 24 hours), 
action taken regarding the IMP, treatment administered, and outcome for each adverse event 
must be recorded both on the source documents and the CRF. 
The relationship of each adverse event to the 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. 
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7.1.3. 
Severity of an Adverse Event  
The severity of each adverse event must be recorded as one of the following: 
Mild: 
No limitation of usual activities 
Moderate: Some limitation of usual activities 
Severe: 
Inability to carry out usual activities 
7.1.4. 
Relationship of an Adverse Event to the Investigational Medicinal Product  
The relationship of an adverse event to the IMP is characterized per Table 5. 
Table 5: 
The Relationship of an Adverse Event to the Investigational Medicinal 
Product  
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 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. 
IMP=investigational medicinal product. 
7.1.5. 
Serious Adverse Events  
For the recording of serious adverse events, the study period is defined for each patient as the 
time period from signature of the ICF 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. 
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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 
• 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 ICF will not be considered 
serious adverse events, unless there was worsening of the pre-existing 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: 
• ALT or AST increase of >3× ULN 
• total bilirubin increase of >2× ULN 
• absence of initial findings of cholestasis (ie, no substantial increase of ALP) 
All Hy’s law events (ie, all 3 of the criteria above) require immediate discontinuation of IMP. 
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 (RSI) by its specificity, severity, outcome, or frequency is 
considered an unexpected adverse event. The RSI for this study is the IB. 
The sponsor’s GPSP will determine the expectedness for all serious adverse events. 
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For the purpose of SUSAR reporting, the version of the IB at the time of occurrence of the 
SUSAR applies. 
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 GPSP. 
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 sex of patient 
• date of 1st 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 
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• results of dechallenge/rechallenge, if known 
• 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 GPSP will distribute the Council for International Organizations 
of Medical Sciences (CIOMS) form/Extensible Markup Language (XML) file to the LSO/CRO 
for submission to the competent authorities, IEC/IRB, and investigators, according to 
regulations. The investigator must ensure that the IEC/IRB is also informed of the event, in 
accordance with national and local regulations. 
Blinding will be maintained for all study personnel. Therefore, in case of a SUSAR, only the 
LSO/CRO will receive the unblinded report for regulatory submission; the others will receive a 
blinded report. 
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 the IEC/IRB, as 
appropriate). 
In addition to notifying the investigators and competent authorities (and the 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 of Special Interest  
For purposes of this protocol, the following are considered protocol-defined adverse events of 
special interest to be sent to the sponsor’s GPSP for evaluation: severe hypersensitivity and 
anaphylaxis, as well as ophthalmic events of at least moderate severity. Hypersensitivity 
reactions will be monitored using the diagnostic criteria for anaphylaxis as outlined by the 2006 
Joint National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis 
Network Second Symposium on Anaphylaxis (Sampson et al 2006). The clinical criteria for 
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diagnosing anaphylaxis are provided in Appendix L. In the event of suspected anaphylaxis, vital 
signs (including oxygen saturation and respiration rate) will be measured.  
The process for reporting a protocol-defined adverse event of special interest is the same as that 
for reporting a serious adverse event (Section 7.1.5.3). Protocol-defined adverse events of special 
interest to be reported to GPSP can be either serious or nonserious, according to the criteria 
outlined in Section 7.1.5.1. 
7.1.7. 
Protocol Deviations Because of an Adverse Event  
If a patient experiences an adverse event or medical emergency, then 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 patient becoming pregnant during the study will discontinue the 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 months after administration of the last dose of 
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 patients who are found to be pregnant between 
screening and baseline, provided that no protocol-related procedures were applied. 
All female patients (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 
voluntary abortion). Female partners of men participating in the study who become pregnant will 
be asked to sign an ICF. If the pregnancy continues to term, the outcome (health of the infant up 
to 8 weeks of age), including details of birth and the 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, one 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. 
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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 
in the patient’s source documents, regardless of whether or not an adverse event occurs as a 
result. 
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. 
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. 
6. Occupational exposure: Exposure to an IMP, as a result of one’s professional or 
nonprofessional 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 (Table 6) 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 
both on the source documents and the CRF as an adverse event and will be 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 the 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 the 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. However, in case of 
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abnormal coagulation during screening (baseline period), a local retest can be authorized by the 
sponsor on a case-by-case basis. 
Table 6: 
Clinical Laboratory Tests  
Serum chemistry 
Hematology and coagulation 
Urinalysis 
Calcium 
Phosphate 
Sodium 
Potassium 
Chloride 
Creatinine 
Glucose 
BUN 
Total cholesterol 
LDL  
HDL 
Triglycerides 
Urate 
ALT 
AST 
LDH 
GGT 
ALP 
Bicarbonate 
Carbon dioxide 
Protein 
Albumin 
Bilirubin 
Direct bilirubin 
Hemoglobin 
Hematocrit 
Erythrocytes 
Platelets 
Leucocytes 
− Neutrophils 
− Lymphocytes 
− Eosinophils 
− Monocytes 
− Basophils 
Lymphocytes atypical 
Prothrombin INR 
Protein 
Glucose 
Ketones 
Hemoglobin 
pH 
Specific gravity 
Microscopic tests 
− Bacteria 
− Erythrocytes 
− Leucocytes 
− Crystals 
− Casts 
ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea 
nitrogen; GGT=gamma glutamyl transpeptidase; HDL=high-density lipoprotein; INR=international normalized 
ratio; LDH=lactate dehydrogenase; LDL=low-density lipoprotein. 
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7.4.1. 
Serum Chemistry, Hematology, and Urinalysis  
Clinical laboratory tests (serum chemistry, hematology and coagulation, and urinalysis) will be 
performed at the time points detailed in Table 3. At visits where IMP is administered, clinical 
laboratory tests should be performed predose. Clinical laboratory tests will be performed using 
the central laboratory. Specific laboratory tests to be performed are provided in Table 6. Note, 
reflex tests (eg, red blood cell [RBC] shapes, RBC morphology, and other microscopic findings) 
may be triggered automatically. 
7.4.2. 
Other Clinical Laboratory Tests  
7.4.2.1. 
Human Chorionic Gonadotropin Tests  
Human chorionic gonadotropin tests in serum or urine will be performed for all WOCBP at the 
time points detailed in Table 3. At visits where IMP is administered, β-HCG tests should be 
performed predose. Any patient who becomes pregnant during the study will be withdrawn. 
Procedures for reporting the pregnancy are provided in Section 7.2. 
7.4.2.2. 
Follicle-Stimulating Hormone Tests  
Postmenopausal women will have a follicle-stimulating hormone test at screening (visit 1); see 
Table 3. 
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 3. 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 abnormal 
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 (blood pressure [systolic/diastolic], respiratory rate, body temperature, and pulse) will 
be measured at the time points detailed in Table 3. 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 blood pressure and pulse are measured, the patient must rest in a supine or 
semi-erect/seated position 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 signs value, the 
measurement should be repeated as soon as possible. Any abnormal vital signs value that is 
judged by the investigator as clinically significant will be recorded both on the source documents 
and the CRF as an adverse event and will be monitored as described in Section 7.1.2. 
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7.7. 
Electrocardiography  
A single 12-lead ECG will be performed at the time points detailed in Table 3. This procedure 
will be performed predose. 
A qualified physician at a central diagnostic center will provide an interpretation of the ECG. 
ECGs should be performed and transmitted according to the central ECG reading instructions 
provided in the ECG user manual. ECG equipment will be provided to all clinical sites. Although 
the ECG interpretation will be provided centrally, the clinical evaluation of the ECG remains the 
investigator’s responsibility. 
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 
If results are abnormal, the ECG will be repeated 1 time.  
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 document 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 document file. 
The investigator’s interpretation will be recorded on the CRF regardless of the central reading 
interpretation. Any ECG finding that is judged by the investigator as clinically significant 
(except at the screening visit [visit 1]) will be considered an adverse event, recorded on the 
source documents and the CRF, and monitored as described in Section 7.1.2.  
Objective alerts are predefined as described in the central ECG reading manual. In these cases, 
the site and the sponsor will be informed immediately.  
7.8. 
Immunogenicity  
Blood samples for serum ADA assessment will be collected at the time points detailed in 
Table 3. Only the samples from fremanezumab-treated patients will be analyzed for ADAs.  
7.9. 
Assessment of Local Tolerability and Pain  
Spontaneous reports of injection site reactions will be recorded as adverse events 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. 
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7.10. 
Assessment of Suicidality  
Any suicide attempt in the past, suicidal ideation with a specific plan in the past 2 years prior to 
screening (visit 1), or current suicidal ideation will result in patient exclusion. 
Investigators will inquire about and evaluate suicidal ideation, plan, and behavior based on their 
clinical judgement and refer patients to psychiatric care as appropriate. 
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8. 
ASSESSMENT OF PHARMACOKINETICS/IMMUNOGENICITY  
8.1. 
Pharmacokinetic Assessment  
Sampling for pharmacokinetics will be sparse. The fremanezumab pharmacokinetic 
concentrations will be analyzed using a population pharmacokinetic model and will be reported 
separately from the clinical study report (CSR); individual pharmacokinetic concentration data 
will be summarized and listed in the CSR. 
Patients will be asked to return to the study center after visit 2, visit 3, or visit 4 for 2 additional 
blood sampling visits to measure plasma fremanezumab concentration (one being 3 to 10 days 
after either visit 2, visit 3, or visit 4 and the other being 15 to 20 days after either visit 2, visit 3, 
or visit 4). If 2 additional visits are not possible for the patient, then the patient must return for 
only 1 additional pharmacokinetic blood sampling at either of the aforementioned time points. 
When patients return to the study center for additional blood sampling, then inquiries about 
adverse events and concomitant medications will be performed. 
Blood samples (8 mL for the predose sample at visit 2; 4 mL for all other samples) will be 
collected via venipuncture or indwelling catheter (for details, see the Laboratory Manual) at the 
time points detailed in Table 3 for plasma concentration measurements of fremanezumab. The 
dates and times of IMP administration and the date and time of each pharmacokinetic sample 
collection will be recorded in the source documents and entered into the CRF. 
Samples from patients who received the active IMP will be analyzed for the concentration of 
fremanezumab using a validated method. Samples from patients who were randomized to receive 
placebo will not be analyzed.  
Details on sample handling, storage, shipment, and analysis are provided in the Laboratory 
Manual. 
8.2. 
Pharmacodynamic Assessment  
Pharmacodynamic parameters are not evaluated in this study. 
8.3. 
Immunogenicity Testing  
Samples from patients who receive the active IMP will be analyzed for ADA using a validated 
method. Samples from patients who receive placebo will not be analyzed. 
Blood samples (10 mL for the predose sample at visit 2; 6 mL for all other samples) will be 
collected via venipuncture or indwelling catheter (for details, see the Laboratory Manual) at the 
time points detailed in Table 3 for immunogenicity testing. The dates and times of IMP 
administration and the date and time of each ADA sample collection will be recorded in the 
source documents and entered into the CRF. 
Details on sample handling, storage, shipment, and analysis are provided in the Laboratory 
Manual. 
8.4. 
Assessment of Exploratory Biomarkers  
Biomarkers are not evaluated in this study. 
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9. 
STATISTICS  
This section describes the statistical analysis as foreseen at the time of planning the study. 
Changes, additions, and further details about the analyses will be described in the statistical 
analysis plan. After finalization of the statistical analysis plan, any additional analyses or 
changes to analyses that may be required will be fully disclosed in the CSR. 
9.1. 
Sample Size and Power Considerations  
Using study data from 2 completed Phase 3 US pivotal studies in migraine, it is estimated that 
163 completers per treatment group (ie, combined fremanezumab groups and placebo group) will 
provide at least 90% power to detect the assumed treatment difference at a significance level 
of 0.05. Assuming a 12% discontinuation rate, approximately 372 patients will be randomized in 
this study (93 patients in each fremanezumab treatment group and 186 patients in the placebo 
group). The primary efficacy analysis will consider all fremanezumab-treated patients as 
1 group. 
 
 
 
 
 
 
 
 
 
To ensure adequate representation of patients with both migraine types (EM and CM), the 
enrollment minimum of either migraine type is 30%. In addition, primary efficacy analysis will 
be stratified by EM and CM, and subgroup analysis for EM and CM will be conducted.  
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 IMP and have at least 10 days of diary entries after 
baseline. 
In the mITT analysis set, treatment will be assigned based on the treatment to which patients 
were randomized, regardless of which treatment they actually received. 
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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 treatment without any important deviations such as important inclusion/exclusion 
criteria deviations or any important deviations or omissions of the IMP 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  
9.3.1. 
Handling Withdrawals and Missing Data  
For all variables, only the observed data from the patients will be used in the statistical analyses, 
ie, there is no plan to estimate missing data, unless otherwise specified. Detailed data imputation 
rules 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. In 
addition, the primary and secondary efficacy endpoints will also be analyzed using the per-
protocol analysis set. 
9.4.1. 
Patient Disposition  
Data from patients screened; patients screened but not randomized and reason for not being 
randomized; patients randomized; patients randomized but not treated; patients in the ITT, 
safety, and PP analysis sets; patients who complete the IMP; and patients who discontinue the 
IMP will be summarized using descriptive statistics. Data from patients who discontinue the IMP 
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 examined to assess the comparability of the treatment 
groups and will be summarized using descriptive statistics. For continuous variables, descriptive 
statistics (number [n], mean, SD, median, minimum, and maximum) will be provided. For 
categorical variables, patient counts and percentages will be provided. Categories for missing 
data will be presented if necessary. 
9.5. 
Efficacy Analysis  
For the purpose of this study, a migraine day is endorsed when at least 1 of the following 
situations occurs:  
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• A calendar day (0:00 to 23:59) demonstrating at least 2 consecutive hours of a headache 
meeting the criteria for migraine with or without aura 
• A calendar day (0:00 to 23:59) demonstrating at least 2 consecutive hours of a headache 
meeting the criteria for probable migraine, a migraine subtype where only 1 migraine 
criterion is missing 
• A calendar day (0:00 to 23:59) demonstrating a headache of any duration that was treated 
with migraine-specific medications (triptans and ergot compounds) 
Migraine classification definitions are presented below. 
CM is defined as: 
The patient fulfills the following criteria for CM in prospectively collected baseline information 
during the 28-day baseline period: 
• Headache occurring on ≥15 days 
• On ≥8 days, fulfilling any of the following: 
− ICHD-3 diagnostic criteria C and D for 1.1 Migraine without aura (Appendix J) 
− ICHD-3 criteria B and C for 1.2 Migraine with aura (Appendix J) 
− 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. 
EM is defined as: 
The patient fulfills the following criteria for EM in prospectively collected baseline information 
during the 28-day baseline 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 (Appendix J) 
− ICHD-3 criteria B and C for 1.2 Migraine with aura (Appendix J) 
− 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. 
Missing data or visits due to the COVID-19 pandemic will be evaluated for the primary and 
secondary endpoints. COVID-19 may have an impact on patients’ migraine symptoms, with 
headache reported to be a common complication as a result of contracting the disease. All 
COVID-19 cases will be included in the primary analysis; however, observations following 
COVID-19 diagnosis will be discarded from the calculation of the monthly average endpoint. 
The data handling strategy will be detailed in the statistical analysis plan. 
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9.5.1. 
Primary Endpoint  
The primary efficacy endpoint is the mean change from baseline in the monthly average number 
of migraine days during the 12-week period after the 1st dose of IMP. 
The monthly average number of migraine days during the 12-week period after the 1st dose of 
study drug will be derived and normalized to 28 days equivalent using the following formula. 
∑𝐷𝑎𝑦𝑠 𝑜𝑓 𝑚𝑖𝑔𝑟𝑎𝑖𝑛𝑒 𝑜𝑣𝑒𝑟 𝑡ℎ𝑒 12 𝑤𝑒𝑒𝑘 𝑝𝑒𝑟𝑖𝑜𝑑  
∑𝐷𝑎𝑦𝑠 𝑤𝑖𝑡ℎ 𝑎𝑠𝑠𝑒𝑠𝑠𝑚𝑒𝑛𝑡𝑠 𝑟𝑒𝑐𝑜𝑟𝑑𝑒𝑑 𝑖𝑛 𝑡ℎ𝑒 𝑒𝐷𝑖𝑎𝑟𝑦 𝑓𝑜𝑟 𝑡ℎ𝑒 12 𝑤𝑒𝑒𝑘 𝑝𝑒𝑟𝑖𝑜𝑑 ×  28   (1) 
9.5.2. 
Secondary Endpoints  
The secondary efficacy endpoints are as follows: 
• mean change from baseline in the number of migraine days during the 4-week period 
after the 1st dose of IMP 
• mean change from baseline in the monthly average number of days that any acute 
headache medications were used during the 12-week period after the 1st dose of IMP 
• 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 IMP 
• mean change from baseline in the monthly average number of days with headache of at 
least moderate severity during the 12-week period after the 1st dose of IMP 
Similar to the primary endpoint, the monthly average number of days of efficacy variables 
(eg, days of headache of at least moderate severity and days of acute headache medication use) 
during the 12-week period after the 1st dose of study drug will be derived and normalized to 
28 days equivalent using the following formula. 
∑𝐷𝑎𝑦𝑠 𝑜𝑟 ℎ𝑜𝑢𝑟𝑠 𝑜𝑓 𝑒𝑓𝑓𝑖𝑐𝑎𝑐𝑦 𝑣𝑎𝑟𝑖𝑎𝑏𝑙𝑒 𝑜𝑣𝑒𝑟 𝑡ℎ𝑒 12 𝑤𝑒𝑒𝑘 𝑝𝑒𝑟𝑖𝑜𝑑  
∑𝐷𝑎𝑦𝑠 𝑤𝑖𝑡ℎ 𝑎𝑠𝑠𝑒𝑠𝑠𝑚𝑒𝑛𝑡𝑠 𝑟𝑒𝑐𝑜𝑟𝑑𝑒𝑑 𝑖𝑛 𝑡ℎ𝑒 𝑒𝐷𝑖𝑎𝑟𝑦 𝑓𝑜𝑟 𝑡ℎ𝑒 12 𝑤𝑒𝑒𝑘 𝑝𝑒𝑟𝑖𝑜𝑑 ×  28   (2) 
The monthly average number of migraine days during a 4-week period after each dose will be 
derived and normalized to 28 days equivalent using the following formula, where monthly data 
separated by each visit of study drug dosing: 
∑𝐷𝑎𝑦𝑠 𝑜𝑟 ℎ𝑜𝑢𝑟𝑠 𝑜𝑓 𝑒𝑓𝑓𝑖𝑐𝑎𝑐𝑦 𝑣𝑎𝑟𝑖𝑎𝑏𝑙𝑒 𝑑𝑢𝑟𝑖𝑛𝑔 𝑡ℎ𝑒 4 𝑤𝑒𝑒𝑘 𝑝𝑒𝑟𝑖𝑜𝑑  
∑𝐷𝑎𝑦𝑠 𝑤𝑖𝑡ℎ 𝑎𝑠𝑠𝑒𝑠𝑠𝑚𝑒𝑛𝑡𝑠 𝑟𝑒𝑐𝑜𝑟𝑑𝑒𝑑 𝑖𝑛 𝑡ℎ𝑒 𝑒𝐷𝑖𝑎𝑟𝑦 𝑓𝑜𝑟 𝑡ℎ𝑒 4 𝑤𝑒𝑒𝑘 𝑝𝑒𝑟𝑖𝑜𝑑  ×  28    (3) 
9.5.3. 
Other Efficacy Endpoints  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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9.5.4. 
Planned Method of Analysis  
The mITT analysis set (Sections 9.2.1, 9.2.2, and 9.2.4) will be used for all efficacy analyses. 
Summaries will be presented by treatment group. In addition, the primary and secondary efficacy 
endpoints will also be analyzed using the per-protocol analysis set. 
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9.5.4.1. 
Primary Efficacy Analysis  
The primary comparison will be made between the combined fremanezumab groups versus the 
placebo group in the primary efficacy variable: mean change from baseline in the monthly 
average number of migraine days during the 12-week double-blind treatment period after the 1st 
dose of IMP. The primary efficacy analysis will consider all fremanezumab-treated patients as 
1 group (ie, regardless of dosing regimen or migraine type). 
An estimand in general includes the following 4 interrelated attributes: population of interest, 
variable (endpoint) of interest, intercurrent events (ICEs) along with the strategy for handling 
ICEs, and population-level summary for the endpoint.  
The estimand selected for the primary analysis will assess the 12-week monthly average number 
of migraine days as initially randomized in the mITT analysis set.  
The ICEs that may affect the efficacy endpoint will include instances where a patient early 
terminates from the IMP, receives the wrong IMP due to medication errors, or receives a rescue 
medication due to worsening symptoms. If observations are collected after the occurrences of the 
ICEs, the observations will be included in the calculation of the primary endpoint for the primary 
analysis. 
The population-level summaries would be the adjusted mean changes from baseline in monthly 
average number of migraine days for the treatment groups and corresponding 95% confidence 
intervals. 
An analysis of covariance (ANCOVA) will be performed, including treatment and stratification 
factors of migraine type (CM vs EM) and preventive medication use as fixed factors, as well as 
baseline number of migraine days as a covariate in the model. A 95% confidence interval for the 
treatment difference between the combined fremanezumab groups versus the placebo group will 
be derived through an appropriate contrast, and p-values for the comparison will be presented. 
Further details will be presented in the statistical analysis plan. 
9.5.4.2. 
Sensitivity Analysis  
A sensitivity analysis may be performed to assess the primary estimand using mixed-effects 
model for repeated measures (MMRM) as a different missing data handling approach. The 
MMRM model will include treatment and stratification factors of migraine type (CM vs EM) and 
preventive medication use as fixed factors, as well as treatment-by-month interaction effects, and 
baseline number of migraine days as a covariate with an unstructured covariance matrix. The 
12-week monthly average number of migraine days will be estimated by the LS means of the 
overall treatment effect over 3 months.  
An additional sensitivity analysis may be conducted to assess a different estimand, ie, treatment 
effects due to initially randomized treatment as actually taken. For patients who early terminate 
from study drugs in the monthly dosing regimen group or start a rescue medication, observations 
collected more than 4 weeks after the last dose or after starting a rescue medication will be 
treated as missing and will not be used in the calculation of monthly average number of migraine 
days. 
Finally, the primary analysis will be repeated in the ITT analysis set (in case there is a 
10% difference in patient count in any treatment group) and PP analysis set. 
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9.5.4.3. 
Secondary Efficacy Analysis  
Comparisons of secondary endpoints will be made between the combined fremanezumab groups 
versus the placebo group. Analysis of the continuous secondary endpoints (monthly average 
number of days of efficacy endpoints) will be similar to the analysis of the primary efficacy 
endpoint. The responder endpoints will be analyzed using logistic regression, including treatment 
and stratification factors of migraine type (CM vs EM) and preventive medication use as fixed 
factors, as well as baseline number of migraine days as a covariate in the model. The secondary 
efficacy analyses will consider all fremanezumab-treated patients as 1 group. Further details will be 
presented in the statistical analysis plan. 
A fixed-sequence, hierarchical testing procedure will be implemented to control the type 1 error 
rate at 0.05 for formal hypothesis testing of the secondary endpoints. Upon the success of the 
primary analysis, the first secondary endpoint in the sequence will be tested at a significance 
level of 0.05, and a p-value ≤0.05 will be interpreted inferentially. The process will continue 
following the order of the sequence until a point when the test for the efficacy endpoint fails, ie, 
2-sided p-value >0.05. Subsequently, no further test results will be interpreted inferentially. The 
sequence of testing will follow the order specified for secondary endpoints in Section 9.5.2. 
9.5.4.4. 
Other Efficacy Analysis  
 
 
 
 
  
 
 
 
9.6. 
Multiple Comparisons and Multiplicity  
The type 1 error will be controlled at a significance level of 0.05 using the appropriate method 
for the analysis of the primary efficacy endpoint, which is conducted by pooling the 
fremanezumab patients in the 2 dosing regimens. 
A fixed-sequence, hierarchical testing procedure will be implemented upon achieving the success 
of the primary analysis to control the type 1 error rate at 0.05 for formal hypothesis testing of the 
secondary endpoints. The sequence of testing will follow the order specified for secondary 
endpoints in Section 9.5.2. 
9.7. 
Safety Analysis  
Safety analyses will be performed on the safety analysis set. 
Safety assessments and time points are provided in Table 3. 
All adverse events will be coded using the Medical Dictionary for Regulatory Activities. Each 
patient will be counted only once in each preferred term or system organ class category for the 
analyses of safety. Summaries will be presented for all adverse events (overall and by severity), 
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adverse events determined by the investigator to be related to the test IMP (ie, reasonable 
possibility; defined as related or with missing relationship [overall and by severity]), serious 
adverse events, and adverse events leading to discontinuation from the study. Summaries will be 
presented by treatment group. Patient listings of serious adverse events and adverse events 
leading to discontinuation will be presented. 
Changes in clinical 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. 
The use of concomitant medications will be summarized by therapeutic class using descriptive 
statistics. Concomitant medications will include all medications taken while the patient is treated 
with the IMP. 
Safety data will be summarized descriptively by treatment group. For continuous variables, 
descriptive statistics (n, mean, SD, median, minimum, and maximum) will be provided for actual 
values and changes from baseline to each time point. For categorical variables, patient counts 
and percentages will be provided. Descriptive summaries of serious adverse events, patient 
discontinuations 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 CSR. 
9.8. 
Tolerability Analysis  
Spontaneously reported local tolerability findings will be listed and summarized descriptively. 
9.9. 
Pharmacokinetic Analysis  
Pharmacokinetic plasma concentration results (fremanezumab) will be tabulated descriptively at 
each planned sampling time point by treatment group. 
The pharmacokinetic data from this study will be pooled with the data from other fremanezumab 
studies and assessed for comparability. Summary statistics of fremanezumab pharmacokinetic 
parameters model-based predictions of weight-adjusted exposures will be compared and will be 
reported separately. 
9.10. 
Immunogenicity Analysis  
Summary of immunogenicity results will be provided, and the incidence of immunogenicity will 
be calculated. This analysis will be reported separately. 
9.11. 
Planned Interim Analysis  
Two interim analyses are planned. The first interim analysis is planned when the last patient has 
completed the double-blind period. A second interim analysis 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 
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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 second database lock. 
9.12. 
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 CSR, 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  
Refer to Appendix C for information regarding quality control and quality assurance. This 
includes information about protocol amendments, deviations, responsibilities of the investigator 
to study personnel, study monitoring, and audit and inspection. 
Refer to Appendix G for the definition of a clinical product complaint and investigator 
responsibilities in the management of a clinical product complaint. 
11. 
COMPLIANCE STATEMENT  
This study will be conducted in full accordance with current China GCP, 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 GCP 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 IB 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 IEC/IRB, and with competent authorities. 
See Appendix D for the ethics expectations of informed consent, competent authorities and IEC 
and IRB, confidentiality regarding study patients, and requirements for registration of the clinical 
study. 
12. 
DATA MANAGEMENT AND RECORD KEEPING  
See Appendix H for information regarding data management and record keeping. 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, for example, 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 an 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  
See Appendix I for information regarding the publication policy. 
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15. 
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Bigal ME, Lipton RB. Clinical course in migraine: conceptualizing migraine transformation. 
Neurology 2008;71(11):848-55. 
Chinese Medical Association Pain Society (CMAPS). Guide to the prevention and treatment of 
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D’Amico D, Tepper SJ. Prophylaxis of migraine: general principles and patient acceptance. 
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Dodick DW, Ashina M, Brandes JL, Kudrow D, Lanteri-Minet M, Osipova V, et al. ARISE: A 
phase 3 randomized trial of erenumab for episodic migraine. Cephalalgia 2018a;38(6):1026-37. 
Dodick DW, Silberstein SD, Bigal ME, Yeung PP, Goadsby PJ, Blankenbiller T, et al. Effect of 
fremanezumab compared with placebo for prevention of episodic migraine: a randomized 
clinical trial. JAMA 2018b;319(19):1999-2008. 
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 al. EFNS guideline on the drug 
treatment of migraine—revised report of an EFNS task force. Eur J Neurol 2009;16(9):968-81. 
Ferrari M, Diener H, Ning X, Galic M, Cohen J, Yang R, et al. Fremanezumab versus placebo 
for migraine prevention in patients with documented failure to up to four migraine preventive 
medication classes (FOCUS): a randomised, double-blind, placebo-controlled, phase 3b trial. 
Lancet 2019;394(10203):1030-40. 
GBD 2016 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and 
national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 
195 countries, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. 
Lancet 2017;390:1211–59. 
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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. 
Headache Classification Committee of the International Headache Society (IHS). The 
International Classification of Headache Disorders, 3rd edition. Cephalalgia 2018;38(1):1‑211. 
Ho TW, Edvinsson L, Goadsby PJ. CGRP and its receptors provide new insights into migraine 
pathophysiology. Nat Rev Neurol 2010;6(10):573–82. 
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. 
Lipton RB, Gandhi SK, Cohen JM, Cloud B, Ramirez-Campos V, Ahn AH, et al. Patient 
satisfaction with fremanezumab treatment for chronic or episodic migraine: results from a web-
based patient survey following completion of a 1-year extension study. Poster P272LB. 
Presented at the 61st Annual Scientific Meeting of the American Headache Society (AHS); 
July 11-14, 2019; Philadelphia, Pennsylvania. 
Liu R, Yu S, He M, Zhao G, Yang X, Qiao X, et al. Health-care utilization for primary headache 
disorders in China: a population-based door-to-door survey. J Headache Pain 2013;14(1):47. 
Park JW, Shin HE, Kim JS, Lee KS. Assessing migraine disability by diary-based measurement: 
relationship to the characteristics of individual headache attacks. Eur J Neurol 2008;15:817-21. 
Puledda F, Messina R, and Goadsby PJ. An update on migraine: current understanding and 
future directions. J Neurol 2017;264(9):2031-9. 
Reuter U, Goadsby PJ, Lanteri-Minet M, Wen S, Hours-Zesiger P, Ferrari MD, et al. Efficacy 
and tolerability of erenumab in patients with episodic migraine in whom two-to-four previous 
preventive treatments were unsuccessful: a randomised, double-blind, placebo-controlled, phase 
3b study. Lancet 2018;392(10161):2280-7. 
Sakai F, Suzuki N, Kim B-K, Igarashi H, Hirata K, Takeshima T, et al. Efficacy and safety of 
fremanezumab for chronic migraine prevention: Multicenter, randomized, double-blind, 
placebo-controlled, parallel-group trial in Japanese and Korean patients. Headache 
2021;61:1092-01. 
Sakai F, Suzuki N, Kim B-K, Tatsuoka Y, Imai N, Ning X, et al. Efficacy and safety of 
fremanezumab for episodic migraine prevention: Multicenter, randomized, double-blind, 
placebo-controlled, parallel-group trial in Japanese and Korean patients. Headache 
2021;61:1102-11. 
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 DW, 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. 
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Silberstein SD, Dodick DW, Bigal ME, Yeung PP, Goadsby PJ, Blankenbiller T, et al. 
Fremanezumab for the preventive treatment of chronic migraine. N Engl J Med 
2017;377(22):2113-22. 
Tfelt-Hansen P, Olesen J. Taking the negative view of current migraine treatments: the unmet 
needs. CNS Drugs 2012;26(5):375-82. 
Tfelt-Hansen P, Pascual J, Ramadan N, Dahlöf C, D’Amico 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. 
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 02 with Revision 01 Dated 08 March 2023  
The primary reason for this revision of protocol amendment 02 was to clarify which medications should be recorded in the eDiary and 
that automatically triggered reflex tests applies to hematology tests. All major changes to the protocol body are listed below in the 
table and are reflected in the synopsis, as applicable. Minor editorial changes (eg, typos and punctuation) have been made to the 
protocol (and protocol synopsis, as appropriate). 
Changes to the Protocol 
Original text with changes shown 
New wording 
Reason/Justification for change 
Section 6.1.1. Electronic Headache Diary Device 
…will record any acute migraine medications (the name 
of the drug, the number of tablets/capsules, and the dose 
in milligrams per tablet/capsule) taken on each day. These 
acute medications are opioids, barbiturates, triptans, 
ergots, non-steroidal anti-inflammatory drugs (NSAIDs), 
acetaminophen and their combination products. 
…will record any acute migraine medications (the name 
of the drug, the number of tablets/capsules, and the dose 
in milligrams per tablet/capsule) taken on each day. These 
acute medications are opioids, barbiturates, triptans, 
ergots, non-steroidal anti-inflammatory drugs (NSAIDs), 
acetaminophen and their combination products. 
Clarification on which medications 
should be recorded in the eDiary. 
Section 7.4.1Serum Chemistry, Hematology, and Urinalysis 
Note, reflex tests (ie, microanalysis tests like squamous 
epithelial cells and mucous threadseg, red blood cell 
[RBC] shapes, RBC morphology, and other microscopic 
findings) test may be triggered automatically. 
Note, reflex tests (eg, red blood cell [RBC] shapes, RBC 
morphology, and other microscopic findings) may be 
triggered automatically. 
Reflex tests should entail 
hematology and not urine tests. 
 
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16.2. 
Amendment 02 Dated 14 February 2023  
The primary reason for this amendment is to include planned interim analyses, to modify the inclusion/exclusion criteria to assist with 
recruitment rates, to specify that the secondary efficacy endpoints will also be analyzed using the per-protocol analysis set, and to 
extend specific site visit windows for local public health emergencies. All major changes to the protocol body are listed below in the 
table and are reflected in the synopsis, as applicable. Table 3 (Study Procedures and Assessments) and Table 6 (Clinical Laboratory 
Tests) have been revised to reflect changes described below. Minor editorial changes (eg, typos and punctuation) have been made to 
the protocol (and protocol synopsis, as appropriate). 
Changes to the Protocol 
Original text with changes shown 
New wording 
Reason/Justification for change 
Section 1.2.2.2 Clinical Safety and Efficacy Studies 
One Phase 4 study (Study TV48125-MH-40142) is was 
currently being conducted (last patient last visit: 31 
August 2021) to evaluate… 
One Phase 4 study (Study TV48125-MH-40142) was 
conducted (last patient last visit: 31 August 2021) to 
evaluate… 
Update study status 
Section 3.1 General Study Design and Study Schematic Diagram 
Traditional Chinese therapy (includingother than herbal 
medicine) and acupuncture are allowed if the patient is on a 
stable dose/regimen for at least 2 months (consecutive) 
before screening. 
Traditional Chinese therapy (including herbal medicine) 
and acupuncture are allowed if the patient is on a stable 
dose/regimen for at least 2 months (consecutive) before 
screening. 
Alignment of text with updated 
relaxation of inclusion criteria to aid 
with recruitment 
• 
fremanezumab 225 mg sc once a month 
(approximately every 4 weeks [28 days]), for a total of 
3 doses; one 225-mg injection and 2 placebo injections at 
visit 2 and one 225-mg injection at visits 3 and 4… 
• 
placebo sc once a month (approximately every 4 
weeks [28 days]), for a total of 3 doses; 3 placebo 
injections at visit 2 and 1 placebo injection at visits 3 and 
4… 
(Note: For this study, monthly dosing refers to dosing 
approximately every 4 weeks [28 days].) 
 
fremanezumab 225 mg sc once a month 
(approximately every 4 weeks [28 days]), for a total of 
3 doses; one 225-mg injection and 2 placebo injections at 
visit 2 and one 225-mg injection at visits 3 and 4… 
• 
placebo sc once a month (approximately every 4 weeks 
[28 days]), for a total of 3 doses; 3 placebo injections at 
visit 2 and 1 placebo injection at visits 3 and 4 
Combined text statement with 
information in bullet points 
FollowA follow up visits for ADA sample collection will 
occur approximately 1 month and 3 months after the last 
dose of study drug (visit 7), at the EOT/ET visit (visit 8) 
Follow-up visits for ADA sample collection will occur 
approximately 1 months and 3 months after the last dose of 
study drug (visit 7), at the EOT/ET visit (visit 8) and at the 
end of study (EOS) visit (visit 9), respectively. 
Clarification of ADA sample 
collection during follow-up visits 
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Original text with changes shown 
New wording 
Reason/Justification for change 
and approximately 2 months after visit 8 at the end of study 
(EOS) visit (visit 9), respectively. 
The EOSend of study is defined as the last visit of the last 
patient (follow-up visit, visit 9). Two interim analyses are 
planned. The first 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 (visit 5). A second interim database lock will occur 
following the end of the open-label period (visit 8). Final 
database lock will occur following the end of the follow-
up period. 
The study duration will be approximately 2 years, from 
approximately Q1/Q2Q3 2022 to approximately Q1Q2 
2024. 
The EOS is defined as the last visit of the last patient 
(follow-up visit, visit 9). Two interim analyses are 
planned. The first 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 (visit 5). A second interim database lock will occur 
following the end of the open-label period (visit 8). Final 
database lock will occur following the end of the follow-
up period. 
The study duration will be approximately 2 years, from 
approximately Q3 2022 to approximately Q2 2024. 
Added interim analyses and updated 
study period due to experienced 
delays 
In the event of an public health emergency situation (eg, 
pandemic or potential pandemic), the investigational 
center will inform the patient of the safeguards being 
taken… 
In the event of an emergency situation (eg, pandemic or 
potential pandemic), the investigational center will inform 
the patient of the safeguards being taken… 
Revised language to be aligned 
within the protocol 
Section 3.2 Planned Number of Patients and Countries 
The study is expected to start in approximately Q3Q1/Q2 
2022 and last until approximately Q2Q1 2024 
The study is expected to start in approximately Q3 2022 
and last until approximately Q2 2024. 
Updated study period due to 
experienced delays 
Section 3.5 Schedule of Study Procedures and Assessments 
Table 3 Study Procedures and Assessments 
c 
In case of ana public health emergency situation (eg, 
pandemic or potential pandemic), visit windows for post 
baseline visits may be extended to 14 calendar days, 
except for visit 2. The window for visit 2 may only be 
extended to 7 calendar days in case of an emergency 
situation (eg, pandemic or potential pandemic). In case of 
an out-of-window visit, the date of the next visit will be 
calculated based on the actual date of the last 
administration of study drug. 
Table 3 Study Procedures and Assessments 
c 
In case of an emergency situation (eg, pandemic or 
potential pandemic), visit windows for post baseline visits 
may be extended to 14 calendar days, except for visit 2. 
The window for visit 2 may only be extended to 
7 calendar days in case of an emergency situation (eg, 
pandemic or potential pandemic). In case of an out-of-
window visit, the date of the next visit will be calculated 
based on the actual date of the last administration of study 
drug. 
Amended visit window to mitigate 
impact from an emergency situation 
(eg, pandemic or possible 
pandemic) 
Section 4.1 Patient Inclusion Criteria “g” 
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Reason/Justification for change 
[Revision 1] The patient has a clinical history of migraine 
that is confirmed during a prospectively recorded 28-day 
baseline period with the following characteristics: 
- 
Patient has 4 or more migraine days consistent 
with the characteristics of migraine (Appendix J) 
or probable migraine (a migraine subtype where 
only 1 migraine criterion is missing) or used a 
triptan or ergot derivative to treat an ongoing 
headache. 
- 
Patient has 42 or more days per month that are 
completely free of migraine headache or 
associated migraine symptoms. 
[Revision 1] The patient has a clinical history of migraine 
that is confirmed during a prospectively recorded 28-day 
baseline period with the following characteristics: 
- 
Patient has 4 or more migraine days consistent 
with the characteristics of migraine (Appendix J) 
or probable migraine (a migraine subtype where 
only 1 migraine criterion is missing) or used a 
triptan or ergot derivative to treat an ongoing 
headache. 
- 
Patient has 2 or more days per month that are 
completely free of migraine headache or 
associated migraine symptoms. 
Relaxation of inclusion criteria to 
aid with recruitment 
Section 4.1 Patient Inclusion Criteria “i” 
[Revision 1] Other concomitant medications (excluding 
including herbal medicine) and acupuncture for migraine 
or other conditions are allowed for all patients, provided 
that the patient has been on a stable dose regimen for at 
least 2 months of consecutive use prior to screening (visit 
1) with no expectation to change dosing regimen or 
change to another medication during the treatment phase 
of the study.  
[Revision 1] Other concomitant medications (including 
herbal medicine) and acupuncture for migraine or other 
conditions are allowed for all patients, provided that the 
patient has been on a stable dose regimen for at least 
2 months of consecutive use prior to screening (visit 1) 
with no expectation to change dosing regimen or change 
to another medication during the treatment phase of the 
study. 
Relaxation of inclusion criteria to 
aid with recruitment 
Section 4.2 Patient Exclusion Criteria “f” 
Known current infection or any history of infection with 
human immunodeficiency virus, tuberculosis, or Lyme 
disease, or hepatitis B or C virus, or a known or suspected 
active infection of coronavirus disease 2019 (COVID-19). 
Known current infection or any history of infection with 
human immunodeficiency virus, tuberculosis, or Lyme 
disease, or a known or suspected active infection of 
coronavirus disease 2019 (COVID-19). 
Update and relaxation of exclusion 
criteria to aid with recruitment 
Section 4.2 Patient Exclusion Criteria “w” 
[New Criterion] Known current infection or history of 
infection in the past 6 months with hepatitis B or C 
viruses. 
[New criterion] Known current infection or history of 
infection in the past 6 months with hepatitis B or C 
viruses. 
Update and relaxation of exclusion 
criteria to aid with recruitment 
Section 4.4 Replacement of Patients 
Early termination rate and screen failures due to ana 
public health emergency situation (eg, pandemic or 
Early termination rate and screen failures due to an 
emergency situation (eg, pandemic or potential pandemic) 
Clarification 
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Reason/Justification for change 
potential pandemic) will be monitored during the study. 
In order to maintain study power, an excess loss of 
patients will be replaced (eg, if there are >5% of patients 
lost to ana public health emergency situation [eg, 
pandemic or potential pandemic], additional patients may 
be recruited). 
will be monitored during the study. In order to maintain 
study power, an excess loss of patients will be replaced 
(eg, if there are >5% of patients lost to an emergency 
situation [eg, pandemic or potential pandemic], additional 
patients may be recruited). 
Section 5.6 Prior and Concomitant Medication or Therapy 
…Traditional Chinese therapy (includingother than herbal 
medicine) and acupuncture are allowed if the patient is on 
a stable dosing regimen for at least 2 months 
(consecutive) before screening. 
Traditional Chinese therapy (including herbal medicine) 
and acupuncture are allowed if the patient is on a stable 
dosing regimen for at least 2 months (consecutive) before 
screening. 
Alignment of text with updated 
relaxation of inclusion criteria to aid 
with recruitment 
Section 5.9.1 Maintenance of Randomization 
At the time of the first interim analysis (after the end of 
study), after receiving the unblinding request from the 
Teva statistician, the service provider will provide the 
unblinded IMP assignment according to the processes 
defined in the relevant standard operating procedure. 
At the time of the first interim analysis, after receiving the 
unblinding request from the Teva statistician, the service 
provider will provide the unblinded IMP assignment 
according to the processes defined in the relevant standard 
operating procedure. 
Updated according to included 
interim analyses 
Section 7.1.2 Recording and Reporting of Adverse Events 
For the recording of adverse events, the study period is 
defined for each patient as the time period from the 
beginning of study treatment signature of the ICF to the 
end of the follow-up period. The follow-up period of the 
recording of adverse events is defined as 36 months after 
the last dose of IMP. 
For the recording of adverse events, the study period is 
defined for each patient as the time period from signature 
of the ICF to the end of the follow-up period. The follow-
up period of the recording of adverse events is defined as 
3 months after the last dose of IMP. 
Correction for inconsistencies 
within the protocol. Adverse event 
reporting starts with each subject 
signing the informed consent form. 
The follow-up period is 3 months. 
Section 7.1.5 Serious Adverse Events  
For the recording of serious adverse events, the study 
period is defined for each patient as the time period from 
the beginning of study treatment signature of the ICF to 
the end of the follow‐up period. 
For the recording of serious adverse events, the study 
period is defined for each patient as the time period from 
signature of the ICF to the end of the follow‐up period.  
Correction for inconsistencies 
within the protocol. Adverse event 
reporting starts with each subject 
signing the informed consent form. 
Section 7.4 Clinical Laboratory Test 
Not Applicable 
Table 6 Clinical Laboratory Test 
Clarification that total cholesterol is 
being tested 
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Original text with changes shown 
New wording 
Reason/Justification for change 
Added “Total Cholesterol” to the column with serum 
chemistry tests 
Section 7.4.1 Serum Chemistry, Hematology, and Urinalysis 
Specific laboratory tests to be performed are provided in 
Table 6. Note, reflex (ie, microanalysis tests like 
squamous epithelial cells and mucous threads) tests may 
be triggered automatically. 
Specific laboratory tests to be performed are provided in 
Table 6. Note, reflex (ie, microanalysis tests like 
squamous epithelial cells and mucous threads) test may be 
triggered automatically. 
Clarification that reflex tests may be 
triggered automatically but are not 
required by the protocol 
Section 9.2.4 Per-Protocol Analysis Set 
…only patients who complete treatment without any 
important deviations such as important 
inclusion/exclusion criteria deviations or any important 
violationsdeviations or omissions of the IMP 
administration. 
…only patients who complete treatment without any 
important deviations such as important 
inclusion/exclusion criteria deviations or any important 
deviations or omissions of the IMP administration. 
Correction of criteria for per-
protocol analysis subset 
Section 9.4 Study Population 
Summaries will be presented by treatment group and for 
all patients. In addition, the primary and secondary 
efficacy endpoints will also be analyzed using the per-
protocol analysis set. 
Summaries will be presented by treatment group and for 
all patients. In addition, the primary and secondary 
efficacy endpoints will also be analyzed using the per-
protocol analysis set. 
Clarification that the primary and 
secondary endpoints will also be 
analyzed using the per-protocol 
analysis set 
Section 9.5.4 Planned Method of Analysis 
Summaries will be presented by treatment group. In 
addition, the primary and secondary efficacy endpoints 
will also be analyzed using the per-protocol analysis set. 
In addition, the primary and secondary efficacy endpoints 
will also be analyzed using the per-protocol analysis set. 
Clarification that the primary and 
secondary endpoints will also be 
analyzed using the per-protocol 
analysis set 
Section 9.11 Planned Interim Analysis 
There will be no formal interim analysis. Two interim 
analyses are planned. The first interim analysis is planned 
when the last patient has completed the double-blind 
period. A second interim analysis 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 
Two interim analyses are planned. The first interim 
analysis is planned when the last patient has completed 
the double-blind period. A second interim analysis 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 
Added interim analyses 
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Reason/Justification for change 
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 second database 
lock. 
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 second database 
lock. 
Appendix A Clinical Laboratories and other Departments and Institutions 
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. 
 
 
 
 
 
Teva Branded 
Pharmaceutical Products 
R&D, Inc. 
Tel: 
  
Cell: 
 
 
 
 
Teva Pharmaceuticals, 
 
 
 
 
Cell: 
 
  
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. 
 
 
Teva Pharmaceuticals, 
 
 
 
 
Cell: 
 
  
 
Updated contact information 
Appendix C Quality Control and Quality Assurance 
Deviations from the study conduct due to emergency 
situations (eg, pandemic or potentialthe COVID 19 
pandemic), including… 
Deviations from the study conduct due to emergency 
situations (eg, pandemic or potential pandemic), 
including… 
Revised language to be aligned 
within the protocol 
In case of an emergency situation (eg, pandemic or 
potentialthe COVID 19 pandemic), where study 
monitors… 
In case of an emergency situation (eg, pandemic or 
potential pandemic), where study monitors… 
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Reason/Justification for change 
In case of an emergency situation (eg, pandemic or 
potentialthe COVID 19 pandemic), where auditors… 
In case of an emergency situation (eg, pandemic or 
potential pandemic), where auditors… 
Appendix H Data Management and Record Keeping 
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 (visit 8).  
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 (visit 8).  
Added interim analyses 
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16.3. 
Administrative Letter 01 Dated 26 July 2022  
 
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16.4. 
Amendment 01 Dated 15 September 2021  
The primary reason for this amendment is to add an open-label treatment period at the request of the China National Medicinal 
Products Administration’s Center for Drug Evaluation and the ethics committee. Associated objectives and endpoints were added, and 
the randomization stratification factors were modified to include stratification by EM and CM migraine types. Furthermore, it was 
clarified that additional visits for pharmacokinetic assessment are required for the double-blind treatment period. 
All major changes to the protocol body are listed below in the table and are reflected in the synopsis, as applicable. Minor editorial 
changes (typos, punctuation, etc) have been made to the protocol (and protocol synopsis, as appropriate). 
Changes to the Protocol 
Original text with changes shown 
New wording 
Reason/justification for change 
Title Page (Other sections affected by this change: Amendment History and Investigator Agreement) 
Clinical Study Protocol with Revision Amendment 01 
… 
A Multicenter, Randomized, Double-Blind, 
Placebo-Controlled Efficacy and Safety Study with an 
Open-Label Treatment Period of Fremanezumab 
Administered Subcutaneously Monthly or Quarterly for the 
Preventive Treatment of Migraine in Adult Chinese Patients  
A Randomized, Double-Blind, Placebo-Controlled Study 
with an Open-Label Period on Efficacy and Safety of 
Fremanezumab in Chinese Adults with Migraine 
... 
Protocol with Amendment 01 Approval Date: 
15 September 2021 
Clinical Study Protocol with Amendment 01 
… 
A Multicenter, Randomized, Double-Blind, 
Placebo-Controlled Efficacy and Safety Study with an 
Open-Label Treatment Period of Fremanezumab 
Administered Subcutaneously Monthly or Quarterly for 
the Preventive Treatment of Migraine in Adult Chinese 
Patients  
A Randomized, Double-Blind, Placebo-Controlled 
Study with an Open-Label Period on Efficacy and 
Safety of Fremanezumab in Chinese Adults with 
Migraine 
... 
Protocol with Amendment 01 Approval Date: 
15 September 2021 
Updated version and revised the 
title of the protocol  
Section 1.1 Introduction (Other sections affected by this change: Sections 3.3 and 5.3.1) 
Fremanezumab was approved for use in adults in the United 
States (US) on 14 September 2018 and was approved by the 
European Medicines Agency (EMA) in March 2019, and 
marketing authorization applications have been submitted 
and approved in several countries worldwide, including 
Fremanezumab was approved for use in adults in the 
United States (US) on 14 September 2018 and was 
approved by the European Medicines Agency (EMA) 
in March 2019, and marketing authorization 
applications have been submitted and approved in 
several countries worldwide, including Canada, 
Noted completion and publication 
of pivotal studies supporting 
approval 
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New wording 
Reason/justification for change 
Canada, Australia, Korea, and Japan. Pivotal studies leading 
to these approvals have been published. 
Australia, Korea, and Japan. Pivotal studies leading to 
these approvals have been published. 
Section 1.1 Introduction (Other sections affected by this change: Sections 3.2 and 3.3) 
The purpose of the study is to confirm the efficacy and safety 
of fremanezumab in adult Chinese patients with the 
diagnosis of migraine in mainland China and Hong Kong. 
The purpose of the study is to confirm the efficacy and 
safety of fremanezumab in adult Chinese patients with 
the diagnosis of migraine in China. 
Clarified location of study conduct 
Section 1.2.2.2 Clinical Safety and Efficacy Studies (Other sections affected by this change: Section 3.3) 
Three Otsuka-sponsored studies in Japanese and Korean 
patients with EM and CM to evaluate the efficacy and safety 
of fremanezumab have been completed. These studies are 
2 Phase 2b/3 double-blind, placebo-controlled studies in 
approximately 900 patients (406-102-00001 and 406-102-
00002; Sakai et al 2021a, 2021b) and 1 long-term study in 
50 patients (406-102-00003; manuscript accepted by Drug 
Safety as of 31 August 2021). The study designs of the 
Otsuka studies are the same as those of the HALO studies. 
Efficacy results demonstrated that treatment with 
fremanezumab monthly and quarterly was associated with 
statistically significant and clinically meaningful 
improvements on all primary and secondary efficacy 
measures. The safety profile observed in these studies was 
found to be consistent with that seen in the global pivotal 
efficacy studies; no safety signals were identified. These 
studies, together with the global HALO studies, led to 
marketing authorization in Japan and Korea in 2021. 
Fremanezumab at the doses tested was generally safe and 
well tolerated for 3 months in patients with EM migraine. 
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. 
Three Otsuka-sponsored studies in Japanese and 
Korean patients with EM and CM to evaluate the 
efficacy and safety of fremanezumab have been 
completed. These studies are 2 Phase 2b/3 
double-blind, placebo-controlled studies in 
approximately 900 patients (406-102-00001 and 406-
102-00002; Sakai et al 2021a, 2021b) and 1 long-term 
study in 50 patients (406-102-00003; manuscript 
accepted by Drug Safety as of 31 August 2021). The 
study designs of the Otsuka studies are the same as 
those of the HALO studies. Efficacy results 
demonstrated that treatment with fremanezumab 
monthly and quarterly was associated with statistically 
significant and clinically meaningful improvements on 
all primary and secondary efficacy measures. The 
safety profile observed in these studies was found to be 
consistent with that seen in the global pivotal efficacy 
studies; no safety signals were identified. These 
studies, together with the global HALO studies, led to 
marketing authorization in Japan and Korea in 2021. 
Fremanezumab at the doses tested was generally safe 
and well tolerated for 3 months in patients with 
migraine. 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. 
Added efficacy and safety results 
from Otsuka-sponsored studies in 
Japanese and Korean patients 
Clarified the indication in patients 
treated with fremanezumab for 
3 months 
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Section 2.1 Primary and Secondary Study 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 Chinese 
patients with migraine. The 
primary efficacy analysis will 
consider all fremanezumab 
treated patients as 1 group. 
The primary endpoint is the 
mean change from baseline in 
the monthly average number 
of migraine days during the 
12-week period after the 1st 
dose of investigational 
medicinal product (IMP). 
The secondary objective of the 
study is to further demonstrate 
the efficacy of fremanezumab 
administered as monthly and 
quarterly sc injections to adult 
Chinese patients with 
migraine. The secondary 
efficacy analyses will consider 
all fremanezumab treated 
patients as 1 group. 
The secondary endpoints are 
as follows: 
• mean change from baseline 
in the number of migraine 
days during the 4 week 
period after the 1st dose of 
IMP 
• mean change from baseline 
in the monthly average 
number of days that any 
acute headache medications 
were used during the 12-
week period after the 1st 
dose of IMP 
• 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 
IMP  
• mean change from 
baseline in the monthly 
average number of days 
with headache of at least 
moderate severity during 
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 
Chinese patients with 
migraine. The primary 
efficacy analysis will 
consider all fremanezumab 
treated patients as 1 group. 
The primary endpoint is the 
mean change from baseline 
in the monthly average 
number of migraine days 
during the 12-week period 
after the 1st dose of 
investigational medicinal 
product (IMP). 
The secondary objective of 
the study is to further 
demonstrate the efficacy of 
fremanezumab 
administered as monthly 
and quarterly sc injections 
to adult Chinese patients 
with migraine. The 
secondary efficacy analyses 
will consider all 
fremanezumab treated 
patients as 1 group. 
The secondary endpoints 
are as follows: 
• mean change from 
baseline in the number 
of migraine days during 
the 4 week period after 
the 1st dose of IMP 
• mean change from 
baseline in the monthly 
average number of days 
that any acute headache 
medications were used 
during the 12-week 
period after the 1st dose 
of IMP 
• 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 IMP  
• mean change from 
baseline in the monthly 
average number of days 
Clarified the make-up of the study 
population 
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the 12-week period after the 
1st dose of IMP 
A secondary objective of the 
study is to evaluate the safety 
and tolerability of 
fremanezumab administered as 
monthly and quarterly sc 
injections to adult Chinese 
patients with migraine. 
The safety/tolerability 
endpoints are as follows: 
• occurrence of adverse 
events throughout the study 
• clinical laboratory (serum 
chemistry, hematology, 
coagulation, and urinalysis) 
test results at specified time 
points 
ADA=antidrug antibody; ECG=electrocardiogram; 
IMP=investigational medicinal product; sc=subcutaneous. 
with headache of at least 
moderate severity during 
the 12-week period after 
the 1st dose of IMP 
A secondary objective of 
the study is to evaluate the 
safety and tolerability of 
fremanezumab 
administered as monthly 
and quarterly sc injections 
to adult Chinese patients 
with migraine. 
The safety/tolerability 
endpoints are as follows: 
• occurrence of adverse 
events throughout the 
study 
• clinical laboratory 
(serum chemistry, 
hematology, coagulation, 
and urinalysis) test 
results at specified time 
points 
ADA=antidrug antibody; ECG=electrocardiogram; 
IMP=investigational medicinal product; sc=subcutaneous. 
Section 2.2 Pharmacokinetic and Other Objectives and Endpoints (Other sections affected by this change: Sections 9.5.3 and 9.5.4.4) 
Pharmacokinetic and other endpoints for the double-blind 
treatment period to address the objective to further 
characterize fremanezumab safety, efficacy, and 
pharmacokinetics are as follows: 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacokinetic and other endpoints for the double-
blind treatment period to address the objective to 
further characterize fremanezumab safety, efficacy, and 
pharmacokinetics are as follows: 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Defined the new objectives and 
endpoints relevant to the added 
open-label treatment period  
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Section 3.1 General Study Design and Study Schematic Diagram (Other sections affected by this change: Sections 2.2, 3.3, 3.5, 5.1, 5.4, 5.6, 8.1, 
9.5.4.1, 9.5.4.4, and Appendix B) 
This is a multicenter, randomized, double-blind, placebo-
controlled study with an open-label treatment period to 
evaluate the efficacy, safety, and tolerability of monthly and 
quarterly sc fremanezumab for the preventive treatment of 
migraine in adults. The study will consist of a screening visit, 
a baseline period (4 weeks), a 12-week double-blind 
treatment period, a 12-week open-label treatment period, and 
a follow-up period lasting approximately 3 months after the 
last dose of IMP (ie, 2 months after the end of treatment 
[EOT]/early termination [ET] visit). 
The total duration of patient participation in the study is 
planned to be approximately 69 months. 
This is a multicenter, randomized, double-blind, 
placebo-controlled study with an open-label treatment 
period to evaluate the efficacy, safety, and tolerability 
of monthly and quarterly sc fremanezumab for the 
preventive treatment of migraine in adults. The study 
will consist of a screening visit, a baseline period 
(4 weeks), a 12-week double-blind treatment period, a 
12-week open-label treatment period, and a follow-up 
period lasting approximately 3 months after the last 
dose of IMP (ie, 2 months after the end of treatment 
[EOT]/early termination [ET] visit). 
Added open-label treatment period 
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… 
Patients must return to the study center after visit 2, visit 3, 
or visit 4 for 2 additional blood sampling visits to measure 
plasma fremanezumab concentration. Additional details on 
these visits are provided in Section 8.1. 
Following 12 weeks of randomized treatment, patients enter 
the 12-week open-label treatment period to receive 
fremanezumab 225 mg sc once a month (approximately 
every 4 weeks) for a total of 3 doses (one 225-mg injection at 
visits 5, 6, and 7). 
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 3 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 EOT study visit (visit 8) will be scheduled. 
Patients should return to the care of their treating physicians 
after visit 8. Patients should be treated with standard of care 
after withdrawal from or termination of the 24-week 
treatment period/study, as appropriate. 
(Note: For this study, monthly dosing refers to dosing 
approximately every 4 weeks [28 days].) 
… 
Patients will have treatment evaluations performed at visit 8 
(EOT visit), approximately 4 weeks after administration of 
the final dose of study drug. 
A follow-up visit for anti drug antibody (ADA) sample 
collection will occur approximately 23 months after the last 
dose of study drug at the EOT/ET visit (visit 58) and 
approximately 2 months after visit 8 at the end of study visit 
(visit 9). 
… 
The study duration will be approximately 2 years from Q3 
2021 approximately Q1/Q2 2022 to approximately Q1 
2024Q2 2023. 
The total duration of patient participation in the study 
is planned to be approximately 9 months. 
… 
Patients must return to the study center after visit 2, 
visit 3, or visit 4 for 2 additional blood sampling visits 
to measure plasma fremanezumab concentration. 
Additional details on these visits are provided in 
Section 8.1. 
Following 12 weeks of randomized treatment, patients 
enter the 12-week open-label treatment period to 
receive fremanezumab 225 mg sc once a month 
(approximately every 4 weeks) for a total of 3 doses 
(one 225-mg injection at visits 5, 6, and 7). 
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 3 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 EOT study visit (visit 8) will be 
scheduled. Patients should return to the care of their 
treating physicians after visit 8. Patients should be 
treated with standard of care after withdrawal from or 
termination of the 24-week treatment period/study, as 
appropriate. 
(Note: For this study, monthly dosing refers to dosing 
approximately every 4 weeks [28 days].) 
… 
Patients will have treatment evaluations performed at 
visit 8 (EOT visit), approximately 4 weeks after 
administration of the final dose of study drug. 
A follow-up visit for ADA sample collection will occur 
approximately 3 months after the last dose of study 
drug at the EOT/ET visit (visit 8) and approximately 
2 months after visit 8 at the end of study visit (visit 9). 
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… 
The study duration will be approximately 2 years from 
approximately Q1/Q2 2022 to approximately Q1 2024. 
Note: Blood samples for plasma drug concentration will be 
collected at visits 2, 3, 4, 5, and 64. Patients will be asked to 
return to the study center after visit 2, visit 3, or visit 4 for up 
to 2 additional visits after any dose of IMP for blood 
sampling for visits to measure plasma fremanezumab 
concentration determination and(one being 3 to 10 days after 
either visit 2, visit 3, or visit 4 and the other being 15 to 20 
days after either visit 2, visit 3, or visit 4). If 2 additional 
visits are not possible for the patient, then the patient must 
return for only 1 additional pharmacokinetic blood sampling 
at either of the aforementioned time points. When patients 
return to the study center for additional blood sampling, then 
inquiries about adverse events and concomitant medications. 
These visits should occur during the following time periods 
relative to any dose of IMP: 3 to 10 days and/or 15 to 20 
days after IMP administration will be performed. 
Note: Blood samples for plasma drug concentration 
will be collected at visits 2, 3, and 4. Patients will be 
asked to return to the study center after visit 2, visit 3, 
or visit 4 for 2 additional blood sampling visits to 
measure plasma fremanezumab concentration (one 
being 3 to 10 days after either visit 2, visit 3, or visit 4 
and the other being 15 to 20 days after either visit 2, 
visit 3, or visit 4). If 2 additional visits are not possible 
for the patient, then the patient must return for only 1 
additional pharmacokinetic blood sampling at either of 
the aforementioned time points. When patients return 
to the study center for additional blood sampling, then 
inquiries about adverse events and concomitant 
medications will be performed. 
Clarified that additional visits for 
pharmacokinetic assessment are 
required for the double-blind 
treatment period 
Section 3.1 General Study Design and Study Schematic Diagram (Other sections affected by this change: Sections 3.3, 5.8, 9.5.4.1, 9.5.4.2, and 9.5.4.3) 
Randomization using electronic interactive response 
technology (IRT) will be stratified based on sex, migraine 
type (CM vs EM) and preventive medication use, and region 
to ensure balance. 
Randomization using electronic interactive response 
technology (IRT) will be stratified based on migraine 
type (CM vs EM) and preventive medication use to 
ensure balance. 
Changed randomization 
stratification 
Section 3.3 Justification for Study Design and Selection of Population 
...No ethnic differences are expected or observed in the 
safety or efficacy of fremanezumab used for the preventive 
treatment of migraine. 
 
…Both fremanezumab dosing regimens are approved in the 
US, the EU, Australia, Israel, and several additional 
countries.  
Study design elements, including the duration of the double-
blind and open-label treatment periods; dosing regimen; 
inclusion/exclusion criteria; and efficacy, safety, and 
...No ethnic differences are expected or observed in the 
safety or efficacy of fremanezumab used for the 
preventive treatment of migraine. 
 
…Both fremanezumab dosing regimens are approved 
in the US, the EU, Australia, Israel, and several 
additional countries.  
Study design elements, including the duration of the 
double-blind and open-label treatment periods; dosing 
regimen; inclusion/exclusion criteria; and efficacy, 
Added rational for combining 
patients with CM and patients with 
EM for primary analysis. 
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pharmacokinetic assessments are completely consistent with 
the pivotal HALO studies and all fremanezumab migraine 
efficacy studies completed so far. 
Throughout the global fremanezumab clinical program, 
patients with the full range of clinical severities, from the 
episodic to chronic subtypes of migraine, both separately and 
combined, have consistently demonstrated similar efficacy 
and safety with fremanezumab treatment by the same 
measures. Therefore, in this study, the primary analysis will 
consider patients representing the entire disease spectrum of 
migraine as a single study population stratified by EM and 
CM. Moreover, this study population is fully consistent with 
the currently approved indication for migraine in the US, 
Canada, EU, and other countries, and fully reflects the 
intended population for use in Chinese patients. In order to 
provide added granularity to the migraine subtypes, data for 
patients with EM and CM will be provided as subgroup 
analyses. Pharmacokinetic samples will be collected during 
the treatment and follow-up periods and analyzed using a 
population pharmacokinetic (PPK) modeling approach. 
Pharmacokinetic plasma concentration results for 
fremanezumab will be tabulated descriptively at each 
planned sampling time point by treatment group. The 
pharmacokinetic data from this study will be compared with 
the general migraine population data in order to demonstrate 
comparability. Anti-drug antibody samples will be collected 
and analyzed during and after the treatment period. 
Primary efficacy will be measured by the change from 
baseline in the monthly average number… 
safety, and pharmacokinetic assessments are 
completely consistent with the pivotal HALO studies 
and all fremanezumab migraine efficacy studies 
completed so far. 
Throughout the global fremanezumab clinical program, 
patients with the full range of clinical severities, from 
the episodic to chronic subtypes of migraine, both 
separately and combined, have consistently 
demonstrated similar efficacy and safety with 
fremanezumab treatment by the same measures. 
Therefore, in this study, the primary analysis will 
consider patients representing the entire disease 
spectrum of migraine as a single study population 
stratified by EM and CM. Moreover, this study 
population is fully consistent with the currently 
approved indication for migraine in the US, Canada, 
EU, and other countries, and fully reflects the intended 
population for use in Chinese patients. In order to 
provide added granularity to the migraine subtypes, 
data for patients with EM and CM will be provided as 
subgroup analyses. Pharmacokinetic samples will be 
collected during the treatment and follow-up periods 
and analyzed using a population pharmacokinetic 
(PPK) modeling approach. Pharmacokinetic plasma 
concentration results for fremanezumab will be 
tabulated descriptively at each planned sampling time 
point by treatment group. The pharmacokinetic data 
from this study will be compared with the general 
migraine population data in order to demonstrate 
comparability. Anti-drug antibody samples will be 
collected and analyzed during and after the treatment 
period. 
Primary efficacy will be measured by the change from 
baseline in the monthly average number… 
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Section 3.5 Schedule of Study Procedures and Assessments 
Table 3 Study Procedures and Assessments 
c 
In case of a public health emergency, visit windows may 
be extended to 7 calendar days. In case of an out-of-window 
visit, the date of the next visit will be calculated based on the 
actual date of the last administration of study drug. 
Table 3 Study Procedures and Assessments 
c 
In case of a public health emergency, visit 
windows may be extended to 7 calendar days. In case 
of an out-of-window visit, the date of the next visit will 
be calculated based on the actual date of the last 
administration of study drug. 
Added the method of calculating 
the next visit for cases of 
out-of-window visits 
Section 4.1 Patient Inclusion Criteria 
g. The patient has a clinical history of migraine that is 
confirmed during a prospectively recorded 28-day baseline 
period with the following characteristics: 
− Patient has 4 or more headache migraine days 
consistent with the characteristics of migraine 
(Appendix J) or probable migraine (a migraine 
subtype where only 1 migraine criterion is missing) 
or used a triptan or ergot derivative to treat an 
ongoing headache. 
− Patient has 4 or more days per month that are 
completely free of migraine headache or associated 
migraine symptoms. 
g. The patient has a clinical history of migraine that 
is confirmed during a prospectively recorded 28-day 
baseline period with the following characteristics: 
− Patient has 4 or more migraine days consistent 
with the characteristics of migraine ( Appendix
 
J) or probable migraine (a migraine subtype 
where only 1 migraine criterion is missing) or 
used a triptan or ergot derivative to treat an 
ongoing headache. 
− Patient has 4 or more days per month that are 
completely free of migraine headache or 
associated migraine symptoms. 
Clarified the clinical history of 
migraine in patients 
Section 4.2 Patient Exclusion Criteria 
b. Has used an intervention/device (eg, scheduled nerve 
blocks or transcranial magnetic stimulation) for migraine, or 
in the head or neck area, during the 2 months prior to 
screening (visit 1). 
b. Has used an intervention/device (eg, scheduled 
nerve blocks or transcranial magnetic stimulation) for 
migraine, or in the head or neck area, during the 
2 months prior to screening (visit 1). 
Clarified the use of 
interventional/device by the patient 
prior to screening 
Section 5.1.1.1 Starting Dose and Dose Levels 
The starting dose of fremanezumab will be either 675 mg or 
225 mg at visit 2 (day 1), depending on the treatment group. 
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 double-blind period and 
225 mg for the open-label treatment period. 
The starting dose of fremanezumab will be either 675 
mg or 225 mg at visit 2 (day 1), depending on the 
treatment group. 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 double-blind period and 225 mg for the open-label 
treatment period. 
Clarified the maximal dose 
administered for the double-blind 
and open-label periods 
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Section 7.10 Assessment of Suicidality 
Any patient should be excluded if any suicidal behaviors are 
reported suicide attempt in the past, suicidal ideation with a 
specific plan in the past 2 years prior to screening (visit 1), or 
current suicidal ideation will result in patient exclusion. 
Any patient with lifetime suicidal behaviors (actual, 
interrupted, and aborted attempts and preparatory actions) 
and current suicidal ideation should be excluded and/or 
discontinued from study treatment. Investigators will inquire 
about and evaluate suicidal ideation, plan, and behavior 
based on their clinical judgement and refer patients to 
psychiatric care as appropriate. 
Any suicide attempt in the past, suicidal ideation with a 
specific plan in the past 2 years prior to screening 
(visit 1), or current suicidal ideation will result in 
patient exclusion. 
Investigators will inquire about and evaluate suicidal 
ideation, plan, and behavior based on their clinical 
judgement and refer patients to psychiatric care as 
appropriate. 
Clarified the assessment of 
suicidality that will result in patient 
exclusion 
Section 9.1 Sample Size and Power Considerations 
Therefore, the sample size and power estimation were 
conducted, assuming that the treatment difference between 
fremanezumab and placebo is 1.6 days (common SD 4.45 
days). 
To ensure adequate representation of patients with both 
migraine types (EM and CM), the enrollment minimum of 
either migraine type is 30%. In addition, primary efficacy 
analysis will be stratified by EM and CM and subgroup 
analysis for EM and CM will be conducted. 
Therefore, the sample size and power estimation were 
conducted, assuming that the treatment difference 
between fremanezumab and placebo is 1.6 days 
(common SD 4.45 days). 
To ensure adequate representation of patients with both 
migraine types (EM and CM), the enrollment minimum 
of either migraine type is 30%. In addition, primary 
efficacy analysis will be stratified by EM and CM and 
subgroup analysis for EM and CM will be conducted. 
Clarified enrollment minimums for 
each migraine type 
Appendix A CLINICAL LABORATORIES AND OTHER DEPARTMENTS AND INSTITUTIONS 
Bioanalytical 
Pharmacokinetics 
Evaluation 
Accurant Biotechnology 
Co, Ltd 
Room 505, Floor 5 
No.8 Jiafeng Road 
Free Trade Zone, 
Shanghai 200131 
China 
Bioanalytical 
Immunogenicity Evaluation 
Accurant Biotechnology 
Co, Ltd 
Room 505, Floor 5 
No.8 Jiafeng Road 
Bioanalytical 
Pharmacokinetics 
Evaluation 
Accurant Biotechnology 
Co, Ltd 
Room 505, Floor 5 
No.8 Jiafeng Road 
Free Trade Zone, 
Shanghai 200131 
China 
Bioanalytical 
Immunogenicity 
Evaluation 
Accurant Biotechnology 
Co, Ltd 
Room 505, Floor 5 
No.8 Jiafeng Road 
Clarified the address 
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Free Trade Zone, 
Shanghai 200131 
China 
Free Trade Zone, 
Shanghai 200131 
China 
Appendix K PREVENTIVE MIGRAINE MEDICATIONS ALLOWED FOR 30% OF THE STUDY POPULATION FOR THE DURATION OF 
THE STUDY 
The use of up to 1 preventive migraine medication is allowed 
for the duration of the study for up to 30% of the total 
population of patients (see Section .)5.6 
Preventive migraine medications allowed for the duration of 
the study specifically include the following (if they were 
previously prescribed for migraine or for another indication): 
The chronic use of up to 1 of the following concomitant 
medications is allowed in up to 30% of patients and should 
be entered in the electronic case report form (eCRF) pages 
specific for migraine preventive medication. Patients using 
up to 1 of the following migraine preventive medications for 
any condition at the time of study enrollment will be allowed 
to remain on the medication. Patients must have been on a 
stable, well-tolerated dose regimen of this medication for at 
least 2 months prior to screening (visit 1) and would be 
expected to remain on this medication for the duration of the 
study. For the remaining 70% of patients, the chronic use of 
the following medications are not allowed for migraine or for 
any other indications. PRN (ie, taken as needed) use of the 
following medications are allowed during the course of the 
study. PRN use of these medications should be reported in 
the eCRF as concomitant medications. Patients should be 
trained and should not report PRN use of these medications 
in the electronic headache diary. PRN use is defined as any 
treatment regimen outside of the prescribing information or 
local treatment guidelines. Patients will be allowed to use 
acute medications to treat acute migraine attacks as needed, 
with the exception of medications containing opioids and 
barbiturates. 
 
The chronic use of up to 1 of the following 
concomitant medications is allowed in up to 30% of 
patients and should be entered in the electronic case 
report form (eCRF) pages specific for migraine 
preventive medication. Patients using up to 1 of the 
following migraine preventive medications for any 
condition at the time of study enrollment will be 
allowed to remain on the medication. Patients must 
have been on a stable, well-tolerated dose regimen of 
this medication for at least 2 months prior to screening 
(visit 1) and would be expected to remain on this 
medication for the duration of the study. For the 
remaining 70% of patients, the chronic use of the 
following medications are not allowed for migraine or 
for any other indications. PRN (ie, taken as needed) use 
of the following medications are allowed during the 
course of the study. PRN use of these medications 
should be reported in the eCRF as concomitant 
medications. Patients should be trained and should not 
report PRN use of these medications in the electronic 
headache diary. PRN use is defined as any treatment 
regimen outside of the prescribing information or local 
treatment guidelines. Patients will be allowed to use 
acute medications to treat acute migraine attacks as 
needed, with the exception of medications containing 
opioids and barbiturates. 
• beta-blockers: atenolol, propranolol, metoprolol, 
nadolol, and timolol 
• calcium channel blockers/benzocycloheptenes: 
flunarizine and pizotifen 
Revised the use of preventative 
migraine medications allowed for 
30% of the study population for the 
duration of the study 
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New wording 
Reason/justification for change 
• beta-blockers: atenolol, propranolol, metoprolol, nadolol, 
and timolol 
• calcium channel blockers/benzocycloheptenes: flunarizine 
and pizotifen 
• antidepressants: amitriptyline, venlafaxine, nortriptyline, 
and duloxetine 
• anti-epileptic medications: topiramate, valproate, and 
divalproate 
• onabotulinumtoxinA 
Other agents that are not on this list but used for migraine 
prevention that may be used per local guidelines or clinical 
practice preference are considered to have questionable 
efficacy for migraine prevention and are therefore treated the 
same as other concomitant medications (ie, recorded as 
concomitant medications on the case report form) and DO 
NOT need to be captured in eCRF pages specific for 
migraine preventive medications. 
• antidepressants: amitriptyline, venlafaxine, 
nortriptyline, and duloxetine 
• anti-epileptic medications: topiramate, valproate, 
and divalproate 
• onabotulinumtoxinA 
Other agents that are not on this list but used for 
migraine prevention that may be used per local 
guidelines or clinical practice preference are considered 
to have questionable efficacy for migraine prevention 
and are therefore treated the same as other concomitant 
medications (ie, recorded as concomitant medications 
on the case report form) and DO NOT need to be 
captured in eCRF pages specific for migraine 
preventive medications. 
 
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16.5. 
Revision 01 Dated 01 April 2021  
The primary reason for this revision of the original protocol is to revise the contract research 
organization listed in Appendix A of the protocol. In addition, the other endpoint of “assessment 
of ADA during and after the treatment period” was removed, as ADAs will be evaluated as part 
of the secondary safety analysis. Minor editorial changes (typos, punctuation, etc) have been 
made to the protocol (and protocol synopsis, as appropriate). 
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APPENDIX A. CLINICAL LABORATORIES AND OTHER 
DEPARTMENTS AND INSTITUTIONS  
Sponsor’s Authorized Representative 
 
 
Teva Branded Pharmaceutical Products R&D, Inc. 
Tel: 
 
Cell: 
 
 
Sponsor’s Medical Expert/Contact Point designated 
by the Sponsor for Further Information on the 
Study 
 
 
 
Teva Branded Pharmaceutical Products R&D, Inc. 
Tel:
 
Cell: 
 
 
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. 
 
 
Teva Pharmaceuticals, 
 
 
Cell: 
 
  
Contract Research Organization 
Pharmaceutical Research Associates, Inc. 
4130 Parklake Avenue Suite 400 
Raleigh, North Carolina 27612 
USA 
Coordinating Clinical Laboratory 
Contracting entity 
ICON Laboratory Services, Inc. – Ireland 
South County Business Park, 
Leopardstown, Dublin 18, Ireland 
ICON Laboratory Services, Inc. – China 
Floor 1-3, No 3 Building, Hongda 
Industrial Park, No. 8 Hongda North Road, 
Yizhhuang Development Zone, Daxing District, 
Beijing, 100176, China 
Bioanalytical Pharmacokinetics Evaluation 
Accurant Biotechnology Co, Ltd 
Room 505, Floor 5 
No.8 Jiafeng Road 
Free Trade Zone, Shanghai 200131 
China 
Bioanalytical Immunogenicity Evaluation 
Accurant Biotechnology Co, Ltd 
Room 505, Floor 5 
No.8 Jiafeng Road 
Free Trade Zone, Shanghai 200131 
China 
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APPENDIX B. STUDY PROCEDURES AND ASSESSMENTS BY VISIT  
1. Procedures for Screening (Visit 1, Days -28 to -1) (Baseline Period) 
The screening visit (visit 1) will take place not more than 28 (+3) days before the 
randomization 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 medications and treatment history 
• perform clinical laboratory tests 
• perform physical examination (including height and weight) 
• perform 12-lead electrocardiogram (ECG) 
• perform vital signs measurements 
• perform serum beta-human chorionic gonadotropin (β-HCG) pregnancy test (for women 
of childbearing potential [WOCBP]) and follicle-stimulating hormone test (for 
postmenopausal women) 
• inform patients of study restrictions and compliance requirements 
• provide the electronic headache diary device 
• complete electronic headache diary entries 
2. Procedures During Administration of Investigational Medicinal Product(s) 
(Baseline [Visit 2, Day 1 +3 days]) (Double-Blind Treatment Period) 
Patients who meet the inclusion and exclusion criteria at visit 1 will enter a 28-day baseline 
period (when headache information will be captured daily in an electronic headache diary 
device) and then will continue to visit 2, when additional baseline assessments will be 
conducted. 
The following procedures will be performed at visit 2: 
• review inclusion and exclusion criteria 
• assign randomization/treatment number 
• perform clinical laboratory tests 
• collect blood samples for plasma concentration of the investigational medicinal product 
(IMP) 
− Patients will be asked to return to the study center after visit 2, visit 3, or visit 4 
for 2 additional blood sampling visits to measure plasma fremanezumab 
concentration (one being 3 to 10 days after either visit 2, visit 3, or visit 4 and the 
other being 15 to 20 days after either visit 2, visit 3, or visit 4). If 2 additional 
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visits are not possible for the patient, then the patient must return for only 
1 additional pharmacokinetic blood sampling at either of the aforementioned time 
points. When patients return to the study center for additional blood sampling, 
then inquiries about adverse events and concomitant medications will be 
performed. 
• collect blood samples for serum antidrug antibody (ADA) assessment 
• perform physical examination (including weight) 
• perform 12-lead ECG 
• perform vital signs measurements 
• perform urine pregnancy test (for WOCBP) 
• review study compliance 
• complete electronic headache diary entries 
• review the electronic headache diary 
• perform adverse event inquiry 
• administer the IMP 
• assess for hypersensitivity/anaphylaxis  
• perform concomitant medication inquiry 
3. Procedures During Administration of Investigational Medicinal Product(s) (Visit 3, 
Day 29 ±3 days) (Double-Blind Treatment Period) 
The following procedures/assessments will be performed at visit 3: 
• collect blood samples for plasma concentration of the IMP 
− Patients will be asked to return to the study center after visit 2, visit 3, or visit 4 
for 2 additional blood sampling visits to measure plasma fremanezumab 
concentration (one being 3 to 10 days after either visit 2, visit 3, or visit 4 and the 
other being 15 to 20 days after either visit 2, visit 3, or visit 4). If 2 additional 
visits are not possible for the patient, then the patient must return for only 
1 additional pharmacokinetic blood sampling at either of the aforementioned time 
points. When patients return to the study center for additional blood sampling, 
then inquiries about adverse events and concomitant medications will be 
performed. 
• perform physical examination (including weight) 
• perform vital signs measurements 
• perform urine pregnancy test (for WOCBP) 
• review study compliance 
• complete electronic headache diary entries 
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• review the electronic headache diary 
• perform adverse events inquiry 
• administer the IMP 
• assess for hypersensitivity/anaphylaxis  
• perform concomitant medication inquiry 
4. Procedures During Administration of Investigational Medicinal Product(s) (Visit 4, 
Day 57 ±3 days) (Double-Blind Treatment Period) 
The following procedures/assessments will be performed at visit 4: 
• perform clinical laboratory tests 
• collect blood samples for plasma concentration of the IMP 
− Patients will be asked to return to the study center after visit 2, visit 3, or visit 4 
for 2 additional blood sampling visits to measure plasma fremanezumab 
concentration (one being 3 to 10 days after either visit 2, visit 3, or visit 4 and the 
other being 15 to 20 days after either visit 2, visit 3, or visit 4). If 2 additional 
visits are not possible for the patient, then the patient must return for only 
1 additional pharmacokinetic blood sampling at either of the aforementioned time 
points. When patients return to the study center for additional blood sampling, 
then inquiries about adverse events and concomitant medications will be 
performed. 
• collect blood samples for serum ADA assessment 
• perform physical examination (including weight) 
• perform 12-lead ECG 
• perform vital signs measurements 
• perform urine pregnancy test (for WOCBP) 
• review study compliance 
• complete electronic headache diary entries 
• review the electronic headache diary 
• perform adverse events inquiry 
• administer the IMP 
• assess for hypersensitivity/anaphylaxis  
• perform concomitant medication inquiry 
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5. Procedures During Administration of Investigational Medicinal Product(s) (Visit 5, 
Day 85 ±5 days) (Open-Label Treatment Period) 
The following procedures/assessments will be performed at visit 5: 
• perform clinical laboratory tests 
• perform physical examination (including weight) 
• perform vital signs measurements 
• perform urine pregnancy test (for WOCBP) 
• review study compliance 
• complete electronic headache diary entries 
• review the electronic headache diary 
• complete the Patient Global Impression of Change (PGIC) scale 
• perform adverse events inquiry 
• administer the IMP 
• assess for hypersensitivity/anaphylaxis  
• perform concomitant medication inquiry 
6. Procedures During Administration of Investigational Medicinal Product(s) (Visit 6, 
Day 113 ±5 days) (Open-Label Treatment Period) 
The following procedures/assessments will be performed at visit 6: 
• perform vital signs measurements 
• perform urine pregnancy test (for WOCBP) 
• review study compliance 
• complete electronic headache diary entries 
• review the electronic headache diary 
• perform adverse events inquiry 
• administer the IMP 
• assess for hypersensitivity/anaphylaxis  
• perform concomitant medication inquiry 
7. Procedures During Administration of Investigational Medicinal Product(s) (Visit 7, 
Day 141 ±5 days) (Open-Label Treatment Period) 
The following procedures/assessments will be performed at visit 7: 
• perform vital signs measurements 
• perform urine pregnancy test (for WOCBP) 
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• review study compliance 
• complete electronic headache diary entries 
• review the electronic headache diary 
• perform adverse events inquiry 
• administer the IMP 
• assess for hypersensitivity/anaphylaxis  
• perform concomitant medication inquiry 
8. Procedures During End of Treatment/Early Termination Visit (Visit 8, Day 169 
±5 days) 
The following procedures/assessments will be performed at visit 8: 
• perform clinical laboratory tests 
• collect blood samples for plasma concentration of the IMP 
• collect blood samples for serum ADA assessment 
• perform physical examination (including weight) 
• perform 12-lead ECG 
• perform vital signs measurements 
• perform serum β-HCG pregnancy test (for WOCBP) 
• perform urine pregnancy test (for WOCBP) 
• review study compliance 
• complete electronic headache diary entries 
• review the electronic headache diary 
• return the electronic headache diary device 
• complete the PGIC scale 
• perform adverse events inquiry 
• assess for hypersensitivity/anaphylaxis  
• perform concomitant medication inquiry 
9. Procedures During Follow-up (Visit 9, Day 225 ±15 days) 
The following procedures/assessments will be performed at visit 9:  
• collect blood samples for serum ADA assessment 
• perform physical examination (including weight) 
• perform vital signs measurements 
• perform adverse events inquiry 
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• perform concomitant medication inquiry 
In addition, if the clinical laboratory tests, physical examination, or 12-lead ECG performed 
at visit 8 (EOT/ET) showed an abnormality, the assessment should be repeated during the 
follow-up visit. 
10. 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 the following: 
• perform vital signs measurements 
• review study compliance 
• review the electronic headache diary 
• perform adverse events inquiry 
• perform concomitant medication inquiry 
Other procedures and assessments may be performed at the discretion of the investigator and 
should be documented in the CRF. 
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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 Independent Ethics 
Committee/Institutional Review Board (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 Protocol 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 an important protocol deviation. Important 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 Good Clinical Practice (GCP) 
guidelines; noncompliance to investigational medicinal product (IMP) administration; and use of 
prohibited medications. Important protocol deviations will be identified and recorded in the 
patient’s source. All important protocol deviations will be reported to the responsible IEC/IRB, 
as required. 
When an important 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. 
Changes in the inclusion and exclusion criteria of the protocol are not prospectively granted by 
the sponsor. If investigational center personnel learn that a patient who did not meet protocol 
inclusion and exclusion criteria was entered in a study, they must immediately inform the 
sponsor of the important 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. 
Deviations from the study conduct due to emergency situations (eg, pandemic or potential 
pandemic), including implemented contingency measures and their impact (eg, patient 
discontinuation from treatment with IMP and/or study, alternative procedures used to collect 
critical safety and/or efficacy data, etc), will be described in the appropriate sections of the 
clinical study report, as applicable. 
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 
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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. 
Study Monitoring 
To ensure compliance with GCP guidelines, the study monitor or representative is responsible 
for ensuring that patients have signed the informed consent form and the study is conducted 
according to applicable standard operating procedures (SOPs), the protocol, and other written 
instructions and regulatory guidelines. 
The study monitor is the primary association between the sponsor and the investigator. The main 
responsibilities of the study monitors 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 monitors 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 (case report forms and other pertinent source data records, including specific electronic 
source documents 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. 
In case of an emergency situation (eg, pandemic or potential pandemic), where study monitors 
may not be able to access the investigational centers for on-site visits, investigational centers will 
be monitored remotely, where allowed, and in accordance with local regulations. 
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. 
In case of an emergency situation (eg, pandemic or potential pandemic), where auditors may not 
be able to access the investigational centers for on-site visits, investigational centers will be 
audited remotely, where allowed, and in accordance with local regulations. 
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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 
Independent Ethics Committee/Institutional Review Board (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 (ICF), 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 ICFs, 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. 
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 
give 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 case report forms (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, 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 trial registry websites. 
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APPENDIX E. BIRTH CONTROL METHODS AND PREGNANCY 
TESTING  
Contraception recommendations and pregnancy testing should encompass all investigational 
medicinal products (IMPs), as well as non-IMPs (eg, background therapy), and the measures to 
be followed should be based on the medicinal product with the highest risk. 
Assessment of likelihood of possible interaction between the 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 (eg, 
cytochrome P450 [CYP] 4A inducers).  
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) are 
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. 
Fremanezumab is an immunoglobulin G2 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 a 
significant cytokine release (tumor necrosis factor-α, interleukin-6, interferon-γ, or 
interleukin-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 (documented hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy) or congenitally sterile 
• postmenopausal 
Postmenopausal women: 
• one year postmenopausal (no menses for 12 months without an alternative medical cause 
plus an increased concentration of follicle-stimulating hormone of more than 35 U/L) in 
women not using hormonal contraception or hormonal replacement therapy 
Description of different birth control methods 
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. 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 1st 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 1st dose of 
IMP 
• Intrauterine device and intrauterine hormone-releasing system need to be in place at least 
2 months before the screening visit (visit 1) 
• Bilateral tubal occlusion 
• 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 
Unacceptable birth control methods: 
Periodic abstinence (calendar, symptothermal, and post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and lactational amenorrhoea method are not acceptable methods 
of contraception. Female condom and male condom should not be used together. 
Male contraception 
Male patients that are not sterile and have female partners of childbearing potential should use 
highly effective birth control. 
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Appendix F. 
LOST TO FOLLOW-UP  
A patient will be considered lost to follow-up if he/she 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, 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 documented 
attempts via 2 different methods [telephone, text, email, certified letter, etc]). 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. 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 investigational medicinal product (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, the following: 
• suspected contamination 
• questionable stability (eg, color change, flaking, or crumbling) 
• defective components 
• missing or extra units (eg, the 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, 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 
clinical.productcomplaints@tevapharm.com 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 taken or used according to protocol (Yes/No) 
• description or nature of complaint 
• associated serious adverse event (Yes/No) 
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• 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 IMPs, 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 a 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 documents 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 H. DATA MANAGEMENT AND RECORD KEEPING  
Direct Access to Source Data and Documents 
All patient data must have supportive original source documents 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, Independent Ethics Committee/Institutional 
Review Board (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, or 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 
for the unambiguous identification of each patient. 
Data Collection 
Data will be collected using CRFs that are specifically designed for this study. The data collected 
in the CRFs will be captured in a clinical data management system (CDMS) that meets the 
technical requirements described in 21CFR Part 11 (United States of America) 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 in the CRF. 
If data are processed from other sources (eg, central laboratory, bioanalytical laboratory, central 
image center, electronic diary data, or 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 documents in the medical records, or equivalent, before they are transcribed to 
the CRF. Data may not be recorded directly in 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. 
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. 
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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 standard operating procedures (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 
(visit 8). 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) 
• safety reports 
• financial disclosure reports/forms 
• reports of receipt, use, and disposition of the IMPs 
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• 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 contract 
research organization 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 I. 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 J. INTERNATIONAL CLASSIFICATION OF HEADACHE 
DISORDERS, 3RD REVISION, DIAGNOSTIC CRITERIA  
For further details, refer to (IHS 2018) and/or CMAPS 2016. 
1.1 Migraine without aura 
a. at least 5 attacks fulfilling criteria b through d 
b. headache attacks lasting 4 to 72 hours (untreated or unsuccessfully treated) 
c. headache has at least 2 of the following 4 characteristics: 
− unilateral location 
− pulsating quality 
− moderate or severe pain intensity 
− aggravation by, or causing avoidance of, routine physical activity (eg, walking or 
climbing stairs) 
d. during headache, presence of at least one of the following: 
− nausea and/or vomiting 
− photophobia and phonophobia 
e. not better accounted for by another International Classification of Headache 
Disorders, 3rd revision [ICHD-3] diagnosis 
1.2 Migraine with aura 
a. at least 2 attacks fulfilling criteria b and c 
b. one or more of the following fully reversible aura symptoms: 
− visual 
− sensory 
− speech and/or language 
− motor 
− brainstem 
− retinal 
c. at least 2 of the following 4 characteristics: 
− at least 1 aura symptom spreads gradually over ≥5 minutes and/or 2 or more 
symptoms occur in succession 
− each individual aura symptom lasts 5 to 60 minutes 
− at least 1 aura symptom is unilateral 
− the aura is accompanied, or followed within 60 minutes, by headache  
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d. not better accounted for by another ICHD-3 diagnosis, and transient ischemic attack 
has been excluded 
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APPENDIX K. PREVENTIVE MIGRAINE MEDICATIONS ALLOWED 
FOR 30% OF THE STUDY POPULATION FOR THE 
DURATION OF THE STUDY  
The chronic use of up to 1 of the following concomitant medications is allowed in up to 30% of 
patients and should be entered in the electronic case report form (eCRF) pages specific for 
migraine preventive medication. Patients using up to 1 of the following migraine preventive 
medications for any condition at the time of study enrollment will be allowed to remain on the 
medication. Patients must have been on a stable, well-tolerated dose regimen of this medication 
for at least 2 months prior to screening (visit 1) and would be expected to remain on this 
medication for the duration of the study. For the remaining 70% of patients, the chronic use of 
the following medications are not allowed for migraine or for any other indications. PRN (ie, 
taken as needed) use of the following medications are allowed during the course of the study. 
PRN use of these medications should be reported in the eCRF as concomitant medications. 
Patients should be trained and should not report PRN use of these medications in the electronic 
headache diary. PRN use is defined as any treatment regimen outside of the prescribing 
information or local treatment guidelines. Patients will be allowed to use acute medications to 
treat acute migraine attacks as needed, with the exception of medications containing opioids and 
barbiturates. 
• beta-blockers: atenolol, propranolol, metoprolol, nadolol, and timolol 
• calcium channel blockers/benzocycloheptenes: flunarizine and pizotifen 
• antidepressants: amitriptyline, venlafaxine, nortriptyline, and duloxetine 
• anti-epileptic medications: topiramate, valproate, and divalproate 
• onabotulinumtoxinA 
Other agents that are not on this list but used for migraine prevention that may be used per local 
guidelines or clinical practice preference are considered to have questionable efficacy for 
migraine prevention and are therefore treated the same as other concomitant medications (ie, 
recorded as concomitant medications on the case report form) and DO NOT need to be captured 
in eCRF pages specific for migraine preventive medications. 
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Appendix L. 
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: 
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (eg, generalized hives, pruritus or flushing, and swollen 
lips-tongue-uvula) and at least one of the following: 
a. respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced peak 
expiratory flow [PEF], and hypoxemia) 
b. reduced blood pressure or associated symptoms of end-organ dysfunction 
(eg, hypotonia [collapse], syncope, and incontinence) 
2. 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, and swollen 
lips-tongue-uvula) 
b. respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF, 
and hypoxemia) 
c. reduced blood pressure or associated symptoms (eg, hypotonia [collapse], syncope, 
and incontinence) 
d. persistent gastrointestinal symptoms (eg, crampy abdominal pain and vomiting) 
3. 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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SAP_001.pdf: 
 
 
 
 
Statistical Analysis Plan 
 
 
A Randomized, Double-Blind, Placebo-Controlled Study with an Open-Label 
Period on Efficacy and Safety of Fremanezumab in Chinese Adults with Migraine 
 
 
Study Number TV48125-CNS-30088 
 
 
NCT05458011 
 
 
SAP Approval Date: 25 January 2024 


 
Placebo-Controlled Study–Migraine 
Statistical Analysis Plan 
Study TV48125-CNS-30088 
 
1 
 
  
STATISTICAL ANALYSIS PLAN 
Study TV48125-CNS-30088 with Protocol Amendment 02 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Efficacy and Safety Study 
with an Open-Label Treatment Period of Fremanezumab Administered Subcutaneously 
Monthly or Quarterly for the Preventive Treatment of Migraine in Adult Chinese Patients 
Phase 3 
 
IND number: Not applicable; NDA number: Not applicable;  
EudraCT number: Not applicable 
 
 
Approval Date: 25 January 2024 
 
 
Sponsor 
Teva Branded Pharmaceutical 
Products R&D, Inc. 
145 Brandywine Parkway 
West Chester, Pennsylvania 19380 
United States of America 
 
 
 
 
 
Prepared by: 
  
, Global Statistics and Data Sciences.  
 
  
, Global Statistics and Data Sciences.  
 
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STATISTICAL ANALYSIS PLAN APPROVAL 
 
Study No.: 
TV48125-CNS-30088  
 
Study Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Efficacy and 
Safety Study with an Open-Label Treatment Period of Fremanezumab Administered 
Subcutaneously Monthly or Quarterly for the Preventive Treatment of Migraine in Adult 
Chinese Patients 
 
Statistical Analysis Plan for:  
 
 Interim Analysis  
 
 Integrated Summary of Efficacy 
 
 Final Analysis 
 
 
 Integrated Summary of Safety 
 
Amendment: NA 
 
Author: 
      
 
 
 
 
, Global Statistics and Data Sciences    
  
, Global Statistics and Data Sciences. 
 
 
 
______________________________________________________________________________ 
Approver: 
      
 
 
                      Date 
, Global Statistics and Data Sciences 
 
 
 
___________________________________________________________________________ 
Approver: 
 
 
                         
 
Date 
 
 
Executed signature pages are maintained separately within the Trial Master File 
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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................................7 
INTRODUCTION ...........................................................................................................................9 
1. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................10 
1.1. 
Primary and Secondary Study Objectives and Endpoints ..........................................10 
1.2. 
Pharmacokinetic and Other Objectives and Endpoints ..............................................11 
2. 
STUDY DESIGN .......................................................................................................14 
2.1. 
General Design ...........................................................................................................14 
2.2. 
Randomization and Blinding ......................................................................................18 
2.3. 
Data Monitoring Committee .......................................................................................19 
2.4. 
Sample Size and Power Considerations .....................................................................19 
2.5. 
Sequence of Planned Analyses ...................................................................................19 
2.5.1. 
Planned Interim Analyses ...........................................................................................19 
2.5.2. 
Final Analyses and Reporting .....................................................................................20 
3. 
ANALYSIS SETS ......................................................................................................21 
3.1. 
Intent-to-Treat Analysis Set ........................................................................................21 
3.2. 
Modified Intent-to-Treat Analysis Sets ......................................................................21 
3.3. 
Safety Analysis Sets ...................................................................................................21 
3.4. 
Per-Protocol Analysis Set ...........................................................................................21 
4. 
GENERAL ISSUES FOR DATA ANALYSIS ..........................................................22 
4.1. 
General ........................................................................................................................22 
4.2. 
Specification of Baseline Values ................................................................................22 
4.3. 
Handling Withdrawals and Missing Data ...................................................................22 
4.4. 
Study Days and Visits .................................................................................................23 
5. 
STUDY POPULATION .............................................................................................24 
5.1. 
General ........................................................................................................................24 
5.2. 
Patient Disposition ......................................................................................................24 
5.3. 
Demographics and Baseline Characteristics ...............................................................24 
5.4. 
Medical History ..........................................................................................................24 
5.5. 
Prior Therapy and Medication ....................................................................................25 
5.6. 
Childbearing Potential and Methods of Contraception ..............................................25 
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5.7. 
Study Protocol Violations ...........................................................................................25 
6. 
EFFICACY ANALYSIS ............................................................................................26 
6.1. 
General ........................................................................................................................26 
6.2. 
Primary Efficacy Endpoint and Analysis ...................................................................28 
6.2.1. 
Primary Estimand .......................................................................................................28 
6.2.2. 
Primary Analysis of the Primary Estimand ................................................................29 
6.2.3. 
Sensitivity Analysis of the Primary Estimand ............................................................29 
6.2.3.1. 
MMRM Analysis ........................................................................................................29 
6.2.3.2. 
Analysis with Multiple Imputation Method ...............................................................30 
6.2.3.3. 
ANCOVA Analysis using Actual Stratification Factors ............................................31 
6.2.3.4. 
Analysis Split by Treatment Regimen Group .............................................................31 
6.2.4. 
Supplementary Estimands ..........................................................................................31 
6.2.5. 
Analysis of the Supplementary Estimands .................................................................33 
6.2.6. 
Sub-Group Analyses ...................................................................................................33 
6.3. 
Secondary Efficacy Endpoints and Analysis ..............................................................33 
6.3.1. 
Secondary Efficacy Estimands ...................................................................................33 
6.3.2. 
Analysis of Secondary Efficacy Estimands ................................................................34 
6.3.3. 
Supplementary Secondary Efficacy Estimands ..........................................................34 
6.3.4. 
Analysis of Supplementary Secondary Efficacy Estimands .......................................34 
6.4. 
Other Efficacy Endpoints and Analysis ......................................................................34 
6.4.1. 
Exploratory Efficacy Endpoints .................................................................................34 
6.4.2. 
Analysis of Exploratory Endpoints .............................................................................37 
7. 
MULTIPLE COMPARISONS AND MULTIPLICITY ............................................38 
8. 
SAFETY ANALYSIS ................................................................................................39 
8.1. 
General ........................................................................................................................39 
8.2. 
Duration of Exposure to Study Drug ..........................................................................39 
8.3. 
Adverse Events ...........................................................................................................39 
8.4. 
Deaths .........................................................................................................................40 
8.5. 
Clinical Laboratory Tests ...........................................................................................40 
8.5.1. 
Laboratory Values Meeting Hy’s Law Criteria ..........................................................44 
8.5.2. 
Other Clinical Laboratory Tests .................................................................................44 
8.5.2.1. 
Human Chorionic Gonadotropin Test ........................................................................44 
8.5.2.2. 
Follicle-Stimulating Hormone Test ............................................................................44 
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8.6. 
Physical Examinations ................................................................................................44 
8.7. 
Vital Signs ..................................................................................................................44 
8.8. 
Electrocardiography ....................................................................................................45 
8.9. 
Concomitant Medications or Therapies ......................................................................45 
8.10. 
Suicidality ...................................................................................................................46 
9. 
TOLERABILITY VARIABLES AND ANALYSIS..................................................47 
10. 
PHARMACOKINETIC ANALYSIS .........................................................................48 
11. 
IMMUNOGENICITY ANALYSIS ............................................................................49 
12. 
PLANNED INTERIM ANALYSES ..........................................................................50 
13. 
STATISTICAL SOFTWARE ....................................................................................51 
14. 
CHANGES TO ANALYSES SPECIFIED IN THE STUDY PROTOCOL ..............52 
15. 
REFERENCES ...........................................................................................................53 
APPENDIX A. ELECTRONIC HEADACHE DIARY QUESTIONNAIRE ............................54 
APPENDIX B. LOGICS FOR ENDPOINTS DERIVATION ...................................................56 
APPENDIX C. PATIENT’S GLOBAL IMPRESSION OF CHANGE (PGIC) SCALE ...........58 
APPENDIX D. EXAMPLE SAS CODE ....................................................................................59 
 
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LIST OF TABLES 
Table 1: Intercurrent Event Strategies: Primary Estimand ............................................................28 
Table 2: Intercurrent Event Strategies: 1st Supplementary Estimand ............................................31 
Table 3: Intercurrent Event Strategies: 2nd Supplementary Estimand ...........................................32 
Table 4: Intercurrent Event Strategies: 4thSupplementary Estimand ............................................33 
Table 5: Clinical Laboratory Tests ................................................................................................41 
Table 6: Criteria for Potentially Clinically Significant Laboratory Values ...................................43 
Table 7: Criteria for Potentially Clinically Significant Vital Signs ...............................................45 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS  
Abbreviation 
Term 
β-HCG 
beta-human chorionic gonadotropin 
ADA 
antidrug antibody 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil counts 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
BUN 
blood urea nitrogen 
CM 
chronic migraine 
CNS 
central nervous system 
CRF 
case report form 
CS 
compound symmetry 
CSR 
clinical study report 
ECG 
electrocardiography/electrocardiogram 
EM 
episodic migraine 
EOS 
end of study 
EOT 
end of treatment (visit) 
ET 
early termination 
FSH 
follicle-stimulating hormone 
GGT 
gamma glutamyl transpeptidase 
HDL 
high-density lipoprotein 
HGB 
hemoglobin 
ICE 
intercurrent event 
ICHD-3 
International Classification of Headache Disorders, 3rd revision 
IHS 
International Headache Society 
IMP 
investigational medicinal product 
INN 
international nonproprietary name 
INR 
international normalized ratio 
IRT 
interactive response technology 
ITT 
intent-to-treat 
LDH 
lactate dehydrogenase 
LDL 
low-density lipoprotein 
LS 
least square 
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Abbreviation 
Term 
MAR 
missing at random 
MedDRA 
medical dictionary for regulatory activities 
mITT 
modified intent-to-treat 
MMRM 
mixed-effects repeated measures 
MNAR 
missing not at random 
NSAID 
non-steroidal anti-inflammatory drug 
PD 
protocol deviations 
PGIC 
Patient Global Impression of Change 
PP 
per-protocol 
PT 
preferred term 
Q2 
quarter 2 
Q3 
quarter 3 
R&D 
Research and Development 
SAP 
statistical analysis plan 
SAS® 
Statistical Analysis System 
sc 
subcutaneous(ly) 
SD 
standard deviation 
SE 
standard error 
SOC 
system organ class 
SOP 
standard operating procedure 
ULN 
upper limit of normal 
US 
United States 
WBC 
white blood cell 
WHO 
World Health Organization 
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INTRODUCTION  
This Statistical Analysis Plan (SAP) describes the planned analysis and reporting for Teva 
Branded Pharmaceutical Products R&D, Inc. Study TV48125-CNS-30088, (A Multicenter, 
Randomized, Double-Blind, Placebo-Controlled Efficacy and Safety Study with an Open-Label 
Treatment Period of Fremanezumab Administered Subcutaneously Monthly or Quarterly for the 
Preventive Treatment of Migraine in Adult Chinese Patients), and was written in accordance 
with GSD-SOP-702 (Statistical Analysis Plan). 
The reader of this SAP is encouraged to read the study protocol for details on the conduct of this 
study, the operational aspects of clinical assessments, and the timing for completing the 
participation of a patient in this study.  
The SAP is intended to be in agreement with the protocol, especially with regards to the primary 
and all secondary endpoints and their respective analyses. However, the SAP may contain more 
details regarding these particular points of interest, or other types of analyses (eg, other 
endpoints). When differences exist in descriptions or explanations provided in the study protocol 
and this SAP, the SAP prevails; the differences will be explained in the Clinical Study Report 
(CSR). 
 
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1. 
STUDY OBJECTIVES AND ENDPOINTS  
1.1. 
Primary and Secondary Study Objectives and Endpoints  
Note that, for endpoints that are based on a monthly average, “baseline” refers to the monthly 
average value during the 28-day baseline period. 
The primary and secondary study objectives and endpoints are the following: 
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 Chinese patients 
with migraine. The primary efficacy 
analysis will consider all 
fremanezumab-treated patients as 
1 group. 
The primary endpoint is the mean change from baseline in 
the monthly average number of migraine days during the 
12-week period after the 1st dose of investigational medicinal 
product (IMP). 
The secondary objective of the study 
is to further demonstrate the efficacy of 
fremanezumab administered as 
monthly and quarterly sc injections to 
adult Chinese patients with migraine. 
The secondary efficacy analyses will 
consider all fremanezumab-treated 
patients as 1 group. 
The secondary endpoints are as follows: 
• 
mean change from baseline in the number of 
migraine days during the 4-week period after the 
1st dose of IMP 
• 
mean change from baseline in the monthly 
average number of days that any acute headache 
medications were used during the 12-week 
period after the 1st dose of IMP 
• 
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 IMP  
• 
mean change from baseline in the monthly 
average number of days with headache of at least 
moderate severity during the 12-week period 
after the 1st dose of IMP  
A secondary objective of the study is 
to evaluate the safety and tolerability 
of fremanezumab administered as 
monthly and quarterly sc injections to 
adult Chinese patients with migraine. 
The safety/tolerability endpoints are as follows: 
• 
occurrence of adverse events throughout the 
study 
• 
clinical laboratory (serum chemistry, 
hematology, coagulation, and urinalysis) test 
results at specified time points 
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Objectives 
Endpoints 
• 
vital signs (systolic and diastolic blood pressure, 
oral temperature, and pulse rate) measurements 
at each visit (Note: Oxygen saturation and 
respiratory rate will be measured in cases of 
suspected anaphylaxis and severe 
hypersensitivity.) 
• 
12-lead electrocardiogram (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 
• 
assessment of the immunogenicity of 
fremanezumab and the impact of antidrug 
antibodies (ADAs) on clinical outcomes in 
patients exposed to sc fremanezumab 
• 
assessment of the ADA incidence and 
characteristics (eg, titer, kinetics, and 
neutralizing activities) 
ADA=antidrug antibody; ECG=electrocardiogram; IMP=investigational medicinal product; sc=subcutaneous. 
1.2. 
Pharmacokinetic and Other Objectives and Endpoints  
Pharmacokinetic and other endpoints for the double-blind treatment period to address the 
objective to further characterize fremanezumab safety, efficacy, and pharmacokinetics are as 
follows:  
• assessment of plasma concentration of fremanezumab during the 12-week period after 
the 1st dose of investigational medicinal product (IMP) and at the follow-up visit 
using a population pharmacokinetic modeling approach 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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2. 
STUDY DESIGN  
2.1. 
General Design  
This is a multicenter, randomized, double-blind, placebo-controlled study with an open-label 
treatment period to evaluate the efficacy, safety, and tolerability of monthly and quarterly sc 
fremanezumab for the preventive treatment of migraine in adults. The study will consist of a 
screening visit, a baseline period (4 weeks), a 12-week double-blind treatment period, a 12-week 
open-label treatment period, and a follow-up period lasting approximately 3 months after the last 
dose of IMP (ie, 2 months after the end of treatment [EOT]/early termination [ET] visit). A 
follow-up visit 3 months after the last dose of fremanezumab will occur for ADA blood sample 
collection. 
The total duration of patient participation in the study is planned to be approximately 9 months. 
This study will include female and male patients, aged 18 to 70 years, inclusive, with a history of 
migraine (as defined by the International Classification of Headache Disorders, 3rd revision 
[ICHD-3] criteria [IHS 2018, CMAPS 2016]) for at least 12 months prior to screening and a 
prospectively documented diagnosis of migraine confirmed via a review of headache data 
recorded daily in an electronic headache diary device during a 28-day baseline period. 
Up to 30% of patients will be allowed to continue on a stable dose of 1 preventive migraine 
medication listed in the study protocol for migraine prevention or for other chronic conditions 
that they were using before screening (patients must have been taking a stable dose of these 
medications for at least 2 months of consecutive use prior to screening and do not expect to 
change dosing regimens or to change to another medication during the treatment phase of the 
study). Patients will be allowed to use acute medications to treat breakthrough migraines as 
needed, with the exception of medications containing opioids and barbiturates, which cannot be 
used on more than 4 days during the screening period for the treatment of migraine or for any 
other reason. Traditional Chinese therapy (including herbal medicine) and acupuncture are allowed 
if the patient is on a stable dose/regimen for at least 2 months (consecutive) before screening. 
After completing the informed consent process (screening visit [visit 1]), patients will be 
screened for eligibility. Eligible patients will enter a 28-day baseline period. Headache 
information will be captured daily during the screening/baseline period and treatment period 
using an electronic headache diary device. 
After completing the baseline period, patients will be asked to return to the study center on day 1 
(visit 2). Patients who have confirmed migraine and meet all other eligibility criteria (including 
electronic headache diary device compliance criteria during the 28-day baseline period) will be 
randomly assigned in a 1:1:2 ratio to 1 of 3 treatment groups: 
• fremanezumab 225 mg sc once a month (approximately every 4 weeks [28 days]), for 
a total of 3 doses; one 225 mg injection and 2 placebo injections at visit 2 and one 
225 mg injection at visits 3 and 4 
• fremanezumab 675 mg sc once a quarter (once at the beginning of the 12-week 
double-blind treatment period), for a total of 1 dose; three 225 mg injections at visit 2 
and 1 placebo injection at visits 3 and 4 or 
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• placebo sc once a month (approximately every 4 weeks [28 days]), for a total of 
3 doses; 3 placebo injections at visit 2 and 1 placebo injection at visits 3 and 4  
Patients must return to the study center after visit 2, visit 3, or visit 4 for 2 additional blood 
sampling visits to measure plasma fremanezumab concentration.  
During the 12-week open-label treatment period, patients will receive fremanezumab 225 mg sc 
once a month (approximately every 4 weeks) for a total of 3 doses (one 225 mg injection at 
visits 5, 6, and 7). 
At the end of the open-label treatment period (4 weeks after the last dose), an EOT study visit 
(visit 8) will be scheduled. Patients should return to the care of their treating physicians after 
visit 8. Patients should be treated with standard of care after withdrawal from or termination of 
the 24-week treatment period/study, as appropriate. 
(Note: For this study, monthly dosing refers to dosing approximately every 4 weeks [28 days].) 
Randomization using electronic interactive response technology (IRT) will be stratified based on 
migraine type (chronic migraine (CM) vs episodic migraine (EM)) and baseline preventive 
medication use (from protocol appendix K) to ensure balance.  Blinded treatment will be 
administered sc once monthly (ie, approximately every 4 weeks), for a total of 3 doses. First 
treatment administration will occur at visit 2 (day 1), and additional doses will be administered at 
visits 3 and 4. 
The Patient Global Impression of Change (PGIC) scale, safety evaluations, and blood draws for 
pharmacokinetic and immunogenicity analysis will be performed throughout the study according 
to the schedule of study procedures and assessments (see study protocol).  
Patients will have treatment evaluations performed at visit 8 (EOT visit), approximately 4 weeks 
after administration of the final dose of study drug. 
Follow-up visits for ADA sample collection will occur approximately 1 month and 3 months 
after the last dose of study drug (visit 7), at the EOT/ET visit (visit 8) and at the end of study 
visit (visit 9), respectively. 
Patients who discontinue treatment prematurely should be encouraged to continue to attend the 
regular scheduled visits and complete the prescribed safety and efficacy evaluations through the 
EOT/ET visit and the follow-up visit, if at all possible. 
Patients who both discontinue treatment and also withdraw from the study should have EOT/ET 
visit procedures/assessments (see study protocol) performed on the last day that the patient 
receives the IMP or as soon as possible thereafter. The patient should also return for the follow-
up visit approximately 3 months after the last dose of IMP if at all possible. 
The end of study is defined as the last visit of the last patient (follow-up visit, visit 9). Two 
interim analyses are planned. The first 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 
(visit 5). A second interim database lock will occur following the end of the open-label period 
(visit 8). Final database lock will occur following the end of the follow-up period (visit 9).  
Following the first interim database lock, efficacy data from this period will not change but 
certain safety data may be updated to allow subsequent information to be added, eg. stop date, 
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outcome and action taken for study drug for adverse events and end date/ongoing for 
concomitant medications. 
Study procedures and assessments with their timing are summarized in Table 3 of the study 
protocol. The study schematic diagram is shown in Figure 1. 
In the event of a public health emergency, the investigational center will inform the patient of the 
safeguards being taken and will discuss their willingness or feasibility to come to the site for 
upcoming visits. If an ongoing patient cannot go to the site, the Medical Monitor will be notified 
to discuss further plans for that patient. 
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Figure 1: Overall Study Schematic Diagram  
 
ADA=antidrug antibody; IMP=investigational medicinal product; N=planned number of patients in the study population; sc=subcutaneous; V=visit. 
Note: Blood samples for plasma drug concentration will be collected at visits 2, 3, and 4. Patients will be asked to return to the study center after visit 2, visit 3, 
or visit 4 for 2 additional blood sampling visits to measure plasma fremanezumab concentration (one being 3 to 10 days after either visit 2, visit 3, or visit 4 and 
the other being 15 to 20 days after either visit 2, visit 3, or visit 4). If 2 additional visits are not possible for the patient, then the patient must return for only 
1 additional pharmacokinetic blood sampling at either of the aforementioned time points. When patients return to the study center for additional blood 
sampling, then inquiries about adverse events and concomitant medications will be performed.
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2.2. 
Randomization and Blinding  
After the 28-day baseline period, the next 12 weeks of the study will be double-blind. Patients 
and investigators will remain blinded to IMP assignment during this double-blind period. This 
will be followed by a 12-week open-label period.  
A computer-generated master randomization list will be provided to drug packaging facilities. 
The packaging vendor(s) will package the active IMP and placebo each into single-visit kits 
according to Good Manufacturing Practice procedures. Kits will be identical in appearance, and 
each will contain 1 prefilled syringe with either active IMP or placebo. Kits will be administered 
at each dosing visit as specified in the study protocol. 
Patients will be stratified based on migraine type (CM vs EM) and baseline preventive 
medication use. Patients will be randomly assigned to treatment groups by means of a computer-
generated randomization list using electronic IRT. This system is used to ensure a balance across 
treatment groups. The specifications for randomization will be under the responsibility and 
oversight of Teva Global Statistics. 
At visit 2 (day 1), patients will be randomized in a 1:1:2 ratio within the appropriate stratum to 
1 of 3 treatment groups, as assigned by the IRT: 
• fremanezumab 225 mg sc once a month (approximately every 4 weeks), for a total of 
3 doses; one 225 mg injection and 2 placebo injections at visit 2 and one 225 mg 
injection at visits 3 and 4  
• fremanezumab 675 mg sc once a quarter (once at the beginning of the 12-week 
double-blind treatment period), for a total of 1 dose; three 225 mg injections at visit 2 
and 1 placebo injection at visits 3 and 4 or 
• placebo sc once a month (approximately every 4 weeks), for a total of 3 doses; 
3 placebo injections at visit 2 and 1 placebo injection at visits 3 and 4  
The placebo will contain the same vehicle and excipients as those for the active injection. 
In the open-label extension phase starting at week 12, all patients will receive active treatment 
with a monthly dose of 225 mg sc fremanezumab. 
The IRT will manage the initial drug supply, maintenance of adequate study drug supplies on 
site, and study randomization centrally. At the time of each study visit when the study drug is 
administered, the IRT will be queried, and the site personnel will retrieve the study drug from 
refrigerated storage and will administer a 1.5 mL volume from each syringe contained in the 
appropriately numbered kit(s). 
The sponsor’s clinical personnel (and delegates) involved in the study will be blinded to the 
identity of the IMPs until the database is locked for analysis and the IMP assignment is known.  
In the event of an emergency, it will be possible to determine to which treatment group the 
patient has been allocated by accessing the IRT system. All investigational centers will be 
provided with details on how to access the system for code breaking at the start of the study. The 
medical monitor or equivalent should be notified following unblinding. Any unblinding of the 
IMP performed by the investigator must be recorded in the source documents. 
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The randomization list will be assigned to the relevant treatment groups through a qualified 
service provider, eg, via the IRT system. The generation of the randomization list and the 
management of the IRT system will be done by a qualified service provider under the oversight 
of the responsible function at Teva. 
2.3. 
Data Monitoring Committee  
There will be no Data Monitoring Committee/Data and Safety Monitoring Board in this study.  
2.4. 
Sample Size and Power Considerations  
Using study data from 2 completed Phase 3 US pivotal studies in migraine, it is estimated that 
163 completers per treatment group (ie, combined fremanezumab groups and placebo group) will 
provide at least 90% power to detect the assumed treatment difference at a significance level 
of 0.05. Assuming a 12% discontinuation rate, approximately 372 patients will be randomized in 
this study (93 patients in each fremanezumab treatment group and 186 patients in the placebo 
group). The primary efficacy analysis will consider all fremanezumab-treated patients as 
1 group. 
 
 
 
 
 
 
 
 
 
To ensure adequate representation of patients with both migraine types (EM and CM), the 
enrollment minimum of either migraine type is 30%. In addition, primary efficacy analysis will 
be stratified by EM and CM, and subgroup analysis for EM and CM will be conducted.  
2.5. 
Sequence of Planned Analyses  
2.5.1. 
Planned Interim Analyses  
Two interim analyses are planned. The first interim analysis is planned when the last patient has 
completed the double-blind period. At this point, the study will be unblinded and an analysis of 
the double-blind period data performed.  A second interim analysis is planned following the end 
of the open-label period. 
The inferential analysis of efficacy variables for comparison between the fremanezumab 
treatment group (monthly dose and quarterly dose combined) and placebo applies only to the 
double-blind portion of the study, and will be conducted at the time of the first interim lock.   
Type 1 error control, as specified in Section 7 , applies only to the double-blind portion of the 
study. 
Efficacy analysis after the 1st interim, which is the open label portion of the study, is considered 
exploratory and descriptive. This analysis will be done at the time of the second database lock. 
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2.5.2. 
Final Analyses and Reporting  
All analyses identified in this SAP will be performed after the first interim database lock (at the 
end of the double-blind period) and after the second interim database lock (at the end of the 
open-label period) of this study. A final safety analysis will take place after the end of study as 
defined in the study protocol.  
This SAP and any corresponding amendments will be approved before database lock, in 
accordance to GSD-SOP-702 (Statistical Analysis Plan). 
The randomization codes will not be unblinded until this SAP has been approved and issued. 
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3. 
ANALYSIS SETS  
3.1. 
 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. 
3.2. 
Modified Intent-to-Treat Analysis Sets  
The double-blind 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 IMP and have at least 10 days of post 
baseline efficacy assessment on the primary endpoint. The double-blind mITT analysis set will 
be used for the primary estimand analysis and all of its sensitivity analyses.  The open-label 
mITT analysis set is a subset of the ITT analysis set including only patients who receive at least 
1 dose of IMP during the open-label treatment period and have at least 10 days of post baseline 
diary entries during the open-label treatment period. 
In the mITT analysis sets, treatment will be assigned based on the treatment to which patients 
were randomized, regardless of which treatment they actually received.  
3.3. 
Safety Analysis Sets  
The double-blind safety analysis set will include all randomized patients who receive at least 1 
dose of IMP during the double-blind treatment period. The open-label safety analysis set will 
include all patients who receive at least 1 dose of IMP during the open-label treatment period.  
In the safety analysis sets, treatment will be assigned based on the treatment patients actually 
received, regardless of the treatment to which they were randomized. 
3.4. 
Per-Protocol Analysis Set  
The per-protocol (PP) analysis set is a subset of the double-blind mITT analysis set including 
only patients without important deviations such as important inclusion/exclusion criteria 
deviations or any important deviations or omissions of the IMP 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. Patients with less than 75% diary compliance during 
the double-blind treatment period will be excluded from the PP analysis set. Patients who 
received study drug different from the study drug they were randomized to will be excluded from 
the PP analysis set. A blinded data review meeting will be conducted prior to the first interim 
database lock in order to determine the exclusion of the patients from the PP analysis set. 
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4. 
 GENERAL ISSUES FOR DATA ANALYSIS   
4.1. 
General  
Descriptive statistics for continuous variables include n, mean, standard deviation (SD), standard 
error (SE), median, minimum, and maximum. Descriptive statistics for categorical variables 
include patient counts and percentages; missing categories will be displayed as appropriate. 
Data collected at the follow-up visit (visit 9) will be listed only. 
4.2. 
Specification of Baseline Values  
Patients will complete electronic headache diary entries daily for the 28-day run-in period, 
subjectively rating their headaches as mild, moderate, or severe and enter headache information 
about the previous day into the electronic headache diary device. If the run-in period is greater or 
less than 28 days, the baseline values for calculating the change from baseline of the monthly 
values of the efficacy variables will be prorated to 28 days.  
The efficacy baseline values during the 28-day run-in period derived from the electronic 
headache diary device include 
• total number of migraine days 
• total number of days of use of any acute headache medications (as collected in the 
daily diary ie. in addition to randomized treatment) 
• total number of headache days of at least moderate severity 
• total number of headache days of any severity 
• total number of headache hours of at least moderate severity 
• total number of days with nausea or vomiting 
• total number of days with photophobia and phonophobia 
• total number of days of use of migraine-specific acute headache medications (triptans 
and ergot compounds)  
Otherwise baseline value will be the last non-missing value prior to the 1st dose of study drug, 
unless otherwise noted. 
4.3. 
Handling Withdrawals and Missing Data  
If a patient has ≥10 days of electronic headache diary data after the 1st dose of the study drug, 
his/her monthly average number of days/hours of efficacy variables during the 12-week double 
blind period will be prorated to 28 days.  Similarly, if a patient has ≥10 days of electronic 
headache diary data after the 4th dose of the study drug, his/her monthly average number of 
days/hours of efficacy variables during the 12-week open label period will be prorated to 28 
days.  
Patients who have <10 days of electronic headache diary data for the primary endpoint during 
the double blind period will be excluded from the double blind mITT analysis set.  Patients who 
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have <10 days of electronic headache diary data during the open label period will be excluded 
from the open label mITT analysis set. 
A patient’s monthly number of days of efficacy variables during the 4-week period after each 
dose of study drug will be calculated.  If a patient has missing diary days in a month, the 
following method will be used to handle the missing data.  
• If the patient has 10 or more days of electronic headache diary data for a month, the 
monthly number of days/hours of efficacy variables will be prorated to 28 days for 
that month.  
• If the patient has less than 10 days of electronic headache diary data for a month, the 
monthly number of days/hours of efficacy variables will be considered as missing.   
A sensitivity analysis will be performed to assess the primary estimand using mixed-effects 
model for repeated measures (MMRM) as a different missing data handling approach. The 
methods will be described in detail in Section 6.2.3.1. 
Multiple imputation (MI) method will be applied on the primary variable as sensitivity analyses. 
The methods will be described in detail in Section 6.2.3.2.  
4.4. 
Study Days and Visits  
Study days will be numbered relative to the 1st day of study drug administration. The start of 
treatment (visit 2 or day 1) is defined as the date on which a patient takes the 1st dose of study 
drug, as recorded on the study drug administration case report form (CRF). Days will be 
numbered relative to study drug start (ie, ..., –2, –1, 1, 2, ...; with day 1 being the start of study 
drug and day –1 being the day before the start of study drug). 
The 4-week (28-day) visit windows for the electronic headache diary device efficacy endpoints 
will be determined based on the actual dosing day. The run-in phase is defined as day -28 to -1 
before the 1st injection on day 1. The 4-week period after the 1st dose of IMP is from the 
beginning of the 1st injection of study drug to just before the 2nd dose at visit 3/day 28. The 12-
week double-blind treatment period is from the beginning of the 1st injection of study drug to just 
before the 4th dose at visit 5/day 84. The 12-week open-label treatment period is from the 4th 
injection of study drug on visit 5/day 85 to just before the 7th dose at visit 8/day 168 or the end of 
treatment visit. The follow-up period lasting 3 months after the last dose of IMP is from visit 
8/day 169 to visit 9/day 224 or the end of study visit.  Throughout this document, all by month 
efficacy summaries for the headache data will refer to these visit windows.   If the Month 2, 3, 4, 
5, 6 or 7 dosing day is missed, then the dosing day is considered to be previous dosing day +28 
days. For all by-visit summaries, if there are multiple assessments at a postbaseline visit then the 
last non-missing assessment at that visit will be used for the summary. This includes assessments 
at the scheduled and unscheduled visits.  
Unless otherwise stated, Last Assessment for summaries is the last observed postbaseline data. 
For patients who withdraw from the study, data at the early termination visit will be excluded 
from the by-visit summaries but will be included in the Last Assessment summaries.  
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5. 
STUDY POPULATION  
5.1. 
General  
The ITT analysis set will be used for all study population summaries unless otherwise specified. 
Summaries will be presented by migraine classification (ie, CM, EM, and all), treatment group, 
all fremanezumab and for all patients. Study population data will also be listed. 
For continuous variables, descriptive statistics (n, mean, SD, SE, 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.  
5.2. 
Patient Disposition  
Data from patients screened; patients screened but not randomized and reason for not being 
randomized will be summarized only for the overall group using patient counts.  
Patients randomized (ie. ITT analysis set); patients randomized but not treated; patients in the  
double-blind mITT, double-blind safety, and PP analysis sets; reasons for exclusion from the PP 
analysis set, patients who complete the double-blind IMP; and patients who discontinue the 
double-blind IMP (including reason for discontinuation) will be summarized using descriptive 
statistics. Data from patients who discontinue the double-blind IMP will also be summarized by 
reason for withdrawal using descriptive statistics.  Patients in the open-label mITT and the open-
label safety analysis sets, reason for discontinuation from open-label treatment, reason for 
discontinuation from the study and patients who complete the study will also be summarized. 
The denominator for calculating the percentages will be the number of patients in the ITT 
analysis set.  
5.3. 
Demographics and Baseline Characteristics  
Patient demographic and baseline characteristics, including date of birth, age, ethnicity, race, sex, 
weight, height, body mass index, preventive medication use, time since initial migraine 
diagnosis, migraine classification (CM or EM), triptans/ergots use during baseline, migraine with 
aura, and ECG findings, will be examined to assess the comparability of the treatment groups 
and will be summarized using descriptive statistics. Categories for missing data will be presented 
if necessary. 
The baseline electronic headache diary device efficacy variables will be summarized.  
5.4. 
Medical History  
All medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) version 26.0 or higher. The incidence of medical history abnormalities will be 
summarized using descriptive statistics by system organ class (SOC) and preferred term (PT). 
Patients are counted only once in each PT and SOC category. Summaries will be presented by 
treatment group and for all patients. 
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5.5. 
Prior Therapy and Medication  
Any prior therapy, medication, or procedure a patient has had before study drug administration 
(ie, procedures for the treatment of migraine [eg, nerve blocks]) a patient has had within 6 
months before study drug administration and preventive medications taken within 10 years) will 
be recorded on the CRF. Trade name or international nonproprietary name (INN), indication, and 
dosage will be recorded. The sponsor will encode all therapy and medication according to the 
World Health Organization (WHO) drug dictionary (WHODrug) version 2023MAR01DDE or 
higher. 
Details regarding excluded prior medications, including preventive migraine treatments, are 
described in the exclusion criteria in the study protocol. 
The incidence of prior therapies and medications will be listed by double-blind treatment group 
and summarized using descriptive statistics by therapeutic class and PT. Patients are counted 
only once in each therapeutic class category, and only once in each PT category. Prior therapies 
and medications will include all medications taken and therapies administered before the 1st day 
of study drug administration. 
The prior medications will also be summarized for the following categories: 
• butalbital for migraine/headache 
• ergots for migraine/headache 
• non-steroidal anti-inflammatory drugs (NSAIDs) for migraine/headache 
• NSAIDs for other reason than migraine/headache 
• opioids for migraine/headache  
• opioids for reasons other reason than migraine/headache  
• preventive medication from protocol Appendix K for migraine/headache 
• preventive medication from protocol Appendix K for other reason than 
migraine/headache 
• triptans for migraine/headache  
5.6. 
Childbearing Potential and Methods of Contraception  
For female patients, information related to childbearing potential, and menopause will be 
collected and listed.  
For female and male patients, methods of contraception will be collected and listed.  
5.7. 
 Study Protocol Violations   
Protocol deviations (PD) will be collected and reviewed by the study team prior to database lock 
and will be provided in a data listing. Patients with at least 1 important PD will be summarized 
for each category using descriptive statistics. 
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6. 
EFFICACY ANALYSIS  
6.1. 
General  
For the purposes of this study;  
• CM is defined as headache occurring on ≥15 days during the screening period. 
• EM is defined as headache occurring on <15 days during the screening period.  
All e-diary data collected during the screening period, regardless of the duration beyond 28 days 
(e.g., 30 days), will be included and analyzed. There will be no exclusion of any e-diary data 
during the screening period.  
A migraine day is endorsed when at least one of the following situations occurs:  
• A calendar day (0:00 to 23:59) demonstrating at least 2 consecutive hours of a 
headache meeting the criteria for migraine with or without aura 
• A calendar day (0:00 to 23:59) demonstrating at least 2 consecutive hours of a 
headache meeting the criteria for probable migraine, a migraine subtype where only 
1 migraine criterion is missing 
• A calendar day (0:00 to 23:59) demonstrating a headache of any duration that was 
treated with migraine-specific medications (triptans and ergot compounds) 
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 2 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) 
The derivation logic for both migraine day and headache day of at least moderate severity is 
presented in Appendix B.   
In addition, a headache day of any severity is endorsed when at least 1 of the following situations 
occurs:  
• a calendar day (00:00 to 23:59) demonstrating at least 2 consecutive hours of 
headache of any 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) 
The endpoint of headache hours of at least moderate severity is obtained directly from the 
corresponding electronic headache diary device question (Question A5).  
The endpoint of days of use of any acute headache medication is obtained directly from the 
corresponding electronic headache diary device questions (Question C1=Yes or C3=Yes and C2 
has a medication present).   
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The endpoint of days of use of migraine specific acute medications (triptans and ergot 
compounds) is obtained directly from the electronic headache diary device question where 
Question C1=Yes and C2=ergot or triptan.   
Other efficacy variables (days with nausea or vomiting, days with photophobia and 
phonophobia) will be derived using the e-diary data collected through the corresponding 
headache diary questions which can be found in Appendix A. 
Patient satisfaction is measured by the PGIC scale which is a validated generic tool for the 
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.  
Based on the PGIC assessment, a dichotomous scale of “Yes” or “No” will be derived. A 
favorable change is score of 5-7 = ’Yes’, which means there is significant improvement with the 
treatment. If the response is 1-4 = ’No’, it is considered no significant change. 
 
The monthly average number of days or hours of efficacy variables (eg, migraine days, days of 
headache with at least moderate severity, days of headache with any severity, total hours of 
headache with at least moderate severity, days of use of any acute headache medications, days 
with nausea or vomiting, days with photophobia and phonophobia, days of use of migraine-
specific acute headache medications (triptans and ergot compounds) during the 12-week double-
blind period after the 1st dose of study drug and during the 12-week open-label period after the 
4th dose of study drug will be derived and prorated to 28 days equivalent using the following 
formula.  
∑𝐷𝑎𝑦𝑠 𝑜𝑓 𝑒𝑓𝑓𝑖𝑐𝑎𝑐𝑦 𝑣𝑎𝑟𝑖𝑎𝑏𝑙𝑒 𝑜𝑣𝑒𝑟 𝑡ℎ𝑒 12 𝑤𝑒𝑒𝑘 𝑝𝑒𝑟𝑖𝑜𝑑  
∑𝐷𝑎𝑦𝑠 𝑤𝑖𝑡ℎ 𝑎𝑠𝑠𝑒𝑠𝑠𝑚𝑒𝑛𝑡𝑠 𝑟𝑒𝑐𝑜𝑟𝑑𝑒𝑑 𝑖𝑛 𝑡ℎ𝑒 𝑒𝐷𝑖𝑎𝑟𝑦 𝑓𝑜𝑟 𝑡ℎ𝑒 12 𝑤𝑒𝑒𝑘 𝑝𝑒𝑟𝑖𝑜𝑑 ×  28   (1) 
The monthly number of days or hours of efficacy variables during the 4-week double-blind 
period after the 1st dose of study drug and during the 4-week open-label period after the 4th dose 
of study drug will be derived and prorated to 28 days equivalent using the following formula.  
 
∑𝐷𝑎𝑦𝑠 𝑜𝑓 𝑒𝑓𝑓𝑖𝑐𝑎𝑐𝑦 𝑣𝑎𝑟𝑖𝑎𝑏𝑙𝑒 𝑑𝑢𝑟𝑖𝑛𝑔 𝑡ℎ𝑒 4 𝑤𝑒𝑒𝑘 𝑝𝑒𝑟𝑖𝑜𝑑  
∑𝐷𝑎𝑦𝑠 𝑤𝑖𝑡ℎ 𝑎𝑠𝑠𝑒𝑠𝑠𝑚𝑒𝑛𝑡𝑠 𝑟𝑒𝑐𝑜𝑟𝑑𝑒𝑑 𝑖𝑛 𝑡ℎ𝑒 𝑒𝐷𝑖𝑎𝑟𝑦 𝑓𝑜𝑟 𝑡ℎ𝑒 4 𝑤𝑒𝑒𝑘 𝑝𝑒𝑟𝑖𝑜𝑑  ×  28    (2) 
Formula (2) will also be used for the variables during the 4-week period after each dose for 
months 1, 2, and 3 used in the sensitivity analysis for the primary estimand. 
The baseline values will be calculated using all data collected in the run-in period and will be 
derived and prorated to 28 days equivalent using the following formula.  
∑𝐷𝑎𝑦𝑠 𝑜𝑓 𝑒𝑓𝑓𝑖𝑐𝑎𝑐𝑦 𝑣𝑎𝑟𝑖𝑎𝑏𝑙𝑒 𝑑𝑢𝑟𝑖𝑛𝑔 𝑡ℎ𝑒 𝑟𝑢𝑛−𝑖𝑛 𝑝𝑒𝑟𝑖𝑜𝑑  
∑𝐷𝑎𝑦𝑠 𝑤𝑖𝑡ℎ 𝑎𝑠𝑠𝑒𝑠𝑠𝑚𝑒𝑛𝑡𝑠 𝑟𝑒𝑐𝑜𝑟𝑑𝑒𝑑 𝑖𝑛 𝑡ℎ𝑒 𝑒𝐷𝑖𝑎𝑟𝑦 𝑓𝑜𝑟 𝑡ℎ𝑒 𝑟𝑢𝑛−𝑖𝑛 𝑝𝑒𝑟𝑖𝑜𝑑  ×  28   (3) 
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The percentage of reduction in the monthly average number of an efficacy variable will be 
calculated as  
𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒 𝑣𝑎𝑙𝑢𝑒−𝑝𝑜𝑠𝑡𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒 𝑣𝑎𝑙𝑢𝑒
𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒 𝑣𝑎𝑙𝑢𝑒
× 100%   (4) 
where the baseline value is calculated by formula (3) and the postbaseline value in the equation 
is calculated by formula (1) for the variables during the 12-week double-blind period or 12-
week open-label period or by formula (2) for the variables during the 4-week double-blind 
period after 1st dose of study drug or the 4-week open-label period after 4th dose of study drug.  
For the endpoints relating to a percentage reduction the patient is considered as a responder 
reaching 50%, 75%, or 100% reduction if the percent reduction in the efficacy variable as 
calculate by formula (4) is 50% or more, 75% or more, or 100% respectively. If a patient is early 
discontinued from the study, he/she will be counted as a non-responder.   
Summaries will be presented by treatment group in the double-blind period for both the interim 
analysis at the end of the double-blind period and for the interim analysis at the end of the open-
label period. There will be a column for placebo and a column for all fremanezumab-treated 
patients unless otherwise noted. Descriptive statistics for all efficacy data will be presented by-
month over the 12-week period after the 1st dose of study drug for the first interim analysis and 
presented by-month over the 12-week period after the 4th dose of study drug for the second 
interim analysis. 
The mITT analysis sets will be used for all efficacy analyses unless otherwise noted. As 
randomized stratification factors will be used for all relevant analyses unless otherwise noted. 
Summaries will be presented by treatment group as randomized, unless otherwise noted.  
6.2. 
Primary Efficacy Endpoint and Analysis  
6.2.1. 
Primary Estimand  
The primary estimand will be the difference in adjusted means between fremanezumab group 
and placebo group in the population that comprises the patients in the double-blind mITT 
analysis set for the change from baseline in the monthly average number of migraine days during 
the 12-week period after the 1st dose of IMP. The intercurrent events (ICEs) that may affect the 
efficacy endpoint will be handled as per Table 1. 
Table 1: Intercurrent Event Strategies: Primary Estimand  
Intercurrent event 
Strategy 
Patient early terminates from the IMP 
Treatment policy1 
Patient receives the wrong IMP due to 
medication errors 
Treatment policy1 
Patient receives a rescue medication due to 
worsening symptoms 
Treatment policy1 
1Treatment policy: if observations are collected after the occurrences of the ICEs, the observations will be included 
in the calculation of the primary endpoint for the primary analysis. 
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The baseline values will be derived using formula (3). The post baseline values will be derived 
using formula (1), and the change is calculated as postbaseline – baseline value. 
6.2.2. 
Primary Analysis of the Primary Estimand  
The hypothesis testing for the primary analysis is: 
 
where 
 and 
 are the parameters of mean change from baseline in the monthly average 
number of migraine days during the 12-week period after the 1st dose of IMP for the combined 
TEV-48125 treatment groups and the placebo group respectively. 
An analysis of covariance (ANCOVA) will be performed, including treatment (combined TEV-
48125 groups vs. placebo) and stratification factors (as randomized) of migraine type (CM vs 
EM) and baseline preventive medication use (yes vs no) as fixed factors, as well as baseline 
number of migraine days as a covariate in the model. For the individual treatment groups 
(combined TEV-48125 groups and placebo) the least square (LS) mean, standard error (SE) and 
corresponding 95% confidence interval will be presented. For the treatment difference 
(combined TEV-48125 groups - placebo) the LS mean, SE, corresponding 95% confidence 
interval and p-value for comparison will be presented. 
The statistical test will be two-sided at the alpha = 0.05 level of significance. Model fitting 
assumptions will be investigated.  
Example SAS code is provided in Appendix D. 
A hierarchical procedure will be used to control the type 1 error rate, as described in Section 7 .  
6.2.3. 
Sensitivity Analysis of the Primary Estimand  
6.2.3.1. 
MMRM Analysis  
The sensitivity of the primary analysis to missing data will be assessed using mixed-effects 
model for repeated measures (MMRM) via restricted maximum likelihood estimation and 
assuming a missing at random (MAR) mechanism. 
Each patient’s monthly number of migraine days during the 4-week period for month 1, month 2 
and month 3 will be calculated by formula (2) in Section 6.1 based on the electronic headache 
diary device responses for that month. If a patient is early terminated or has intermittent missing 
days (ie. fewer than 10 days of electronic headache diary entries for a month), that month’s value 
will be considered as missing as described in Section 4.3. 
The model will include treatment, month and stratification factors of migraine type (CM vs EM) 
and baseline preventive medication (yes vs no) use as fixed factors and treatment-by-month 
interaction effects, and baseline number of migraine days as a covariate. Patient will be included 
in the repeated statement as a random effect.   The unstructured covariance model will be used 
for repeated observations within patients. If the model does not converge, then simpler 
covariance structures with fewer parameters will be used: heterogeneous autoregressive (1), 
heterogeneous compound symmetry, autoregressive (1), and compound symmetry, and the 
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variance covariance structure which minimizes the Akaike’s information criterion (AIC) will be 
selected. 
The 12-week monthly average number of migraine days will be estimated by the LS means of 
the overall treatment effect over 3 months for each treatment group (combined TEV-48125 
groups and placebo) along with SE and 95% confidence interval, and the LS means will be 
calculated for the treatment difference (combined TEV-48125 groups - placebo) along with SE, 
95% confidence interval and nominal p-value. These calculations will be done by month as well 
as for the overall double-blind treatment period.  
The LS means ±SE of monthly change from baseline values estimated by MMRM will be plotted 
by month for each treatment group.  
Example SAS code is provided in Appendix D. 
In addition, a further MMRM analysis will also be performed to examine the sensitivity of the 
statistical inferences against departure from the assumption of time-independent effect of 
baseline number of migraine days.  The model will be the same as that above, but will include a 
time-by-baseline interaction along with baseline as a continuous covariate.  Therefore the model 
will include the fixed categorical effects of treatment, month, stratification factors of migraine 
type (CM vs EM) and baseline preventive medication (yes vs no) and treatment-by-month 
interaction, as well as the continuous, fixed covariates of baseline number of migraine days and 
baseline number of migraine days-by-month interaction.  Example SAS code is provided in 
Appendix D.  
6.2.3.2. 
Analysis with Multiple Imputation Method  
Multiple imputation (MI) method will be applied to impute the monthly missing data assuming a 
missing not at random (MNAR) mechanism. The data will be processed by the following steps. 
• If a patient has <10 days of electronic headache diary device data in a month, that 
month's value will be considered missing before the MI procedure.  
• For the patients in the active treatment groups who are early terminated with reasons 
of treatment-related adverse event or lack of efficacy, they will be assigned to placebo 
group so their missing values will be imputed using data from the placebo treated 
patients. 
• Run SAS PROC MI procedure to create 100 complete datasets.  
• Within each imputed data set, for a patient who has partial, say X days (X<28), 
electronic headache diary device data in a month, the monthly value will be replaced 
by ∑(𝑜𝑏𝑒𝑟𝑠𝑒𝑣𝑒𝑑 𝑚𝑖𝑔𝑟𝑎𝑖𝑛𝑒 𝑑𝑎𝑦𝑠 ) + (28 −𝑋) ∗𝑖𝑚𝑝𝑢𝑡𝑒𝑑 𝑣𝑎𝑙𝑢𝑒/28  
• The monthly average number of migraine days during the 12-week period after the 
1st dose of study drug will be the average of month 1, month 2, and month 3 values.  
Each dataset will be analyzed using the same ANCOVA model as described in Section 6.2.2. 
The LS means and standard errors from each analysis will be output to a SAS data set. SAS 
MIANALYZE procedure will be used to generate the final LS means (±SE) for the treatment 
groups and the treatment difference (TEV-48125 - placebo) as well as p-values associated with 
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treatment differences. The 95% confidence intervals for the treatment difference will also be 
constructed. 
The output dataset will contain the estimate of the mean difference and the standard error of the 
estimate from each of the 100 datasets.  SAS procedure, PROC MIANALYZE, will be used to 
generate an overall p-value and 95% CI for the treatment difference.   
This sensitivity analysis will be performed on the ITT analysis set.  
Example SAS code is provided in Appendix D.  
6.2.3.3. 
ANCOVA Analysis using Actual Stratification Factors  
The primary ANCOVA analysis will be repeated as a sensitivity analysis using the actual 
stratification factors in the model. This sensitivity analysis will be performed on the double-blind 
mITT analysis set. 
6.2.3.4. 
Analysis Split by Treatment Regimen Group  
A sensitivity analysis will be performed on the primary estimand to assess the sensitivity of the 
analysis to treatment regimen. This analysis will be identical to the primary analysis but where 
the two fremanezumab treated groups will be presented separately. The columns will be placebo, 
TEV-48125 225 mg monthly and TEV-48125 675 mg quarterly and the treatment comparisons 
will be TEV-48125 225 mg monthly – placebo and TEV-48125 675 mg quarterly – placebo. For 
both the individual treatment groups and the treatment comparisons the LS mean, SE and 
corresponding 95% confidence interval will be presented. No p-values will be presented for this 
additional analysis. 
6.2.4. 
Supplementary Estimands  
A supplementary estimand will estimate treatment effect in the hypothetical scenario where no 
one early terminates from study drug. The estimand is the difference in adjusted means between 
fremanezumab group and placebo group in the population that comprises the patients in the 
double-blind mITT  analysis set for the change from baseline in the monthly average number of 
migraine days during the 12-week period after the 1st dose of IMP where the ICEs are handled as 
per Table 2. 
Table 2: Intercurrent Event Strategies: 1st Supplementary Estimand  
Intercurrent event 
Strategy 
Patient early terminates from the IMP 
Hypothetical: For patients in the monthly dosing regimen group 
who early terminate from study drugs, observations collected 
more than 4 weeks after the last dose will be treated as missing. In 
formula (1) an average is taken so these values which are left 
missing due to early termination will be replaced with the average 
for that month of those in the same treatment group who do not 
early terminate. Missing observations prior to early termination 
will not be replaced. 
Patient receives the wrong IMP due to 
medication errors 
Treatment policy1 
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Intercurrent event 
Strategy 
Patient receives a rescue medication due to 
worsening symptoms 
Treatment policy1 
1Treatment policy: if observations are collected after the occurrences of the ICEs, the observations will be included 
in the calculation of the primary endpoint for the primary analysis. 
A second supplementary estimand will estimate treatment effect in the hypothetical scenario 
where no one takes rescue medication (rescue medication is indicated by a response of Yes to C1 
or C3, and a medication present in response to C2 of the electronic headache diary device). A 
rescue medication for migraine is defined as medication that does not abort a migraine, but 
masks the pain for a few hours until the migraine runs its course. 
The estimand is the difference in adjusted means between fremanezumab group and placebo 
group in the population that comprises the patients in the double-blind mITT analysis set for the 
change from baseline in the monthly average number of migraine days during the 12-week 
period after the 1st dose of IMP where the ICEs are handled as per Table 3. 
Table 3: Intercurrent Event Strategies: 2nd Supplementary Estimand  
Intercurrent event 
Strategy 
Patient early terminates from the IMP 
Treatment policy1 
Patient receives the wrong IMP due to 
medication errors 
Treatment policy1 
Patient receives a rescue medication due 
to worsening symptoms 
Hypothetical: For patients who start a rescue medication, 
observations collected after starting rescue medication will be 
treated as missing. In formula (1) an average is taken so these 
values which are left missing due to starting rescue medication 
will be replaced with the average for that month of those in the 
same treatment group who do not start rescue medication. 
1Treatment policy: if observations are collected after the occurrences of the ICEs, the observations will be included 
in the calculation of the primary endpoint for the primary analysis. 
A third supplementary estimand will estimate treatment effect in the population that comprises 
the patients in the ITT analysis set. The estimand is the difference in adjusted means between 
fremanezumab group and placebo group for the change from baseline in the monthly average 
number of migraine days during the 12-week period after the 1st dose of IMP where the ICEs are 
handled as per Table 1. 
Finally, a fourth supplementary estimand will estimate the treatment effect in the population that 
comprises the patients in the PP analysis set. The estimand is the difference in adjusted means 
between fremanezumab group and placebo group for the change from baseline in the monthly 
average number of migraine days during the 12-week period after the 1st dose of IMP where the 
relevant ICE is handled as per Table 4. 
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Table 4: Intercurrent Event Strategies: 4thSupplementary Estimand  
Intercurrent event 
Strategy 
Patient receives a rescue medication due to 
worsening symptoms 
Treatment policy1 
1Treatment policy: if observations are collected after the occurrences of the ICEs, the observations will be included 
in the calculation of the primary endpoint for the primary analysis. 
6.2.5. 
Analysis of the Supplementary Estimands  
The supplementary estimands will be analyzed using the same methods as the primary estimand, 
as detailed in Section 6.2.2. 
6.2.6. 
Sub-Group Analyses  
The primary analysis with ANCOVA method defined in Section 6.2.2 and MMRM analysis 
defined in Section 6.2.3.1 will also be applied to the following subgroups for the primary 
endpoint using a ‘by’ statement with the subgroup variable of interest. The subgroup variable 
will not be included in the model. Instead of the randomized stratification, the actual 
stratification will be used.  
• Patients by migraine type (CM, EM) 
6.3. 
Secondary Efficacy Endpoints and Analysis  
6.3.1. 
Secondary Efficacy Estimands  
The secondary estimands are as follows: 
• The difference in adjusted means between fremanezumab group and placebo group in the 
population that comprises the patients in the mITT analysis set for the change from 
baseline in the number of migraine days during the 4-week period after the 1st dose of 
investigational medicinal product (IMP).  
• The difference in adjusted means between fremanezumab group and placebo group in the 
population that comprises the patients in the mITT analysis set for the change from 
baseline in the monthly average number of days that any acute headache medications 
were used during the 12-week period after the 1st dose of IMP. 
• The odds ratio of fremanezumab group with placebo group in the population that 
comprises the patients in the mITT analysis set n for the 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 IMP. 
• The difference in adjusted means between fremanezumab group and placebo group in the 
population that comprises the patients in the mITT analysis set  for the change from 
baseline in the monthly average number of days with headache of at least moderate 
severity during the 12-week period after the 1st dose of IMP. 
For all secondary estimands the ICEs will be handled as per Table 1. 
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For the first secondary efficacy estimand the baseline values will be derived using formula (3). 
The postbaseline values during the 4-week period will be derived using formula (2) and the 
change is calculated as postbaseline – baseline value. For the second and fourth secondary 
efficacy estimands the baseline values will be derived using formula (3). The postbaseline values 
during the 12-week period will be derived using formula (1), and the change is calculated as 
postbaseline – baseline value.  
For the third secondary efficacy estimand the percent reduction will be calculated using formula 
(4). If a patient is early discontinued from the study, he/she will be counted as a non-responder. 
6.3.2. 
Analysis of Secondary Efficacy Estimands  
The first, second, and fourth secondary efficacy estimands which involve the difference in means 
between fremanezumab group and placebo group for change from baseline in efficacy variables 
will be analyzed using the same methods as the primary efficacy endpoint as detailed in Section 
6.2.2 and 6.2.3.1 except the second secondary efficacy estimand model will include baseline 
number of days that any acute headache medications were used instead of baseline number of 
migraine days and the fourth secondary efficacy estimand model will include baseline number of 
days with headache of at least moderate severity instead of baseline number of migraine days. 
The third secondary efficacy estimand involving the responder endpoint will be analyzed using 
logistic regression. The model will include treatment and stratification factors of migraine type 
(CM vs EM) and baseline preventive medication (yes vs no) use as fixed factors, as well as 
baseline number of migraine days as a covariate in the model. For the individual treatment 
groups (combined TEV-48125 groups and placebo) number and percent of responders and non-
responders will be presented. For the treatment comparison (combined TEV-48125 groups with 
placebo) the odds ratio, 95% confidence interval for the odds ratio, and p-value for the treatment 
comparison will be presented.  
Example SAS code is provided in Appendix D. 
6.3.3. 
Supplementary Secondary Efficacy Estimands  
The supplementary secondary efficacy estimands are identical to the secondary efficacy 
estimands but in the per-protocol (PP) analysis set. See Section 6.3.1 for the secondary efficacy 
estimands. 
6.3.4. 
Analysis of Supplementary Secondary Efficacy Estimands  
The analysis of the supplementary secondary efficacy estimands will be identical to the analysis 
of the secondary efficacy estimands. See Section 6.3.2 for details. 
6.4. 
Other Efficacy Endpoints and Analysis  
6.4.1. 
Exploratory Efficacy Endpoints  
  
 
 
 
 
 
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6.4.2. 
Analysis of Exploratory Endpoints  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
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7. 
MULTIPLE COMPARISONS AND MULTIPLICITY  
A fixed-sequence, hierarchical testing procedure will be implemented to control the type 1 error 
rate at 0.05 for formal hypothesis testing of the secondary endpoints at the end of the double-
blind period (i.e., 1st interim). Upon the success of the primary analysis, the first secondary 
endpoint in the sequence will be tested at a significance level of 0.05, and a p-value ≤0.05 will be 
interpreted inferentially. The process will continue following the order of the sequence until a 
point when the test for the efficacy endpoint fails, ie, 2-sided p-value >0.05. Subsequently, no 
further test results will be interpreted inferentially. The sequence of testing upon the success of 
the primary analysis will be as follows:  
1. mean change from baseline in the number of migraine days during the 4-week period 
after the 1st dose of IMP  
2. mean change from baseline in the monthly average number of days with headache of at 
least moderate severity during the 12-week period after the 1st dose of IMP  
3. 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 IMP  
4. mean change from baseline in the monthly average number of days that any acute 
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8. 
SAFETY ANALYSIS  
8.1. 
General  
Safety analyses will be performed on the safety analysis set. Summaries will be presented by 
treatment group in double-blind period for both the interim analysis at the end of the double-
blind period and for the interim analysis at the end of the open-label period (TEV-48125 225 mg 
monthly, TEV-48125 675 mg quarterly and placebo). A column for all fremanezumab-treated 
patients will be provided and a total column will also be provided. 
For continuous variables, descriptive statistics (n, mean, SD, median, minimum, and maximum) 
will be provided for actual values and changes from baseline to each time point. For categorical 
variables, patient counts and percentages will be provided. 
Missing values will be reported as missing and no imputation will be undertaken. 
All data during the follow-up period, i.e., after the open-label period, will be listed only. 
8.2. 
Duration of Exposure to Study Drug  
Duration of treatment (days treated) for the double-blind treatment period is the number of days 
on treatment starting from the 1st study drug administration day to the week 12 or double-blind 
early withdrawal visit day (week 12 or double-blind early withdrawal visit day – first day of 
study drug + 1). For patients who are lost to follow-up during the double-blind treatment period, 
the EOT visit date is defined as the last study drug administration + 27. 
Duration of treatment (days treated) for the open-label treatment period is the number of days on 
treatment starting from the 1st study drug administration day in the open-label treatment period to 
the week 24 or open-label early withdrawal visit day (week 24 or open-label early withdrawal 
visit day – first day of study drug in the open-label treatment period + 1). For patients who are 
lost to follow-up during the open-label treatment period, the EOT visit date is defined as the last 
study drug administration + 27. 
Duration of treatment (days) during the double-blind and open-label periods will be summarized 
using descriptive statistics. 
8.3. 
Adverse Events  
All adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) version 26.0 or higher.  
For adverse event recording, 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. Adverse events will 
be presented separately for the double-blind period and for the open-label period. 
Adverse events will be collected at each visit via adverse event inquiry.  
The following are considered protocol-defined adverse events of special interest to be sent to the 
sponsor’s Global Patient Safety and Pharmacovigilance for evaluation: severe hypersensitivity 
and anaphylaxis, as well as ophthalmic events of at least moderate severity.  
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Summaries will be presented by migraine classification for all treatment-emergent adverse 
events (overall and by severity), adverse events determined by the investigator to be treatment-
related adverse events (ie, reasonable possibility; defined as related or with missing relationship 
[overall and by severity]), serious adverse events, protocol-defined adverse events of special 
interest, adverse events leading to discontinuation from treatment, adverse events leading to 
discontinuation from the study, non-serious adverse events, injection site reaction adverse events, 
adverse events requiring concomitant or additional treatment, and adverse events leading to 
death.  
The incidence of adverse events will be summarized using descriptive statistics by migraine 
classification, PT and SOC. Each patient will be counted only once in each PT or SOC category 
for the analyses of safety. For the summaries by severity, patients are counted at the greatest 
severity. Adverse events with the missing flag indicating serious will be excluded from the 
summary of serious adverse events but included in the summary of non-serious adverse events. 
Listings for adverse events, deaths, serious adverse events, serious adverse events additional 
information, adverse events leading to discontinuation from treatment, adverse events leading to 
discontinuation from the study, injection site related adverse events requiring concomitant or 
additional treatment given, protocol-defined adverse events, protocol-defined adverse events of 
special interest, and adverse events for patients who did not meet screening criteria will be 
presented. All information pertaining to adverse events noted during the study will be listed by 
subject, detailing verbatim given by the investigator, PT, SOC, date of onset, date of resolution, 
severity, and relationship to treatment. The onset of adverse events will also be shown relative 
(in number of days) to the 1st day of treatment. In addition, MedDRA dictionary terms for 
adverse event descriptions, and adverse event preferred terms by patient number and treatment 
group will be presented. 
8.4. 
Deaths  
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. 
8.5. 
Clinical Laboratory Tests  
Clinical laboratory tests (serum chemistry, hematology and coagulation, and urinalysis) will be 
performed using the central laboratory at the time points detailed in the study protocol. Specific 
laboratory tests to be performed are listed below in Table 5. 
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Table 5: Clinical Laboratory Tests  
Serum chemistry 
Hematology and coagulation 
Urinalysis 
Calcium 
Phosphate 
Sodium 
Potassium 
Chloride 
Creatinine 
Glucose 
BUN 
LDL 
HDL 
Triglycerides 
Urate 
ALT 
AST 
LDH 
GGT 
ALP 
Bicarbonate 
Carbon dioxide 
Protein 
Albumin 
Bilirubin 
Direct bilirubin 
Hemoglobin 
Hematocrit 
Erythrocytes 
Platelets 
Leucocytes 
− Neutrophils 
− 
Lymphocytes 
− 
Eosinophils 
− 
Monocytes 
− 
Basophils 
Lymphocytes atypical 
Prothrombin INR 
Protein 
Glucose 
Ketones 
Hemoglobin 
pH 
Specific gravity 
Microscopic tests 
− 
Bacteria 
− 
Erythrocytes
− 
Leucocytes 
− 
Crystals 
− 
Casts 
ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea 
nitrogen; GGT=gamma glutamyl transpeptidase; HDL=high-density lipoprotein; INR=international normalized 
ratio; LDH=lactate dehydrogenase; LDL=low-density lipoprotein. 
Laboratory test results will be presented in standard international (SI) units.  
Summary statistics for chemistry, hematology, urinalysis, and coagulation laboratory tests will 
be presented at baseline, weeks 0, 8, 12 for double-blind and week 24 for open-label, and last on 
study assessment for both periods. Laboratory values and changes from baseline to each visit and 
last on study assessment will be summarized using descriptive statistics. Shifts (below, within, 
and above the normal range) from baseline to each visit and last on study assessment will be 
summarized using patient counts. Listings of all individual patients’ laboratory test results will 
be presented. 
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 
both on the source documentation and the CRF as an adverse event. The incidence of potentially 
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clinically significant abnormal results will be summarized using descriptive statistics with the 
criteria specified in Table 6. The potentially clinically significant abnormal laboratory values 
will include all postbaseline values (including scheduled, unscheduled, and early termination 
visits) for the summaries. Listings of patients who have potentially clinically significant 
abnormal laboratory data will be presented.  
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Table 6: Criteria for Potentially Clinically Significant Laboratory Values  
Test 
Criterion value 
Serum chemistry 
 
  Alanine aminotransferase (ALT) 
3x ULN 
  Aspartate aminotransferase (AST) 
3x ULN 
  Alkaline phosphatase 
3x ULN 
  Gamma-glutamyl transpeptidase (GGT) 
3x ULN 
  Lactate dehydrogenase (LDH) 
3x ULN 
  Blood urea nitrogen (BUN) 
10.71 mmol/L 
  Creatinine 
177 mol/L 
  Uric acid 
Men 
625 mol/L 
 
 
Women 
506 mol/L 
  Bilirubin (total) 
 2x ULN 
Potassium 
≤3 mmol/L or ≥6 mmol/L 
Calcium 
≤1.5 mmol/L or ≥3.5 mmol/L 
Hematology and Coagulation 
  Hematocrit 
Men 
<0.37 L/L 
 
 
Women 
<0.32 L/L 
  Hemoglobin 
Men 
115 g/L 
 
 
Women 
95 g/L 
  White blood cell (WBC) counts 
3 x 109/L  
20 x 109/L 
  Eosinophils 
10% 
  Absolute neutrophil counts (ANC) 
1 x 109/L 
  Platelet counts 
75 x 109/L  
700 x 109/L 
  INR 
≥ 1.5x ULN 
Urinalysis 
  Blood (HGB) 
2 unit increase from baseline 
  Glucose 
2 unit increase from baseline 
  Ketones 
2 unit increase from baseline 
  Total protein 
2 unit increase from baseline 
HGB=Hemoglobin; INR=International Normalized Ratio; ULN=upper limit of normal range. 
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8.5.1. 
Laboratory Values Meeting Hy’s Law Criteria  
All occurrences of possible drug-induced liver injury that meet Hy's law criteria as defined in the 
protocol will be included in adverse events reporting. 
8.5.2. 
Other Clinical Laboratory Tests  
8.5.2.1. 
Human Chorionic Gonadotropin Test  
Serum beta-human chorionic gonadotropin (β-HCG) tests will be performed for all women of 
childbearing potential at screening (visit 1) and visit 8. Urine pregnancy tests will be performed 
for all women of childbearing potential at visit 2 to 7 and the EOT/early termination visit. 
Pregnancy test results will be listed. 
8.5.2.2. 
Follicle-Stimulating Hormone Test  
Postmenopausal women will have a follicle-stimulating hormone (FSH) test at screening. Results 
will be listed. 
8.6. 
Physical Examinations  
Physical examinations, including height (to be measured at the screening visit only) and weight 
will be performed at screening, weeks 0, 4, 8, 12, 24 and last on study assessment. 
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 a 
potentially clinically significant change (worsening) compared with a baseline value will be 
considered an adverse event and recorded on the CRF, and monitored as described in the study 
protocol. Abnormal findings at baseline will be summarized by treatment group using patient 
counts. Shifts from baseline to weeks 4, 8, 12 for double-blind and week 24 for open-label and 
last on study assessment for both periods will be summarized using patient counts. Listings of 
findings for all physical examinations will be presented. 
Descriptive statistics for weight and height will be provided. 
8.7. 
Vital Signs  
Vital signs (blood pressure [systolic/diastolic], respiratory rate, body temperature, and pulse) will 
be measured at every visit including unscheduled visits.  
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. 
Vital signs values and changes from baseline to each visit and endpoint will be summarized 
using descriptive statistics and vital signs values will be listed. 
Table 7 specifies the criteria for identifying vital signs as potentially clinically significant 
abnormal values. Note that in order to be identified as potentially clinically significant abnormal, 
a value would need to meet both conditions below: i.e., have a value beyond the criterion value 
and a change of at least the magnitude specified in the change from baseline column. The 
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potentially clinically significant abnormal vital signs values will include all postbaseline values 
(including scheduled, unscheduled, and early termination visits) for the summaries. The 
incidence of potentially clinically significant values will be both listed and summarized using 
descriptive statistics. 
Table 7: Criteria for Potentially Clinically Significant Vital Signs  
Vital Sign 
Criterion value 
Change relative to baseline 
Pulse 
120 bpm 
Increase of 15 bpm 
 
50 bpm 
Decrease of 15 bpm 
Systolic blood pressure 
180 mm Hg 
Increase of 20 mm Hg 
 
90 mm Hg 
Decrease of 20 mm Hg 
Diastolic blood pressure 
105 mm Hg 
Increase of 15 mm Hg 
 
50 mm Hg 
Decrease of 15 mm Hg 
Respiratory rate 
<10 breaths/min 
 
Body temperature 
≥38.3C 
Change of 1.1C 
8.8. 
Electrocardiography  
A single 12-lead ECG will be performed at screening, week 0, 8, 24, and at visit 9 (follow-up) if 
assessment at visit 8 (EOT/ET) shows abnormality. This procedure will be performed predose. 
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 
If results are abnormal, the ECG will be repeated 1 time.  
Summary of ECG findings (normal, abnormal not clinically significant and abnormal clinically 
significant) will be presented at baseline. Shifts in ECG finding (normal, abnormal not clinically 
significant and abnormal clinically significant) from baseline to overall result interpretation, 
week 8 for double-blind and week 24 for open-label and last on study assessment (double-blind 
and open-label) will be summarized using patient counts. For overall result interpretation the 
worst post baseline finding for the patient (the abnormal finding if there are both normal and 
abnormal findings) will be used in the summaries. Actual values and changes from baseline to 
each visit and last on study assessment (for both double-blind and open-label periods) will be 
summarized using descriptive statistics. Both result interpretation and values will be listed. 
Any ECG finding that is judged by the investigator as a potentially clinically significant change 
(worsening) compared with the baseline value will be considered an adverse event. 
8.9. 
Concomitant Medications or Therapies  
Any concomitant therapy, medication or procedure up to the end of the study period will be 
recorded on the CRF. Generic or trade name, indication, and dosage will be recorded. The 
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sponsor will encode all therapy and medication according to the World Health Organization 
Drug Dictionary (WHODrug) version 2023MAR01DDE or higher. 
Up to 30% of patients will be allowed to remain on stable doses of no more than 1 preventive 
migraine medication presented in the study protocol (in addition to other medications not listed 
in the study protocol) for the duration of the study. Patients on preventive medication must be on 
a stable dose for at least 2 months of consecutive use prior to screening with no expectation to 
change dosing regimen or change to another migraine preventive medications during the 
treatment phase of the study. 
Patients will be allowed to use acute medication to treat breakthrough migraines as needed, with 
the exception of medications containing opioids and barbiturates, which cannot be used on more 
than 4 days during the screening period. Traditional Chinese therapy (including herbal medicine) 
and acupuncture are allowed if the patient is on a stable dosing regimen for at least 2 months 
(consecutive) before screening. 
Concomitant medications will be listed by double-blind treatment group. The incidence of 
concomitant medications will be summarized using descriptive statistics by therapeutic class and 
PT. Patients are counted only once in each therapeutic class category, and only once in each PT 
category. Concomitant medications will include all medications taken while the patient is treated 
with the IMP.  
The subset of concomitant pain medication and medication or therapy for migraine/headache will 
also be summarized by the following indication categories: 
• butalbital for migraine/headache 
• ergots for migraine/headache 
• NSAIDs for migraine/headache 
• NSAIDs for other reason than migraine/headache 
• opioids for migraine/headache  
• opioids for reasons other reason than migraine/headache  
• preventive medication from protocol Appendix K for migraine/headache 
• preventive medication from protocol Appendix K for other reason than 
migraine/headache 
• triptans for migraine/headache 
8.10. 
Suicidality  
Any suicide attempt in the past, suicidal ideation with a specific plan in the past 2 years prior to 
screening (visit 1), or current suicidal ideation will result in patient exclusion.  
Investigators will inquire about and evaluate suicidal ideation, plan, and behavior based on their 
clinical judgement and refer patients to psychiatric care as appropriate. 
Any suicide information collected will be listed. 
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9. 
TOLERABILITY VARIABLES AND ANALYSIS  
Spontaneous reports of injection site reactions will be recorded as adverse events 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. 
Tolerability will be assessed by the following:  
• the number (%) of patients who fail to complete the study due to adverse events 
Spontaneously reported local tolerability findings will be listed and summarized descriptively. 
 
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10. 
PHARMACOKINETIC ANALYSIS  
Pharmacokinetic plasma concentration results (fremanezumab) are collected at visit 2, visit 3, 
visit 4, and visit 8 and patients must return to the study center after visit 2, visit 3, or visit 4 for 2 
additional blood sampling visits (see study protocol for details). Samples from patients who 
received the active IMP will be analyzed for the concentration of fremanezumab using a 
validated method. Samples from patients who were randomized to receive placebo will not be 
analyzed. 
The plasma concentration results will be tabulated descriptively at each planned sampling time 
point by treatment group. Concentration values that are below the lower limit of quantitation 
(<LLOQ) will be treated as 0, and missing values will be ignored in the concentration summary 
tables.  Individual pharmacokinetic concentration data will be summarized and listed in the CSR. 
The pharmacokinetic data from this study will be pooled with the data from other fremanezumab 
studies and assessed for comparability. Summary statistics of fremanezumab pharmacokinetic 
parameters model-based predictions of weight-adjusted exposures will be compared and will be 
reported separately. 
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11. 
IMMUNOGENICITY ANALYSIS  
Samples from patients who receive the active IMP will be analyzed for ADA using a validated 
method. Samples from patients who receive placebo will not be analyzed.  
Blood samples (10 mL for the predose sample at visit 2; 6 mL for all other samples) will be 
collected prior to dosing at visit 2, visit 4, visit 8 (EOT), and visit 9 (EOS) for immunogenicity 
testing.  
Summary of immunogenicity results will be provided, and the incidence of immunogenicity will 
be calculated. This analysis will be reported separately. 
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12. 
PLANNED INTERIM ANALYSES  
Two interim analyses are planned. The first interim analysis is planned when the last patient has 
completed the double-blind period and will use the double-blind period data. A second interim 
analysis is planned following the end of the open-label period and will use the open-label period 
data.  
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 second database lock. 
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13. 
STATISTICAL SOFTWARE  
All data listings, summaries, and statistical analyses will be generated using SAS® version 9.4 or 
later. 
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14. 
CHANGES TO ANALYSES SPECIFIED IN THE STUDY 
PROTOCOL  
The following endpoint has been removed in the SAP due to the necessary data not being 
collected: 
• mean change from baseline in the monthly average number of days with most 
bothersome symptoms during the 12-week period after the 1st dose of IMP 
The wording of the following endpoint has been changed as shown. 
Wording from protocol: 
• 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  
New wording in SAP: 
• assessment of patient satisfaction, as measured by the Patient Global Impression of 
Change (PGIC) scale, at visit 8  
A multiple imputation analysis has been added in Section 6.2.3.2  as an additional sensitivity 
analysis of the primary estimand to assess the sensitivity of the primary analysis to missing data 
assuming the data is missing not at random. 
The definitions for CM and EM have been modified; CM is defined as having  15 headache 
days during the baseline period whilst < 15 headache days during the baseline period is classed 
as EM. 
The following analysis has been removed in the SAP due to minimal COVID-19 diagnoses 
occurring: 
• Missing data or visits due to the COVID-19 pandemic will be evaluated for the 
primary and secondary endpoints. COVID-19 may have an impact on patients’ 
migraine symptoms, with headache reported to be a common complication as a result 
of contracting the disease. All COVID-19 cases will be included in the primary 
analysis; however, observations following COVID-19 diagnosis will be discarded 
from the calculation of the monthly average endpoint. The data handling strategy will 
be detailed in the statistical analysis plan. 
The following subgroup analysis has been removed in the SAP due to disease severity being 
collected daily rather than just once during the baseline period: 
• Patients by disease severity (Mild, Moderate, Severe)  
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15. 
REFERENCES  
Chinese Medical Association Pain Society (CMAPS). Guide to the prevention and treatment of 
migraine in China. Chin J Pain Med 2016;22:721-7. 
Headache Classification Committee of the International Headache Society (IHS). The International 
Classification of Headache Disorders, 3rd edition. Cephalalgia 2018;38(1):1-211. 
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APPENDIX A. ELECTRONIC HEADACHE DIARY QUESTIONNAIRE  
  
The following questions are referring to yesterday 
(00:00 - 23:59) 
A1 
Did you have a headache yesterday?  
A2 
Did you have at least two (2) consecutive hours of headache yesterday? 
A3 
What was the greatest severity that your headache reached yesterday at any time? 
A4 
How many total hours did you have a headache of any severity yesterday? 
A5 
How many total hours of moderate or severe headache did you have yesterday?  
 
  
The following questions are referring to yesterday 
(00:00 - 23:59) 
B1 
Was your headache pain worse on one side (left or right) of your head yesterday? 
B2 
Was your head pain throbbing, pounding or beating like a drum yesterday? 
B3 
Did you have a stomach ache, feel sick to your stomach or did you throw up yesterday? 
B4 
Did light bother you more than when you didn't have a headache (did you experience 
photophobia)? 
B5 
Did sounds bother you more than when you didn't have a headache (did you experience 
phonophobia)? 
B6 
Did you have trouble seeing normally or did you see spots, stars, wavy lines, or flashes during 
your headache yesterday? (This is different from "light bothers you") 
B7 
Did you have feelings such as numbness or tingling in any part of your body or face around the 
time of your headache? 
B8 
Before your headache started, did you notice any of the usual signs that a headache is coming 
yesterday? This could include seeing spots, stars, wavy lines, or flashes or having trouble 
speaking, feeling dizzy or having tingling, numbness or weakness in your arms or legs. 
 
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The following questions are referring to yesterday 
(00:00 - 23:59) 
C1 
Did you take any prescription medications yesterday for your headache/migraine? 
C2 
Which of these medications did you take yesterday? 
C3 
Did you use any non-prescription medication in an effort to get relief from your 
headache/migraine yesterday? 
 
  
The following questions are referring to yesterday 
(00:00 - 23:59) 
E1 
Did you have problems falling asleep yesterday? 
E2 
Which of the following situations best describe your work/school performance yesterday, when 
you did not have a headache?  
E3 
What would better describe how you felt in general yesterday? 
E4 
How much of the time yesterday did you find it difficult to concentrate on what you needed to do? 
E5 
On average, how much of the time yesterday were you very tired, asleep, or feeling drained? 
E6 
Which of the following situations best describe your ability to perform household chores 
yesterday, when you did not have a headache? 
E7 
How engaged were you with your partner's or children's activities yesterday, when you didn't 
have a headache? 
E8 
Overall, how interested were you in doing daily activities yesterday? 
 
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APPENDIX B. LOGICS FOR ENDPOINTS DERIVATION  
  
Migraine day: 1 of the following 5 options 
Primary endpoint 
  
  
  
  
  
OPTION 1 
  
  
OPTION 2 
  
  
  
  
  
Part 1 
1 
A1 
YES 
1 
A1 
YES 
  
2 
A2 
YES 
2 
C1 
YES 
  
  
AND 
3 
C2 
ERGOT OR TRIPTAN  
  
  
 
 
 
  
  
ONE  OF THE FOLLOWING 
  
OPTION 3  
  
  
Part 2 
1 
A3 
Moderate/Severe 
  
 
  
2 
B1 
YES 
1 
A1 
YES 
  
3 
B2 
YES 
2 
C2 
Medication Provided 
  
  
AND 
3 
C3 
YES 
  
  
  
  
  
ONE OF THE FOLLOWING 
  
  
OPTION 4 
  
  
Part 3 
1 
B3 
YES 
  
  
  
  
1 
A1 
YES 
  
2 
B4 
YES 
  
AND 
  
  
AND 
  
ONE OF THE FOLLOWING 
  
  
B5 
YES 
2 
B6 
YES 
  
  
  
  
OR 
  
OPTION  5: PROBABLE MIGRAINE 
B7 
YES 
If Part 1 and Part 2 met from option 1, Part 3 needs ONLY 
one of the following:  
Part 3 
  
 B4 
YES 
  
  
 B5 
YES 
If Part 1 and Part 3 met from option 1, Part 2 needs ONLY 
one of the following: 
Part 2 
1 
A3 
Moderate/Severe 
  
2 
B1 
YES 
  
3 
B2 
YES 
If Part 2 and Part 3 met from option 1, Part 1 needs ONLY 
the following: 
Part 1 
1 
A1 
YES 
 
 
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Headache day of at least moderate severity: 1 of the following 3 options 
 
  
 
 
OPTION 1 
  
1 
A1 
YES 
  
2 
A2 
YES 
  
3 
A3 
Moderate or Severe  
  
  
  
  
OPTION 2 
  
  
1 
A1 
YES 
  
2  
C1 
YES 
  
3  
C2   
ERGOT OR TRIPTAN 
  
OPTION 3 
  
  
  
1 
A1 
YES 
  
2 
C2 
Medication Provided 
 
 
3  
C3   
YES    
    
 
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APPENDIX C. PATIENT’S GLOBAL IMPRESSION OF CHANGE (PGIC) 
SCALE  
 
Date _______________ Patient Name _________________________________ Date of 
Birth____________ 
Chief Complaint (Presenting Problem): ______________________________________ 
 
Since beginning treatment at this clinic, how would you describe the change (if any) in ACTIVITY 
LIMITATIONS, SYMPTOMS, EMOTIONS, and OVERALL QUALITY OF LIFE, related to your 
painful condition? Please circle the number below that matches your degree of change since beginning 
care at this clinic for the above stated chief complaint. 
 
No change 
Almost the 
same 
A little 
better 
Somewhat 
better 
Moderately 
better 
Better 
A great deal 
better 
1 
2 
3 
4 
5 
6 
7 
 
Explanation: 
1 = No change (or condition has 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 
7 = A great deal better, and a considerable 
improvement that has made all the difference 
 
Patient’s signature: X ___________________________________________________________________ 
Do not write in this box - FOR OFFICE USE ONLY. 
NOTE TO HEALTH CARE PROVIDER 
A significant, favorable change is a score of 5- 7 
No significant change is a 1-4 response. 
Note, this is a dichotomous scale (5-7 = yes; 1-4 = no). 
A 2-point change is significant from their last reported score. 
Reference: Hurst H, Bolton J. Assessing the clinical significance of change scores recorded on subjective outcome measures. Journal of Manipulative 
Physiological Therapeutics (IMPT) 2004;27:26-35. 
 
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APPENDIX D.  EXAMPLE SAS CODE   
 
The following sample SAS code pertains to the primary efficacy ANCOVA analysis: 
ODS OUTPUT DIFFS = XXX LSMEANS = XXX 
PROC MIXED DATA = XXX; 
 
CLASS TREATMENT MIGRAINETYPE PREVENTIVEMEDICATION; 
 
MODEL CHG = TREATMENT MIGRAINETYPE PREVENTIVEMEDICATION              
BASE; 
 
LSMEANS TREATMENT / CL PDIFF; 
RUN; 
 
The following SAS code pertains to the main MMRM analysis: 
ODS OUTPUT DIFFS = XXX LSMEANS = XXX 
PROC MIXED DATA=XXX;  
 
CLASS USUBJID MONTH TREATMENT MIGRAINETYPE 
PREVENTIVEMEDICATION; 
 
MODEL CHG=BASE MONTH TREATMENT MIGRAINETYPE 
PREVENTIVEMEDICATION TREATMENT*MONTH; 
 
REPEATED MONTH/SUBJECT=USUBJID TYPE=UN; 
 
LSMEANS TREATMENT TREATMENT*MONTH/PDIFF CL ALPHA=0.05; 
RUN;  
 
The following SAS code pertains to the sensitivity MMRM analysis: 
ODS OUTPUT DIFFS = XXX LSMEANS = XXX 
PROC MIXED DATA=XXX;  
 
CLASS USUBJID MONTH TREATMENT MIGRAINETYPE 
PREVENTIVEMEDICATION; 
 
MODEL CHG=BASE MONTH TREATMENT MIGRAINETYPE 
PREVENTIVEMEDICATION TREATMENT*MONTH BASE*MONTH; 
 
REPEATED MONTH/SUBJECT=USUBJID TYPE=UN; 
 
LSMEANS TREATMENT TREATMENT*MONTH/PDIFF CL ALPHA=0.05; 
RUN;  
VV-05306748 v1.0


 
Placebo-Controlled Study–Migraine 
Statistical Analysis Plan 
Study TV48125-CNS-30088 
 
60 
The following SAS code pertains to the MI analysis: 
PROC MI DATA=XX SEED=98765 OUT=MI_OUT NIMPUTE=100 MAXIMUM=. . . 28 28 
28 28  MINIMUM=. . . 0 0 0 0; 
   
 
CLASS TRTMI MIGRAINETYPE PREVENTIVEMEDICATION; 
  
 
FCS REG(V0=TRTMI MIGRAINETYPE PREVENTIVEMEDICATION 
 /DETAILS) NBITER=100;   
   
 
FCS REG(V1=TRTMI MIGRAINETYPE PREVENTIVEMEDICATION  
V0 /DETAILS) NBITER=100; 
   
 
FCS REG(V2=TRTMI MIGRAINETYPE PREVENTIVEMEDICATION  
V0 V1/DETAILS) NBITER=100; 
   
 
FCS REG(V3=TRTMI MIGRAINETYPE PREVENTIVEMEDICATION 
V0 V1 V2/DETAILS) NBITER=100; 
   
 
VAR TRTMI MIGRAINETYPE PREVENTIVEMEDICATION V0 V1 V2 V3; 
RUN; 
 
where TRTMI is the placebo reassigned treatment group. 
The output dataset from the below SAS code will contain the estimate of the mean difference and 
the standard error of the estimate from each of the 100 datasets 
ODS OUTPUT DIFFS=DIFF LSMEANS=LSM; 
PROC MIXED DATA=UPDATED_MI_OUT METHOD=REML; 
   
BY IMPUTATION;  
   
CLASS TREAT MIGRAINETYPE PREVENTIVEMEDICATION; 
   
MODEL CHG=BASE TREAT MIGRAINETYPE PREVENTIVEMEDICATION; 
   
LSMEANS TREAT/DIFF; 
RUN; 
where TREAT is the planned randomized treatment group. 
 
 
SAS PROC MIANALYZE code is as follows; 
ODS OUTPUT PARAMETERESTIMATES=PARMEST; 
PROC MIANALYZE DATA=MIXED_OUT ALPHA=0.05 THETA0=0; 
BY TREAT; 
MODELEFFECTS ESTIMATE; 
STDERR STDERR; 
RUN; 
where TREAT is the planned randomized treatment group.  
 
 
 
VV-05306748 v1.0


 
Placebo-Controlled Study–Migraine 
Statistical Analysis Plan 
Study TV48125-CNS-30088 
 
61 
The following SAS code pertains to the logistic regression analysis: 
PROC LOGISTIC DATA = XXX; 
CLASS TREATMENT (REF = ‘1’) MIGRAINETYPE 
PREVENTIVEMEDICATIONUSE / PARAM = REF; 
MODEL RESPONSE (EVENT = ‘1’) = TREATMENT MIGRAINETYPE 
PREVENTIVEMEDICATIONUSE BASELINE; 
RUN; 
 
VV-05306748 v1.0