A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study Comparing the Efficacy, Safety, and Tolerability of Subcutaneous Administration of Fremanezumab Versus Placebo for the Preventive Treatment of Episodic Migraine in Pediatric Patients 6 to 17 Years of Age
Phase: PHASE3
Conditions: Migraine
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc.

Clinical Study Protocol 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group 
Study Comparing the Efficacy, Safety, and Tolerability of Subcutaneous 
Administration of Fremanezumab Versus Placebo for the Preventive Treatment of 
Episodic Migraine in Pediatric Patients 6 to 17 Years of Age 
Study Number TV48125-CNS-30083 
NCT04458857 
Protocol with Amendment 09 Approval Date: 24 September 2023 

Placebo-Controlled Study–Pediatric Episodic Migraine 
Clinical Study Protocol with Amendment 09 
Study TV48125-CNS-30083 
1 
 
 
Clinical Study Protocol with Amendment 09 
Study Number TV48125-CNS-30083 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study 
Comparing the Efficacy, Safety, and Tolerability of Subcutaneous Administration of 
Fremanezumab Versus Placebo for the Preventive Treatment of Episodic Migraine in 
Pediatric Patients 6 to 17 Years of Age 
Randomized, Double-Blind, Placebo-Controlled Study of Fremanezumab in Patients (6 to 
17 Years) with Episodic Migraine 
A Study to Test if Fremanezumab is Effective in Preventing Episodic Migraine in Patients 
6 to 17 Years of Age 
Efficacy, Safety, and Tolerability Study (Phase 3) 
IND number: 106,533 
NDA number: Not Applicable 
BLA number: 761089 
EudraCT number: 2019-002055-42 
EMA Decision number of Pediatric Investigation Plan: P/0378/2023 
Article 46 of Regulation (EC) No 1901/2006 applies 
Protocol Approval Date: 28 March 2019 
Protocol with Amendment 01 Approval Date: 21 June 2019 
Protocol with Amendment 02 Approval Date: 05 December 2019 
Protocol with Amendment 03 Approval Date: 03 February 2020 
Protocol with Amendment 04 Approval Date: 20 April 2020 
Protocol with Amendment 05 Approval Date: 27 June 2020 
Protocol with Amendment 06 Approval Date: 27 July 2020 
Protocol with Amendment 07 Approval Date: 20 August 2020 
Protocol with Amendment 08 Approval Date: 09 December 2021 
Protocol with Amendment 09 Version Date: 24 September 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 (ICH); United States (US) Code of 
Federal Regulations (CFR), and European Union (EU) Directives and Regulations (as applicable in the 
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region of the study); national country legislation; and the sponsor’s Standard Operating Procedures 
(SOPs). 
Confidentiality Statement 
This document contains confidential and proprietary information (including confidential commercial 
information pursuant to 21CFR§20.61) and is a confidential communication of Teva Branded 
Pharmaceutical Products R&D, Inc. and/or its affiliates. The recipient agrees that no information 
contained herein may be published or disclosed without written approval from the sponsor. 
© 2023 Teva Branded Pharmaceutical Products R&D, Inc. All rights reserved. 
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AMENDMENT HISTORY  
The protocol for Study TV48125-CNS-30083 (original protocol dated 28 March 2019) has been 
amended and reissued as follows: 
Amendment 09 
24 September 2023 
217 patients randomized to date 
Administrative Letter 06 
21 December 2021 
Amendment 08 
09 December 2021 
51 patients randomized/enrolled to date 
Administrative Letter 05 
10 May 2021 
Administrative Letter 04 
04 February 2021 
Administrative Letter 03 
05 November 2020 
Amendment 07 
20 August 2020 
0 patients randomized/enrolled to date 
The management of study activities during the 
COVID-19 pandemic are detailed in Appendix O. 
The following sections are affected: 
Section 3.1 General Study Design and Study Schematic 
Section 3.5 Schedule of Study Procedures and 
Assessments 
Section 4.4 Replacement of Patients 
Section 9.5 Efficacy Analysis 
Table 1 Study Procedures and Assessments 
Appendix E. Quality Control and Quality Assurance 
Appendix F. Ethics 
Amendment 06 
27 July 2020 
0 patients randomized/enrolled to date 
Administrative Letter 02 
07 July 2020 
Amendment 05 
27 June 2020 
0 patients randomized/enrolled to date 
Amendment 04 
20 April 2020 
0 patients randomized/enrolled to date 
Administrative Letter 01 
10 March 2020 
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Amendment 03 
03 February 2020 
0 patients randomized/enrolled to date 
Amendment 02 
05 December 2019 
0 patients randomized/enrolled to date 
Amendment 01 
21 June 2019 
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  
Original Protocol Dated 28 March 2019 
Clinical Study Protocol with Amendment 09 
IND number: 106,533; NDA number: Not Applicable;  BLA number: 761089; 
EudraCT number: 2019-002055-42 
EMA Decision number of Pediatric Investigation Plan: P/0378/2023 
Article 46 of Regulation (EC) No 1901/2006 applies 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study 
Comparing the Efficacy, Safety, and Tolerability of Subcutaneous Administration of 
Fremanezumab Versus Placebo for the Preventive Treatment of Episodic Migraine in 
Pediatric Patients 6 to 17 Years of Age 
Principal Investigator:   
Title: 
 
Address of Investigational Center: 
 
 
 
 
 
Tel: 
 
 
I have read the protocol with Amendment 09 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 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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COORDINATING INVESTIGATOR AGREEMENT  
Original Protocol Dated 28 March 2019 
Clinical Study Protocol with Amendment 09 
IND number: 106,533; NDA number: Not Applicable;  BLA number: 761089; 
EudraCT number: 2019-002055-42 
EMA Decision number of Pediatric Investigation Plan: P/0378/2023 
Article 46 of Regulation (EC) No 1901/2006 applies 
 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study 
Comparing the Efficacy, Safety, and Tolerability of Subcutaneous Administration of 
Fremanezumab Versus Placebo for the Preventive Treatment of Episodic Migraine in 
Pediatric Patients 6 to 17 Years of Age 
I have read the protocol with Amendment 09 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 and 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 patient information, IMPs shipment and return forms, and other information collected 
during the study, in accordance with my responsibilities under the function of the coordinating 
investigator and in accordance with national and local GCP regulations as well as all other 
national and international laws and regulations. In addition, I will assume the responsibility of 
the coordinating investigator according to a separate contract. 
 
Coordinating Investigator 
 
Title: 
 
 
Address of Investigational Center: 
 
 
 
 
 
Tel: 
 
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Coordinating Investigator 
 
 
 
 
 
 
 
 
Signature 
Date 
Executed signature pages are maintained within the Investigator Site File and Trial Master File. 
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CLINICAL STUDY PROTOCOL SYNOPSIS  
with Amendment 09 
Study Number: TV48125-CNS-30083 
Title of Study: A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group 
Study Comparing the Efficacy, Safety, and Tolerability of Subcutaneous Administration of 
Fremanezumab Versus Placebo for the Preventive Treatment of Episodic Migraine in Pediatric 
Patients 6 to 17 Years of Age 
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc. 
Investigational New Drug (IND) Number: 106,533 
New Drug Application (NDA) Number: Not Applicable (NA) 
Biological License Application (BLA) Number: 761089 
EudraCT Number: 2019-002055-42 
EMA Decision number of Pediatric Investigation Plan: P/0378/2023 
Article 46 of Regulation (EC) No 1901/2006 applies. 
Name of Test Investigational Medicinal Product (IMP): Fremanezumab 
EudraVigilance (EV) code for the IMP, if applicable: SUB181665 
Type of the Study: Efficacy, Safety, and Tolerability Study (Phase 3) 
Indication: Preventive treatment of migraine in pediatric patients (6 to 17 years of age) 
Is this study conducted to investigate the New Use of an approved, marketed product? Yes 
Number of Investigational Centers Planned: Approximately 85 
Countries Planned: 6 to 10 countries 
Planned Study Period: Quarter (Q)1 2020 to Q2 2024 
Number of Patients Planned (total): Approximately 230 randomized episodic migraine (EM) 
patients. 
Study Population: Female and male patients aged 6 to 17 years (inclusive) with a diagnosis of 
migraine for at least 6 months before screening, consistent with the International Classification 
of Headache Disorders, 3rd revision (ICHD-3) criteria (Headache Classification Committee of the 
IHS 2013), and a history of ≤14 migraine days per month in each of the 3 months prior to 
screening, prospectively confirmed by review of headache data recorded daily in an electronic 
headache diary device during a 28-day baseline period. 
Because headache consortium guidelines recommend preventive therapies for patients with EM 
occurring on 4 or more days per month due to the frequency of headaches and high degree of 
disability, approximately 30% of EM patients using no more than 2 migraine preventive 
medications for any condition at the time of study enrollment will be allowed to remain on the 
medication if the medication has at least moderate evidence of efficacy for migraine (Silberstein 
et al 2012). Patients on concomitant preventive medications must have been on a stable, 
well-tolerated dose for at least 2 months prior to screening (visit 1), without anticipated changes 
during the study. A list of migraine preventive medications allowed for any condition for the 
duration of the study is presented in Appendix C. Randomization will be stratified by patients 
with and without preventive medications. 
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Primary and Secondary Objectives and Endpoints  
Objectives 
Endpoints 
The primary objective of the study 
is to evaluate the efficacy of 
fremanezumab as compared to 
placebo for the preventive treatment 
of episodic migraine (EM).  
The primary efficacy endpoint is the mean change from baseline 
(28-day baseline period) in the monthly average number of migraine days 
during the 12-week period after the first dose of study drug.  
A secondary objective is to evaluate 
the safety and tolerability of 
fremanezumab in the preventive 
treatment of EM. 
The safety and tolerability endpoints are as follows: 
• 
occurrence of adverse events throughout the study, 
including local injection site reaction/pain 
• 
abnormal standard 12-lead electrocardiogram (ECG) 
findings 
• 
changes from baseline in vital signs (systolic and diastolic 
blood pressure, pulse, temperature, and respiratory rate), 
height, and weight measurements  
• 
changes from baseline in clinical laboratory (serum 
chemistry, hematology, coagulation, and urinalysis) test 
results 
• 
abnormal physical examination findings 
• 
suicidal ideation and behavior as suggested by the 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
A secondary objective of the study 
is to further demonstrate the efficacy 
of fremanezumab as compared to 
placebo for the preventive treatment 
of EM. 
The secondary efficacy endpoints are as follows: 
• 
mean change from baseline (28-day baseline period) in 
monthly average number of headache days of at least 
moderate severity during the 12-week period after the first 
dose of study drug 
• 
proportion of patients reaching at least 50% reduction in the 
monthly average number of migraine days during the 
12-week period after the first dose of study drug 
• 
mean change from baseline (28-day baseline period) in the 
monthly average number of days of use of any acute 
headache medications during the 12-week period after the 
first dose of study drug 
• 
mean change from baseline (day 1) in migraine-related 
disability score, as measured by the Pediatric Migraine 
Disability Assessment (PedMIDAS) questionnaire, at 
12 weeks after administration of the first dose of study drug 
• 
mean change from baseline (day 1) in quality of life, as 
measured by the Pediatric Quality of Life Inventory 
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Objectives 
Endpoints 
(PedsQL), at 12 weeks after administration of the first dose 
of study drug 
A secondary objective of the study 
is to evaluate the immunogenicity of 
fremanezumab and the impact of 
antidrug antibodies (ADAs) on 
clinical outcomes in patients exposed 
to fremanezumab. 
• 
proportion of patients developing ADAs throughout the 
study. The impact of ADAs on safety and efficacy will be 
analyzed if the number of ADA-positive patients allows. 
Exploratory Objective and Endpoints  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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General Study Design: This is a 4-month, multicenter, randomized, double-blind, 
placebo-controlled, parallel-group study to evaluate the efficacy, safety, and tolerability of 
2 different doses (dependent on patients’ body weight) of subcutaneous (sc) fremanezumab and 
placebo. Enrollment will include male and female patients (6 to 17 years of age, inclusive). 
An interim analysis with blinded sample size re-estimation will be conducted by evaluating the 
pooled variability (standard deviation [SD]) of the primary endpoint using the total number of 
patients regardless of the treatment assignment once 50% (±10%) of patients have completed at 
least 3 months of treatment or have withdrawn from the study early. 
Patients will be randomly assigned in a 1:1 ratio between fremanezumab and placebo treatment 
groups: 
• monthly sc administration of fremanezumab  
• monthly sc administration of matching placebo 
The dose of fremanezumab to be administered will be determined by the patient’s weight at 
randomization (visit 2): 
• Patients weighing ≥45.0 kg will receive monthly sc administration of fremanezumab 
at 225 mg. 
• Patients weighing <45.0 kg will receive monthly sc administration of fremanezumab 
at 120 mg. 
The enrollment target is approximately 230 EM patients, with a goal of approximately 20% of 
those patients in the 6- through 11-year-old age group. 
The study consists of a screening visit, a 28-day baseline period, and a 12-week (84-day) 
treatment period, including a final evaluation at week 12 (end-of-treatment [EOT] visit, 
approximately 4 weeks [28 days] after the final dose of study drug). 
Blinded treatment will be administered sc once monthly (approximately every 28 days) for a 
total of 3 doses. Randomization and first treatment administration will occur at visit 2 (day 1), 
and additional doses will be administered at visits 3 and 4 (approximately every 28 days) until 
the third dose is completed. Final study assessments will be performed at visit 5 (EOT visit), 
approximately 28 days after the third (last) dose of study drug. Overall, patients will participate 
in the current study for up to 4 months (including a 28-day baseline period and a 12-week, 
double-blind treatment period).  
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Approximately 30% of EM patients will be allowed to remain on no more than 2 migraine 
preventive medications for any condition, provided the medication is recognized to have at least 
moderate evidence of efficacy or is commonly used. Additional details on concomitant 
medication information are provided in Appendix C. Patients must have been on a stable, 
well-tolerated dose of this preventive 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 approximately 70% of EM patients, these medications are not allowed for migraine or 
for any other indications. As-needed (PRN) use of these medications are allowed during the 
course of the study. PRN use of these medications should be reported in the electronic case 
report form 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. 
Upon completion of the final study assessments, all eligible patients will be offered enrollment in 
a long-term safety and tolerability study (Study TV48125-CNS-30084), consisting of 9 months 
(36 weeks) of open-label treatment and 5 months of follow-up commencing from the last study 
drug administration. In the long-term safety extension study, patients rolling over from the 
current study will be weighed at visit 2 and will receive monthly fremanezumab with dose 
adjusted per weight category (225 mg in patients ≥45.0 kg or 120 mg in patients <45.0 kg). 
Patients who do not complete this study and patients who complete this study but do not wish to 
continue treatment may enroll in Study TV48125-CNS-30084 for the purpose of attending a 
follow-up visit for safety and ADA assessments approximately 5 months (150 days 
[5 half-lives]) after receiving the last dose of study drug. 
Study procedures and assessments with their time points are shown in Table 1. The study 
schematic diagram is shown in Figure 1. 
In the case that a patient is not able to go to the investigational center or the investigational 
center staff are not able to see patients at the investigational center, certain 
assessments/procedures, as detailed in Table 1, may be performed remotely. 
Brief Summary of Study Design for the Trial Registry(s): 
Method of Randomization and Blinding: The sponsor, investigators, study staff (except for 
staff involved in bioanalytical analyses), and patients will be blinded to treatment assignment. A 
computer-generated master randomization list will be provided to drug packaging facilities. 
Packaging vendor(s) will package active and placebo into single-visit kits according to Good 
Manufacturing Practice procedures. The active drug and placebo kits for each dose will be 
identical in appearance and will contain 1 pre-filled syringe (PFS) (for the 225 mg dose and its 
matching placebo) or 2 vials (for the 120 mg dose and its matching placebo). Adequate kit 
supply for upcoming study visits will be managed by interactive response technology (IRT) and 
kept (refrigerated at 2°C to 8°C) on site. 
This is a randomized study. Randomization will be stratified by country, sex, puberty status 
(Tanner staging scale, see Section 7.5), and preventive medication use at baseline (Yes/No). 
Each patient will undergo randomization in a 1:1 ratio within the stratum to which he or she 
belongs to receive fremanezumab or placebo, as assigned by the IRT. The IRT will manage 
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initial drug supply, maintenance of adequate study drug supplies on site, and study 
randomization centrally. At the time of each study visit, the IRT will be queried, and site 
personnel will retrieve and administer a 1.5 mL volume for patients weighing ≥45.0 kg at 
randomization (visit 2) or a 0.8 mL volume for patients weighing <45.0 kg at randomization 
(visit 2) from each PFS or 2 vials contained in the appropriately numbered kit(s). 
Investigational Medicinal Products: Dose, Pharmaceutical Form, Route of Administration, 
and Administration Rate: Pre-filled syringes or single-use vials (active or placebo) will be 
contained in uniquely numbered kits and stored (refrigerated at 2°C to 8°C) on site. Active 
PFS/vials will contain 150 mg/mL of fremanezumab, and placebo PFS/vials will contain the 
same vehicle and excipients as those for active injections. Each kit will contain 1 PFS (1.5 mL) 
or 2 single-use vials (2 mL vials each containing 0.5 mL).  
Study drug will be administered by qualified study personnel as sc injections approximately 
every 4 weeks (28 days) for a total of 3 doses, as follows:  
• Patients with body weight ≥45.0 kg at randomization (visit 2) who are randomized to 
receive fremanezumab will receive 225 mg of fremanezumab as 1 active injection 
(225 mg/1.5 mL) at visits 2, 3, and 4.  
• Patients with body weight ≥45.0 kg at randomization (visit 2) who are randomized to 
receive placebo will receive a single 1.5 mL placebo injection at visits 2, 3, and 4.  
• Patients with body weight <45.0 kg at randomization (visit 2) who are randomized to 
receive fremanezumab will receive 120 mg of fremanezumab as 1 active injection 
(120 mg/0.8 mL) at visits 2, 3, and 4.  
• Patients with body weight <45.0 kg at randomization (visit 2) who are randomized to 
receive placebo will receive a single 0.8 mL placebo injection at visits 2, 3, and 4.  
Fremanezumab is approved for the preventive treatment of migraine in adults. The recommended 
sc injection sites follow the National Institutes of Health (NIH) Clinical Center Patient Education 
Materials (NIH Clinical Center Patient Education Materials 2016). The suggested injection site 
locations for sc administration are the following: back of upper arms, lower 
abdomen/belly/waistline, and front of thighs. The sc injection and location will be recorded for 
each administration visit (visits 2, 3, and 4).  
A 1.5 mL volume (patients weighing ≥45.0 kg at randomization [visit 2]) or 0.8 mL (patients 
weighing <45.0 kg at randomization [visit 2]) from each visit kit(s) (the full dose given with a 
PFS or taken from the vials) must be injected sc for administration to be considered complete. 
Patients randomized to the placebo group will receive volume-matched doses of placebo. 
See the table below for a description of the test investigational medicinal product (IMP) and 
placebo. 
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IMP name 
Test IMP 
Placebo IMP 
Trade name and INN, if 
applicable, or 
company-assigned number 
Fremanezumab 
None 
Formulation 
Sterile, clear to opalescent, colorless to 
slightly yellow solution for injection 
Sterile, clear to opalescent, colorless 
to slightly yellow solution for 
injection 
Unit dose strength(s)/dosage 
level(s) 
225 mg monthly in patients with body 
weight ≥45.0 kg at randomization 
(visit 2) 
120 mg monthly dose in patients with 
body weight <45.0 kg at randomization 
(visit 2) 
Not applicable 
Route of administration 
Subcutaneous injection 
Subcutaneous injection 
Dosing instructions 
Patients with body weight ≥45.0 kg at 
randomization (visit 2): fremanezumab 
225 mg: 1 active injection 
(225 mg/1.5 mL) at visits 2, 3, and 4 
 
Patients with body weight <45.0 kg at 
randomization (visit 2):  
fremanezumab 120 mg: 1 active 
injection (120 mg/0.8 mL) at visits 2, 3, 
and 4 
Patients with body weight ≥45.0 kg at 
randomization (visit 2):  
Placebo: single 1.5-mL injection at 
visits 2, 3, and 4  
 
Patients with body weight <45.0 kg at 
randomization (visit 2):  
Placebo: single 0.8-mL injection at 
visits 2, 3, and 4. 
Packaging 
IMP will be provided as follows: 
• 
225 mg dose: PFS for 
single-use administration 
• 
120 mg dose: taken from two 
2-mL vials each containing 
0.5 mL of IMP for single use 
administration 
Placebo will be provided as follows: 
• 
1.5-mL injection: PFS for 
single-use administration 
• 
0.8-mL injection: taken from 
two 2-mL vials each 
containing 0.5 mL of 
placebo for single-use 
administration 
Manufacturer 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
IMP=investigational medicinal product; INN=international nonproprietary name; PFS=pre-filled syringe. 
Test IMP: Fremanezumab 
Placebo IMP: Same vehicle and excipients as those for fremanezumab active injection 
Reference IMP: NA 
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Duration of Patient Participation and Maximal Exposure to IMP: Patient participation will 
last for up to 4 months (including a 28-day baseline period and a 12-week, double-blind 
treatment period), after which all eligible patients will be offered enrollment in an open-label, 
long-term safety and tolerability study. Patients who do not complete this study and patients who 
complete this study but do not wish to continue treatment may enroll in Study TV48125-CNS-
30084 for the purpose of attending a follow-up visit for safety and ADA assessments 
approximately 5 months (150 days [5 half-lives]) after receiving the last dose of study drug. 
Study Duration: 51 months, from Q1 2020 to Q2 2024 
End of Study: End of study is defined as the date the last patient attends the EOT/early 
withdrawal visit (visit 5). 
Plans for Treatment or Care after the Patient Has Ended Participation in the Study: All 
eligible patients completing the study will be offered enrollment in the long-term extension 
Study TV48125-CNS-30084, unless it is decided to stop the treatment. 
Inclusion Criteria: Patients may be included in the study only if they meet all of the following 
criteria:  
a. The patient is a male or female between the ages of 6 to 17 years (inclusive) on the 
day of randomization to study drug/IMP. 
b. The patient’s parent(s) or legal guardian(s) must give written informed consent, and 
the patient must give assent (in accordance with local regulations). 
Note: In some countries, patients aged 15 to 17 years (inclusive) may give written 
informed consent; however, the patient’s parent(s) or legal guardian(s) must be 
informed, per local regulations. 
c. The patient has a clinical history of recurrent headache consistent with the diagnosis 
of migraine for at least 6 months before screening, consistent with ICHD-3 criteria 
(Headache Classification Committee of the IHS 2013), and a history of ≤14 headache 
days per month in each of the 3 months prior to screening (visit 1). 
d. The patient or parent/caregiver has maintained a prospectively collected headache 
diary during a 28-day baseline period in which at least 4 migraine days and 
≤14 headache days were recorded. Migraine days have at least 1 of the following 
migraine characteristics: 
− head pain of moderate to severe intensity lasting for 2 or more hours in duration 
and accompanied by either throbbing quality, predominantly unilateral location, 
or aggravation with normal activities. 
− headache is accompanied by a migraine-associated symptom, such as 
photophobia, phonophobia, abdominal pain, nausea, or vomiting. 
− headache is preceded by an aura, as described by ICHD-3 criteria. 
− headache was treated by a nonsteroidal anti-inflammatory drug (NSAID), 
paracetamol, triptan, or ergot preparation. 
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e. The patient does not have chronic daily headache. For the purposes of this study, 
chronic daily headache is operationally defined as <4 headache-free days during the 
28-day baseline period. 
f. [Revision 01] Not using preventive migraine medications (listed in Appendix C) or 
using no more than 2 preventive migraine medications (listed in Appendix C) for 
migraine or other medical conditions, as long as the dose and regimen have been 
stable for at least 2 months prior to screening (visit 1). A list of migraine preventive 
medications allowed for any condition for the duration of the study for approximately 
30% of patients is presented in Appendix C. 
Note: A person is considered to be not using migraine preventive medications (listed 
in Appendix C) when at least 5 half-lives have passed since the last use of the 
medication prior to screening (visit 1) or at least 4 months have passed since the last 
use of Onabotulinium toxin A or B prior to screening (visit 1). The use of other 
agents that are not included in Appendix C but used for migraine prevention is 
permitted during the study; however, these patients will not be counted toward the 
approximately 30% patient limit threshold. 
g. Females who are postmenarchal or ≥12 years of age may be included only if they 
have a negative beta-human chorionic gonadotropin (β-HCG) test at baseline or are 
sterile. Definitions of females of childbearing potential and females who are not of 
childbearing potential are given in Appendix G. 
h. Females who are postmenarchal or ≥12 years of age and sexually active must use 
highly effective birth control methods with their male partners for the duration of the 
study (ie, starting at screening) and for 6 months after the last dose of IMP. Males 
who are sexually active with female partners must use a condom for the duration of 
the study and for 6 months after the last administration of IMP. Further details are 
included in Appendix G. 
i. The patient/caregiver has demonstrated compliance with the electronic headache 
diary during the 28-day baseline period by entry of headache data on a minimum of 
21 out of 28 days (approximately 75% diary compliance). 
j. The patient is in good health, as determined by a medical and psychiatric history, 
medical examination, 12-lead ECG, serum chemistry, hematology, coagulation, 
urinalysis, and serology. 
k. The patient/caregiver must be willing and able to comply with study requirements and 
return to the clinic as required for the duration of the study. 
l. The patient weighs at least 17.0 kg on the day of randomization to study drug/IMP. 
m. The patient has a body mass index ranging from the 5th to 120% of the 95th percentile, 
inclusive, at screening based on the local standard. 
n. The patient has received all recommended age-appropriate vaccines according to 
local standard of care and schedule prior to screening. 
Exclusion Criteria: Patients will be excluded from participating in this study if they meet any of 
the following criteria: 
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a. The patient is using medications containing opioids (including codeine) or 
barbiturates (including Fiorinal®, Fioricet®, or any other combination containing 
butalbital) for the treatment of migraine during the 3 months prior to the day of the 
screening visit. 
b. The patient has used an intervention/device (eg, scheduled nerve block or transcranial 
magnetic stimulation) for the treatment of migraine or in the head or neck area for 
any condition during the 2 months prior to the day of the screening visit. 
c. The patient has any clinically significant cardiovascular (including congenital cardiac 
anomalies or thromboembolic events), endocrine, gastrointestinal, genitourinary, 
hematologic, hepatic, immunologic, neurologic, ophthalmic, pulmonary, renal 
disease, or complications of an infection, at the discretion of the investigator. 
d. [Revision 01] The patient has a current history of a clinically significant psychiatric 
condition, at the discretion of the investigator. Any prior history of a suicide attempt, 
or a history of suicidal ideation with a specific plan within the past 2 years, must be 
excluded  
e. The patient has an ongoing infection or a known history of human immunodeficiency 
virus infection, tuberculosis, Lyme disease, chronic hepatitis B or C, or a known 
active infection of coronavirus disease 2019 (COVID-19). 
f.  The patient has a past or current history of cancer. 
g. The patient is pregnant or nursing.  
h. The patient has a 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. 
i. The patient has participated in another study of an IMP (or a medical device) within 
the 30 days (or 90 days for biologics) or 5 half-lives previous to the day of the 
screening visit (whichever is longer), or is currently participating in another study of 
an IMP (or a medical device). 
j. The patient has had exposure to a mAb targeting the calcitonin gene-related peptide 
(CGRP) pathway (erenumab, eptinezumab, galcanezumab, fremanezumab) during the 
6 months previous to the day of the screening visit. 
k. Previous participation in the Phase 1 pharmacokinetics study 
(Study TV48125-CNS-10141). 
l. In the judgment of the investigator, the patient has an abnormal finding on the 
baseline 12-lead ECG considered clinically significant. 
m. In the judgment of the investigator, the patient has a significantly abnormal finding 
during the 28-day baseline period, including hematology, blood chemistry, 
coagulation tests, or urinalysis values/findings (abnormal tests may be repeated for 
confirmation). 
n. The patient has hepatic enzymes (alanine aminotransferase [ALT], aspartate 
aminotransferase [AST], alkaline phosphatase [ALP]) more than 1.5× the upper limit 
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of normal (ULN) during the 28-day baseline period, after confirmation in a repeat 
test, or suspected hepatocellular damage that fulfills the criteria for Hy’s law. 
o. The patient has serum creatinine more than 1.5× the ULN, clinically significant 
proteinuria (urine dipstick +4), an estimated glomerular filtration rate of 
<75 mL/min/1.73m2, as calculated by the revised Schwartz formula 
(eGFR=[0.413×Ht]/serum creatinine), or evidence of renal disease during the 28-day 
baseline period. 
p. The patient has any history of alcohol or drug abuse. The definition of alcohol or drug 
abuse, including marijuana, is based on the investigator’s clinical judgment. 
q. In the judgment of the investigator, the patient cannot fully participate in or 
successfully complete the study for its full duration for any of the following reasons: 
− The patient is mentally or legally incapacitated or unable to give assent/consent 
for any reason. 
− The patient is in custody due to an administrative or a legal decision or is in 
residential treatment. 
− The patient/caregiver is unable to be contacted in case of emergency. 
− The patient has any other condition, which, in the opinion of the investigator, 
makes the patient inappropriate for inclusion in the study. 
− The patient is a relative of a study center or sponsor employee who is directly 
involved in the study. 
r. Vulnerable patients (eg, people kept in detention) whose vulnerability is based on a 
condition other than the age required for study eligibility. 
s. The patient received a live attenuated vaccine (eg, intranasal flu vaccine, and measles, 
mumps, and rubella vaccine) within the 12-week period prior to screening. 
Note: If a medical need arises during the study, the patient may receive a live 
attenuated vaccine. 
t. The patient has a known hypersensitivity to the active substance or to any of the 
excipients of the study drug. 
u. The patient has a current or past medical history of hemiplegic migraine. 
Statistical Considerations 
Sample Size Rationale: The sample size planned is approximately 220 patients (110 evaluable 
patients completing the study per treatment group). Assuming a treatment difference of 1.8 days 
(reduction in monthly average number of migraine days) and a common SD of 4.31, a sample 
size of 110 patients per treatment group gives at least 87% power for the study to succeed at an 
alpha level of 0.05. Assuming a 4% discontinuation rate, approximately 230 patients 
(115 patients per treatment group) will be randomized. Patients will be randomized to receive 
either monthly sc administration of fremanezumab or placebo. 
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Analysis Sets 
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. 
Safety Analysis Set: The safety analysis set will include all randomized 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. 
Full Analysis Set: The full analysis set will include all patients in the ITT population who 
receive at least 1 dose of study drug and have at least 10 days of diary entries postbaseline for 
efficacy assessments on the primary endpoint. 
Per-Protocol Analysis Set: The per-protocol analysis set will consist of all patients in the Full 
Analysis Set who have completed the study without any important deviations such as, important 
inclusion/exclusion criteria deviations, important deviation or omissions of the IMP 
administration, or unexpected drug concentration findings, and who have at least 75% diary 
compliance after the start of treatment. 
Analysis of Primary Endpoint: The primary efficacy endpoint, the mean change from baseline 
(28-day baseline period) in the monthly average number of migraine days during the 12-week 
period after the first dose of study drug, will be analyzed using an analysis of covariance method. 
The model will include treatment, sex, puberty status, region, baseline weight category (<45.0 kg 
or ≥45.0 kg), and preventive medication use at baseline (Yes/No) as fixed effects and baseline 
number of migraine days as a covariate. Ninety-five percent confidence intervals will be 
constructed for the least squares mean differences between the fremanezumab group and the 
placebo group. An interim analysis with blinded sample size re-estimation will be conducted by 
evaluating the pooled variability (SD) of the primary endpoint using the total number of patients 
regardless of the treatment assignment once 50% (±10%) of patients have completed at least 3 
months of treatment or have withdrawn from the study early. For the purpose of this study, a 
migraine day will be defined as a calendar day where the patient reports either of the following:  
• headache pain that lasts ≥2 hours and is accompanied by ≥1 migraine symptom(s) 
• the patient used acute migraine-specific medication (triptans or ergots) to treat a 
headache of any severity or duration  
The detailed algorithm for deriving migraine days will be described in the statistical analysis 
plan. 
Analysis of Secondary Endpoints: The same analysis used for the primary efficacy endpoint 
will be performed for the continuous secondary efficacy endpoints. For the proportion of 
responders, defined as at least 50% reduction from baseline in the monthly average number of 
migraine days, a logistic regression model will be used with the following factors: treatment, sex, 
region, puberty status, baseline weight category (<45.0 kg or ≥45.0 kg), and preventive 
medication use at baseline (Yes/No). The odds ratio, 95% confidence interval for the odds ratio, 
and p-value for the treatment comparison will be presented. 
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Sensitivity Analysis: A sensitivity analysis for the primary efficacy endpoint will be conducted 
by using multiple imputation method for missing data. Sensitivity analysis using Mixed-Effect 
Model Repeated Measure method also will be conducted for change from baseline to months 1 
through 3 in migraine days. The details will be described in the statistical analysis plan. 
Multiple Comparisons and Multiplicity: A fixed-sequence (hierarchical) testing procedure will 
be implemented to control the Type 1 error rate at 0.05. The sequence of comparisons will start 
with the analysis of the primary endpoint and will follow with the secondary efficacy endpoints. 
Analysis of Exploratory Endpoints: 
 
 
Safety Analyses: Safety analyses will be performed on the safety analysis set. 
Safety assessments and time points are provided in Table 1. 
All adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Each patient will be counted only once in each preferred term or system organ class 
category for the analyses of safety. Summaries will be presented for all adverse events (overall 
and by severity), adverse events determined by the investigator to be related to test IMP (and/or 
PFS) (ie, reasonable possibility) (defined as related or with missing relationship) (overall and by 
severity), serious adverse events, serious adverse device effects, protocol-defined adverse events 
of special interest, and adverse events and adverse device effects causing withdrawal from the 
study. Summaries will be presented by treatment group and for all patients. Patient listings of 
serious adverse events, serious adverse device effects, adverse events, and adverse device effects 
leading to withdrawal will be presented. 
Changes in laboratory, ECG, and vital signs measurements data will be summarized 
descriptively. All values will be compared with predefined criteria to identify potentially 
clinically significant values or changes, and such values will be listed. 
Suicidal ideation and behavior will be measured using the C-SSRS. Data for patients with 
positive findings will be listed. 
The use of concomitant medications will be summarized by therapeutic class using descriptive 
statistics. Concomitant medications will include all medications taken while the patient is treated 
with study drug. 
For continuous variables, descriptive statistics (n, mean, SD, median, minimum, and maximum) 
will be provided for actual values and changes from baseline to each time point. For categorical 
variables, patient counts and percentages will be provided. Descriptive summaries of serious 
adverse events, patient withdrawals due to adverse events, and potentially clinically significant 
abnormal values (clinical laboratory or vital signs) based on predefined criteria will 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. 
Assessment of Local Tolerability and Pain and Tolerability Analysis: Assessment of 
injection site will be performed after administration of each dose of study drug, before the patient 
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leaves the investigational site. Injection site reactions will be recorded as adverse events 
according to the following severity assessment criteria: 
• Assessment of injection site erythema, induration, and ecchymosis will be recorded 
after administration of each dose of study drug according to measurements: 5 to ≤50 
mm (mild), >50 to ≤100 mm (moderate), and >100 mm (severe).  
• Injection site pain will be recorded using the 11-point numerical rating scale and will 
be mapped to mild, moderate, or severe, according to patient’s self-report of pain 
intensity. 
• Appropriate treatment may be provided if necessary, in which case it must be 
recorded as concomitant medication. 
Pharmacokinetic Analysis: Pharmacokinetic plasma concentration results (fremanezumab) will 
be tabulated descriptively at each planned sampling time point by weight cutoff. 
In addition, the most appropriate population pharmacokinetic model will be developed. This 
analysis will be reported separately, as appropriate. 
Pharmacokinetic/Pharmacodynamic Analysis: The pharmacokinetic/pharmacodynamic 
relationship may be estimated by compartmental techniques. The pharmacokinetic parameters 
will be based on fremanezumab measurements. The pharmacodynamic measures will be the 
efficacy/safety responses.  
The pharmacokinetic/pharmacodynamic relationship may be estimated using the most 
appropriate model after comparing different candidate models for their quality of fit. If 
performed, this analysis will be reported separately. 
Immunogenicity Analysis: 
Summary of immunogenicity results will be provided, and the incidence of immunogenicity will 
be calculated. The impact of immunogenicity on the pharmacokinetic profile, drug efficacy, and 
clinical safety will be evaluated if data allows. This analysis will be reported separately. 
Planned Interim Analysis: 
An interim analysis with blinded sample size re-estimation will be conducted by evaluating the 
pooled variability (SD) of the primary endpoint using the total number of patients regardless of 
the treatment assignment once 50% (±10%) of patients have completed at least 3 months of 
treatment or have withdrawn from the study early.  
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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
AMENDMENT HISTORY .............................................................................................................3 
INVESTIGATOR AGREEMENT...................................................................................................5 
COORDINATING INVESTIGATOR AGREEMENT ...................................................................7 
CLINICAL STUDY PROTOCOL SYNOPSIS...............................................................................9 
LIST OF ABBREVIATIONS ........................................................................................................31 
1.
INTRODUCTION AND BACKGROUND INFORMATION ..................................33 
1.1. 
Introduction .................................................................................................................33 
1.2. 
Findings from Nonclinical and Clinical Studies .........................................................35 
1.2.1. 
Nonclinical Studies .....................................................................................................35 
1.2.2. 
Clinical Studies ...........................................................................................................36 
1.2.2.1. 
Clinical Pharmacology Studies ...................................................................................37 
1.2.2.2. 
Clinical Safety and Efficacy Studies ..........................................................................37 
1.3. 
Known and Potential Benefits and Risks to Patients ..................................................37 
1.3.1. 
Known and Potential Benefits and Risks of the Test Investigational 
Medicinal Product(s) and/or Device ...........................................................................37 
1.3.1.1. 
Identified Risks ...........................................................................................................37 
1.3.1.2. 
Important Potential Risk .............................................................................................38 
1.3.2. 
Overall Benefit and Risk Assessment for This Study ................................................38 
2.
STUDY OBJECTIVES AND ENDPOINTS ..............................................................39 
2.1. 
Primary and Secondary Study Objectives and Endpoints ..........................................39 
2.1.1. 
Justification of Primary Endpoint ...............................................................................40 
2.2. 
Exploratory Objective and Endpoints .........................................................................40 
3.
STUDY DESIGN .......................................................................................................42 
3.1. 
General Study Design and Study Schematic Diagram ...............................................42 
3.2. 
Planned Number of Patients and Countries ................................................................45 
3.3. 
Justification for Study Design and Selection of Population .......................................45 
3.4. 
Stopping Rules for the Study ......................................................................................45 
3.5. 
Schedule of Study Procedures and Assessments ........................................................46 
4.
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................50 
4.1. 
Patient Inclusion Criteria ............................................................................................50 
4.2. 
Patient Exclusion Criteria ...........................................................................................51 
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4.3. 
Withdrawal Criteria and Procedures for the Patient ...................................................53 
4.3.1. 
Study-Specific Patient Withdrawal Criteria and Procedures ......................................55 
4.4. 
Replacement of Patients .............................................................................................55 
4.5. 
Rescreening .................................................................................................................55 
4.6. 
Screening Failure ........................................................................................................56 
5. 
TREATMENTS ..........................................................................................................57 
5.1. 
Investigational Medicinal Products Used in the Study ...............................................57 
5.1.1. 
Test Investigational Medicinal Product ......................................................................57 
5.1.1.1. 
Starting Dose and Dose Levels ...................................................................................57 
5.1.1.2. 
Dose Modification and Dose Stratification ................................................................57 
5.1.2. 
Reference Investigational Medicinal Product .............................................................57 
5.1.3. 
Placebo Investigational Medicinal Product ................................................................58 
5.2. 
Preparation, Handling, Labeling, Storage, and Accountability for IMPs ...................60 
5.2.1. 
Storage Conditions and Handling ...............................................................................60 
5.2.2. 
Labeling ......................................................................................................................60 
5.2.3. 
Accountability .............................................................................................................60 
5.3. 
Justification for Investigational Medicinal Products ..................................................61 
5.3.1. 
Justification for Dose of Test Investigational Medicinal Product and/or 
Device .........................................................................................................................61 
5.3.2. 
Justification for Use of Placebo Investigational Medicinal Product ..........................63 
5.4. 
Treatment After the End of the Study .........................................................................63 
5.5. 
Restrictions .................................................................................................................63 
5.6. 
Prior and Concomitant Medication or Therapy ..........................................................64 
5.7. 
Procedures for Monitoring Patient Compliance .........................................................65 
5.8. 
Randomization and Blinding ......................................................................................65 
5.9. 
Maintenance of Randomization and Blinding ............................................................65 
5.9.1. 
Maintenance of Randomization ..................................................................................65 
5.9.2. 
Blinding and Unblinding ............................................................................................66 
5.9.3. 
Data Monitoring Committee .......................................................................................66 
5.10. 
Total Blood Volume ...................................................................................................66 
6. 
ASSESSMENT OF EFFICACY ................................................................................67 
6.1. 
Assessments of Efficacy .............................................................................................67 
6.1.1. 
Electronic Headache Diary .........................................................................................67 
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6.1.2. 
Pediatric Migraine Disability Assessment ..................................................................67 
6.1.3. 
Patient Global Impression of Improvement Scale ......................................................68 
6.1.4. 
Pediatric Quality of Life Inventory .............................................................................68 
7. 
ASSESSMENT OF SAFETY .....................................................................................69 
7.1. 
Adverse Events ...........................................................................................................69 
7.1.1. 
Definition of an Adverse Event ..................................................................................69 
7.1.2. 
Definition of an Adverse Device Effect .....................................................................70 
7.1.3. 
Recording and Reporting of Adverse Events .............................................................70 
7.1.4. 
Recording and Reporting of Adverse Device Effect ..................................................71 
7.1.5. 
Severity of an Adverse Event .....................................................................................71 
7.1.6. 
Relationship of an Adverse Event to the Investigational Medicinal Product 
and/or Device ..............................................................................................................71 
7.1.7. 
Serious Adverse Events and Serious Adverse Device Effects ...................................72 
7.1.7.1. 
Definition of a Serious Adverse Event .......................................................................72 
7.1.7.2. 
Definition of a Serious Adverse Device Effect ..........................................................73 
7.1.7.3. 
Expectedness ...............................................................................................................73 
7.1.7.4. 
Reporting a Serious Adverse Event ............................................................................74 
7.1.8. 
Protocol-Defined Adverse Events of Special Interest ................................................76 
7.1.9. 
Protocol Deviations Because of an Adverse Event ....................................................76 
7.2. 
Pregnancy ...................................................................................................................76 
7.3. 
Medication Error and Special Situations Related to the Investigational 
Medicinal Products .....................................................................................................77 
7.4. 
Clinical Laboratory Tests ...........................................................................................78 
7.4.1. 
Serum Chemistry, Hematology, Coagulation, and Urinalysis ....................................78 
7.4.2. 
Other Clinical Laboratory Tests .................................................................................79 
7.4.2.1. 
Human Chorionic Gonadotropin Tests .......................................................................79 
7.5. 
Physical Examinations ................................................................................................79 
7.6. 
Vital Signs ..................................................................................................................80 
7.7. 
Electrocardiography ....................................................................................................80 
7.8. 
Assessment of Local Tolerability and Pain ................................................................81 
7.9. 
Assessment of Suicidality ...........................................................................................81 
7.10. 
Concomitant Therapy or Medication ..........................................................................81 
8. 
ASSESSMENT OF PHARMACOKINETICS AND IMMUNOGENICITY ............82 
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8.1. 
Pharmacokinetic Assessment ......................................................................................82 
8.1.1. 
Specimen Sampling, Handling, and Shipment ...........................................................82 
8.2. 
Pharmacodynamics Assessment .................................................................................82 
8.3. 
Immunogenicity Testing .............................................................................................82 
8.4. 
Assessment of Exploratory Biomarkers .....................................................................82 
9. 
STATISTICS ..............................................................................................................83 
9.1. 
Sample Size and Power Considerations .....................................................................83 
9.2. 
Analysis Sets ...............................................................................................................83 
9.2.1. 
Intent-to-Treat Analysis Set ........................................................................................83 
9.2.2. 
Safety Analysis Set .....................................................................................................83 
9.2.3. 
Full Analysis Set .........................................................................................................83 
9.2.4. 
Per-Protocol Analysis Set ...........................................................................................83 
9.3. 
Data Handling Conventions ........................................................................................84 
9.3.1. 
Handling Withdrawals and Missing Data ...................................................................84 
9.4. 
Study Population .........................................................................................................84 
9.4.1. 
Patient Disposition ......................................................................................................84 
9.4.2. 
Demographic and Baseline Characteristics ................................................................84 
9.5. 
Efficacy Analysis ........................................................................................................84 
9.5.1. 
Primary Endpoint ........................................................................................................85 
9.5.1.1. 
Estimand for the Primary Endpoint ............................................................................85 
9.5.2. 
Secondary Endpoints ..................................................................................................85 
9.5.3. 
Exploratory/Other Endpoints ......................................................................................85 
9.5.4. 
Planned Method of Analysis .......................................................................................86 
9.5.4.1. 
Primary Efficacy Analysis ..........................................................................................86 
9.5.4.2. 
Sensitivity and Supplementary Analyses ....................................................................87 
9.5.4.3. 
Secondary Efficacy Analysis ......................................................................................87 
9.5.4.4. 
Exploratory Efficacy Analysis ....................................................................................87 
9.6. 
Multiple Comparisons and Multiplicity......................................................................87 
9.7. 
Safety Analysis ...........................................................................................................87 
9.8. 
Tolerability Analysis ..................................................................................................88 
9.9. 
Pharmacokinetic Analysis ..........................................................................................89 
9.10. 
Pharmacokinetic/Pharmacodynamic Analysis ............................................................89 
9.11. 
Immunogenicity Analysis ...........................................................................................89 
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9.12. 
Planned Interim Analysis ............................................................................................89 
9.13. 
Reporting Deviations from the Statistical Plan ..........................................................89 
10. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................90 
11. 
COMPLIANCE STATEMENT ..................................................................................90 
12. 
DATA MANAGEMENT AND RECORD KEEPING ..............................................90 
13. 
FINANCING AND INSURANCE .............................................................................91 
14. 
PUBLICATION POLICY ..........................................................................................91 
15. 
REFERENCES ...........................................................................................................92 
16. 
SUMMARY OF CHANGES TO PROTOCOL .........................................................95 
16.1. 
Amendment 09 Dated 24 September 2023 .................................................................95 
16.2. 
Administrative Letter Dated 21 December 2021 ......................................................108 
16.3. 
Amendment 08 Dated 09 December 2021 ................................................................111 
16.4. 
Administrative Letter Dated 10 May 2021 ...............................................................117 
16.5. 
Administrative Letter Dated 04 February 2021 ........................................................119 
16.6. 
Administrative Letter Dated 05 November 2020 .....................................................120 
16.7. 
Amendment 07 Dated 20 August 2020 ....................................................................122 
16.8. 
Amendment 06 Dated 27 July 2020 .........................................................................126 
16.9. 
Administrative Letter 02 Dated 07 July 2020...........................................................129 
16.10. 
Amendment 05 Dated 27 June 2020 .........................................................................130 
16.11. 
Amendment 04 Dated 20 April 2020 ........................................................................138 
16.12. 
Administrative Letter 01 Dated 10 March 2020 .......................................................141 
16.13. 
Amendment 03 Dated 03 February 2020 ..................................................................142 
16.14. 
Amendment 02 Dated 05 December 2019 ................................................................146 
16.15. 
Amendment 01 Dated 21 June 2019 .........................................................................157 
APPENDIX A. CLINICAL LABORATORIES AND OTHER DEPARTMENTS AND 
INSTITUTIONS .......................................................................................................166 
APPENDIX B. STUDY PROCEDURES AND ASSESSMENTS BY VISIT .........................168 
APPENDIX C. PREVENTIVE MIGRAINE MEDICATIONS FOR ANY 
CONDITION ALLOWED FOR THE DURATION OF THE STUDY FOR 
APPROXIMATELY 30% OF PATIENTS ..............................................................171 
APPENDIX D. CLINICAL CRITERIA FOR DIAGNOSING ANAPHYLAXIS ...................172 
APPENDIX E. QUALITY CONTROL AND QUALITY ASSURANCE ...............................173 
APPENDIX F. ETHICS ............................................................................................................175 
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APPENDIX G. BIRTH CONTROL METHODS AND PREGNANCY TESTING ................177 
APPENDIX H. LOST TO FOLLOW-UP .................................................................................178 
APPENDIX I. GUIDANCE ON SAFETY MONITORING ....................................................179 
APPENDIX J. TOTAL BLOOD VOLUME.............................................................................182 
APPENDIX K. PRODUCT COMPLAINTS ............................................................................183 
APPENDIX L. DATA MANAGEMENT AND RECORD KEEPING ....................................187 
APPENDIX M. PUBLICATION POLICY ..............................................................................190 
APPENDIX N. STORAGE AND DESTRUCTION OF BIOLOGICAL SAMPLES ..............191 
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LIST OF TABLES 
Table 1: 
Study Procedures and Assessments ............................................................................47 
Table 2: 
Investigational Medicinal Products Used in the Study ...............................................59 
Table 3: 
The Relationship of an Adverse Event to the IMP and/or Device .............................72 
Table 4: 
Clinical Laboratory Tests ...........................................................................................79 
 
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LIST OF FIGURES 
Figure 1: 
Overall Study Schematic Diagram .............................................................................44 
Figure 2: 
Decision Tree for Adverse Events and Adverse Device Effects Classification .........71 
 
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LIST OF ABBREVIATIONS  
Abbreviation 
Term 
β-HCG 
Beta-human chorionic gonadotropin 
ADAs 
antidrug antibodies 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase (SGPT) 
AST 
aspartate aminotransferase (SGOT) 
BLA 
Biological License Application 
BP 
blood pressure 
CDMS 
clinical data management system 
CFR 
Code of Federal Regulations (USA) 
CGRP 
calcitonin gene-related peptide 
CH 
cluster headache 
CM 
chronic migraine 
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 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EM 
episodic migraine 
EMA 
European Medicines Agency 
EOT 
end-of-treatment 
EU 
European Union 
EudraCT 
European Clinical Trials 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GPSP 
Global Patient Safety and Pharmacovigilance 
HIV 
human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
ICHD-3 
International Classification of Headache Disorders, 3rd revision 
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Abbreviation 
Term 
IEC 
Independent Ethics Committee 
IgG 
immunoglobulin G 
IgG2 
immunoglobulin G2 
IHS 
International Headache Society 
IMP 
investigational medicinal product 
IND 
Investigational New Drug 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IRT 
interactive response technology 
ITT 
intent-to-treat 
iv 
intravenous 
LSO 
local safety officer 
mAb 
monoclonal antibody 
n 
number 
NDA 
New Drug Application 
NIH 
National Institutes of Health 
NOAEL 
no-observed-adverse-effect level 
NSAID 
nonsteroidal anti-inflammatory drug 
PedMIDAS 
Pediatric Migraine Disability Assessment 
PedsQL 
Pediatric Quality of Life Inventory 
PEF 
peak expiratory flow 
PFS 
pre-filled syringe 
PGI-I 
Patient Global Impression of Improvement 
PPTH 
persistent posttraumatic headache 
PRN 
as-needed 
RBC 
red blood cell 
RTSM 
Randomization and Trial Supply Management 
SAR 
serious adverse reaction 
sc 
subcutaneous 
SD 
standard deviation 
SOP 
Standard Operating Procedure 
SUSAR 
suspected unexpected serious adverse reaction 
ULN 
upper limit of normal 
US or USA 
United States or United States of America 
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1. 
INTRODUCTION AND BACKGROUND INFORMATION  
1.1. 
Introduction  
Fremanezumab is a humanized immunoglobulin G2 (IgG2) Δa/kappa monoclonal antibody 
(mAb) derived from a murine precursor. In September 2018, fremanezumab was approved in the 
United States of America (US) for the preventive treatment of migraine in adults and marketed 
under the trade name AJOVY®. Fremanezumab has also been approved in the European Union 
(EU) and a number of countries worldwide. Fremanezumab is a potent, selective calcitonin 
gene-related peptide (CGRP) binder and blocks both CGRP isoforms (α- and β-CGRP) from 
binding to the CGRP receptor. While the precise mechanism of action by which fremanezumab 
prevents migraine is unknown, it is believed that blocking CGRP prevents activation of the 
trigeminal system. Fremanezumab is highly specific for CGRP and does not bind to closely 
related family members (eg, amylin, calcitonin, intermedin, and adrenomedullin). Two mutations 
were introduced into the constant region of the fremanezumab heavy chain to limit antibody 
effector functions. This loss of function prevents fremanezumab from stimulating 
antibody-dependent cell-mediated cytotoxicity and triggering complement-mediated lysis; these 
activities can lead to unwanted consequences, such as cell lysis, opsonization, and cytokine 
release and inflammation (Armour et al 1999, Zeller et al 2008).  
The safety and tolerability of fremanezumab (intravenous [iv] doses of 0.2 to 2000 mg and 
subcutaneous [sc] doses of 225 to 900 mg) as well as the pharmacokinetic profile of 225 to 
900 mg sc and iv have been well characterized in the Phase 1 development program in adults. 
Furthermore, the safety and effectiveness of fremanezumab have been demonstrated in 2 
Phase 2b studies and 3 Phase 3 studies in adult patients with migraine. The 2 Phase 2b studies 
were a randomized, double-blind, placebo-controlled Phase 2b study of 2 sc dosing regimens of 
fremanezumab (monthly fremanezumab at 900 mg or fremanezumab at 675 mg followed by 
monthly fremanezumab at 225 mg) in patients with chronic migraine (CM) and a randomized, 
double-blind, placebo-controlled Phase 2b study of 2 sc dosing regimens of fremanezumab 
(monthly fremanezumab at 675 or 225 mg) in patients with episodic migraine (EM). 
Two completed, randomized, double-blind, placebo-controlled Phase 3 studies (Studies 
TV48125-CNS-30049 in CM and TV48125-CNS-30050 in EM) and 1 completed, randomized, 
double-blind Phase 3 long-term safety study (Study TV48125-CNS-30051 in migraine [EM and 
CM]) were conducted to further evaluate the efficacy, safety, and tolerability of various dose 
regimens of fremanezumab in the preventive treatment of migraine. Additional studies within the 
migraine development program of fremanezumab include the completed Phase 3b study (Study 
TV48125-CNS-30068) in patients from the EU and US to evaluate the safety and efficacy of 
fremanezumab in migraine patients who have failed multiple preventive medications, 2 ongoing 
Phase 2b/3 studies in Japanese and Korean EM and CM patients (Studies 406-102-00002 and 
406-102-00001, respectively), and 1 ongoing long-term safety study (Study 406-102-00003) in 
CM and EM to evaluate the safety and efficacy of fremanezumab. One Phase 4 study (Study 
TV48125-MH-40142) was conducted to evaluate the efficacy and safety of fremanezumab in 
adult patients with migraine and comorbid major depressive disorder. 
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The pediatric migraine development program includes a completed Phase 1, single-dose, 
open-label study with administration of single sc doses of 75 mg in pediatric migraine patients 6 
to 11 years of age, inclusive (Study TV48125-CNS-10141). 
Fremanezumab is further studied for the preventive treatment of persistent posttraumatic 
headache (PPTH) in 1 Phase 2 study (Study TV48125-CNS-20024) that is comparing the 
efficacy and safety of the sc dose regimen of fremanezumab versus placebo in patients with 
PPTH. Fremanezumab was being studied for the preventive treatment of cluster headache (CH) 
in 3 Phase 3 studies: Study TV48125-CNS-30056 in patients with episodic CH, Study TV48125-
CNS-30057 in patients with chronic CH, and a long-term safety Study TV48125-CNS-30058 in 
CH. All 3 studies were terminated by Teva because a prespecified futility analysis showed that 
the primary endpoint of mean change from baseline in the monthly average number of CH 
attacks during the 12-week treatment period was unlikely to be met.  
Migraine is a prevalent condition characterized by attacks of headache and associated symptoms 
(such as nausea, photophobia, or phonophobia). Among populations of children of all ages, 
migraine prevalence ranges from 8% to 11% (Abu-Arefeh and Russell 1994, Abu-Arafeh et al 
2010, Laurell et al 2004, Ozge et al 2013, Stovner and Andree 2010). The prevalence of migraine 
is substantially lower among children younger than 7 years, ranging from 1% to 3% (Lewis 
2009). The prevalence of migraine in children younger than 12 years is less than one-third of the 
prevalence among adolescents (Fendrich et al 2007, Ozge et al 2013, Stovner and Andree 2010, 
Unalp et al 2007). Therefore, the prevalence of migraine increases throughout childhood, with 
estimates for adolescents comparable to the 12% to 15% prevalence estimates cited for adult 
populations (Buse et al 2013, Burch et al 2015, Stovner and Andree 2010, Victor et al 2010). 
Migraine has been classified by headache frequency in the International Classification of 
Headache Disorders, 3rd revision (ICHD-3) and is described as EM, which is defined as 
headaches occurring on less than 15 days per month, and CM, which is defined as headaches on 
at least 15 days per month for at least 3 months, with the features of migraine on at least 8 days 
per month (Headache Classification Committee of the IHS 2013, Lipton and Silberstein 2015).  
Treatment options for migraine include non-pharmacological biobehavioral strategies and 
pharmacological strategies. Topiramate is the only migraine preventive medication approved for 
pediatric populations, but it is not approved in all regions of the EU and is limited to adolescents 
ages 12 through 17. Non-pharmacological strategies for adults and children with migraine 
include sleep hygiene, exercise, dietary modifications, biofeedback, and stress management 
(O’Brien et al 2012, Silberstein 2000). Pharmacologic agents used for the treatment of migraine 
can be classified as acute (ie, to alleviate the acute migraine attack) or prophylactic (ie, 
preventing headache recurrence). Preventive therapy is indicated for all individuals with CM and 
for those with EM that have high frequency of attacks (Lipton and Silberstein 2015). If given 
during CM, prophylactic treatments could revert the patients to EM and continue to provide 
benefit after remission is achieved (Manack et al 2011). Most specialists require that a child 
experience a minimum of 1 headache per week or 3 to 4 headaches per month to justify 
prophylactic medication. Children who report intensive and prolonged headaches (lasting more 
than 48 hours), even if infrequent, may also be offered prophylactic therapy (Kacperski 2015). It 
is recommended that an adequate trial of at least 6 to 8 weeks should be sustained before 
abandoning a treatment (Kacperski 2015). 
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Overall, authorized medications for the acute and prophylactic treatment of migraine in children 
and medications that are being used off-label in children have limited evidence to support their 
use, require ongoing patient monitoring, or are associated with undesirable or intolerable adverse 
effects (Barnes 2015, Kacperski 2015). Therefore, there is an unmet medical need for a safe and 
effective prophylactic treatment for EM and CM in the pediatric population. 
The purpose of the study is to determine whether fremanezumab is safe and effective in the 
preventive treatment of migraine in pediatric patients with EM. 
1.2. 
Findings from Nonclinical and Clinical Studies  
Brief summaries of nonclinical pharmacokinetics and toxicology studies and clinical studies are 
provided in the following sections. More detailed information is provided in the Investigator’s 
Brochure (IB). 
1.2.1. 
Nonclinical Studies  
The safety of fremanezumab was established in repeat-dose toxicity studies in rats for the 
duration of 3 months and in chronic toxicity studies in cynomolgus monkeys for the duration of 
6 months. Both the iv and sc routes were tested with dose administration once every week. 
Reproduction toxicity studies consisting of fertility and early embryonic development in rats, 
embryo-fetal development in rats and in rabbits, and pre- and postnatal development in rats were 
conducted. In support of the pediatric clinical program, juvenile toxicity studies in rats were 
conducted.  
The pharmacokinetics of fremanezumab were consistent with a typical humanized IgG2 
molecule with a low plasma clearance, low steady state volume of distribution, and a long 
elimination half-life in both rats and monkeys.  
 
 
 
 
Fremanezumab was administered to rats and monkeys by the iv or sc route for up to 3 months in 
duration and by sc route in the 6-month chronic toxicity study in monkeys. 
 
 
 
 
 
Safety pharmacology endpoints were also included in the general toxicology studies, in addition 
to the stand-alone safety pharmacology studies (cardiovascular in monkeys and respiratory and 
central nervous system in rats). 
 
 
  
In an embryo-fetal development study in rabbits, sc injection of dosing fremanezumab to 
pregnant rabbits was well tolerated and did not induce any maternal toxicity at any dose level. 
No evidence of embryo-fetal toxicity was noted in any dose group. In addition, in a combined 
fertility and embryo-fetal development study in rats, no treatment-related effects were noted on 
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estrus cycle, mating behavior, reproductive performance, or on embryo-fetal survival and 
development in any of the experimental animals’ tested dose levels. Additionally, no treatment 
related findings were noted in a pre- and postnatal development study in rats. 
 
 
 
 
 
 
 
 
Overall, no toxicological concerns were identified, and the program is considered supportive for 
repeated (monthly) administration of fremanezumab in pediatric subjects.  
Further details may be found in the current IB.  
1.2.2. 
Clinical Studies  
Overall in the fremanezumab migraine clinical development program, 2853 patients with 
migraine and 474 healthy subjects have received at least 1 dose of fremanezumab in the 
completed clinical studies. In addition, 142 and 380 patients in the 3 CH Phase 3 blinded studies 
(TV48125-CNS-30056, TV48125-CNS-30057, and TV48125-CNS-30058) were treated with 
placebo and fremanezumab, respectively. 
The adult migraine clinical development program is composed of 15 studies with healthy 
subjects and patients with migraine (EM and CM): 9 Phase 1 studies, 2 Phase 2b studies (double-
blind, placebo-controlled), 3 Phase 3 studies (2 double-blind, placebo-controlled studies and 1 
long-term, double-blind safety study [Study TV48125-CNS-30051], and 1 Phase 4 study). All 
studies have been completed.  
 
 
 
 
 
 
  
Six studies in adult migraine patients (2 Phase 2b studies, 3 Phase 3 studies, and 1 Phase 4 study) 
examining the safety and efficacy of fremanezumab have been completed. The Phase 2b CM 
study (Study LBR-101-021) was a multicenter, randomized, double-blind, double-dummy, 
placebo-controlled, parallel-group study comparing 3 sc monthly doses of fremanezumab 
 
 
 
 
 
 
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1.2.2.1. 
Clinical Pharmacology Studies  
Two relevant clinical pharmacology studies have been completed: a Phase 1 bioequivalence 
study comparing the pharmacokinetics of 225 mg of fremanezumab administered sc using an 
autoinjector referenced to a PFS (TV48125-BE-10145) in healthy adult subjects, and a Phase 1, 
single-dose, open-label study with administration of single sc doses of 
 in pediatric 
migraine patients 6 to 11 years of age, inclusive (Study TV48125-CNS-10141). 
1.2.2.2. 
Clinical Safety and Efficacy Studies  
The safety and tolerability of fremanezumab have been studied in all of the studies in the adult 
migraine clinical development program (ie, 9 Phase 1 studies in healthy subjects, 2 Phase 2b 
studies, and 3 Phase 3 studies in patients with migraine. Additional studies are the Phase 3b 
FOCUS study [TV48125-CNS-30068], the Japanese [Otsuka] registration studies, and the Phase 
4 UNITE study [TV48125-MH-40142]). Safety results from these studies are presented in the 
IB. 
Based on the safety results of the completed studies, the safety profile was assessed to include 
the following events as identified risks qualifying as adverse drug reactions: injection site 
induration, injection site erythema, injection site pruritus, injection site rash, and injection site 
pain. None of the identified risks was serious or considered as an important risk. 
No clinically relevant changes in clinical laboratory values, vital signs measurements, or 
electrocardiogram (ECG) findings have been observed in any of the studies to date. 
1.3. 
Known and Potential Benefits and Risks to Patients  
1.3.1. 
Known and Potential Benefits and Risks of the Test Investigational Medicinal 
Product(s) and/or Device  
1.3.1.1. 
Identified Risks  
The identified risks of fremanezumab are the following: 
• Injection site induration 
• Injection site erythema 
• Injection site pruritus 
• Injection site rash 
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• Injection site pain 
None of these risks impact the benefit-risk profile. 
1.3.1.2. 
Important Potential Risk  
Mild and moderate drug hypersensitivity events were observed infrequently and with similar 
incidence in placebo and fremanezumab in the clinical development program, but no anaphylaxis 
or severe hypersensitivity reactions were seen. However, it cannot be excluded that severe events 
may occur in the future. For additional details, refer to the IB. 
Based on the available efficacy and safety data for fremanezumab, the benefit-risk profile is 
favorable. 
1.3.2. 
Overall Benefit and Risk Assessment for This Study  
Based on the current safety profile and the demonstrated efficacy of the sc fremanezumab dosage 
form as observed in adults, the overall risk and benefit assessment for this study is favorable. 
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2. 
STUDY OBJECTIVES AND ENDPOINTS  
2.1. 
Primary and Secondary Study Objectives and Endpoints  
The primary and secondary study objectives and endpoints are as follows: 
Objectives 
Endpoints 
The primary objective of the study is to 
evaluate the efficacy of fremanezumab as 
compared to placebo for the preventive 
treatment of episodic migraine (EM).  
The primary efficacy endpoint is the mean change from 
baseline (28-day baseline period) in the monthly average 
number of migraine days during the 12-week period after the 
first dose of study drug. 
A secondary objective is to evaluate the 
safety and tolerability of fremanezumab in the 
preventive treatment of EM. 
The secondary safety and tolerability endpoints are as 
follows: 
• 
occurrence of adverse events throughout the 
study, including local injection site reaction/pain 
• 
abnormal standard 12-lead electrocardiogram 
(ECG) findings 
• 
changes from baseline in vital signs (systolic and 
diastolic blood pressure, pulse, temperature, and 
respiratory rate), height, and weight measurements 
• 
changes from baseline in clinical laboratory 
(serum chemistry, hematology, coagulation, and 
urinalysis) test results 
• 
abnormal physical examination findings 
• 
suicidal ideation and behavior as suggested by the 
Columbia-Suicide Severity Rating Scale 
(C-SSRS) 
A secondary objective of the study is to 
further demonstrate the efficacy of 
fremanezumab as compared to placebo for the 
preventive treatment of EM. 
The secondary efficacy endpoints are as follows: 
• 
mean change from baseline (28-day baseline 
period) in monthly average number of headache 
days of at least moderate severity during the 
12-week period after the first dose of study drug 
• 
proportion of patients reaching at least 50% 
reduction in the monthly average number of 
migraine days during the 12-week period after the 
first dose of study drug 
• 
mean change from baseline (28-day baseline 
period) in the monthly average number of days of 
use of any acute headache medications during the 
12-week period after the first dose of study drug 
• 
mean change from baseline (day 1) in migraine-
related disability score, as measured by the 
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Objectives 
Endpoints 
Pediatric Migraine Disability Assessment 
(PedMIDAS) questionnaire, at 12 weeks after 
administration of the first dose of study drug  
• 
mean change from baseline (day 1) in quality of 
life, as measured by the Pediatric Quality of Life 
Inventory (PedsQL), at 12 weeks after 
administration of the first dose of study drug  
A secondary objective of the study is to 
evaluate the immunogenicity of 
fremanezumab and the impact of antidrug 
antibodies (ADAs) on clinical outcomes in 
patients exposed to fremanezumab. 
• 
proportion of patients developing ADAs 
throughout the study. The impact of ADAs on 
safety and efficacy will be analyzed if the number 
of ADA-positive patients allows. 
2.1.1. 
Justification of Primary Endpoint  
This design is consistent with the recommendations of the International Headache Society (IHS) 
for controlled trials of preventive drugs in migraine (Tfelt-Hansen et al 2012). 
By definition, the IHS diagnostic criteria for EM include patients who suffer 6 to 14 headache 
days per month and/or treat the headache with an acute migraine-specific medication. Headache 
and migraine days are defined differently in the protocol. For the inclusion criteria, the minimal 
requirement for migraine days during a 28-day baseline period is 4. This requirement is 
consistent with migraine preventive treatment guidelines and also with the Teva adult EM study 
inclusion criteria. 
As per the guidelines for controlled trials of preventive treatment of EM of the IHS, Teva 
considers that the most appropriate primary endpoint to capture is the change from baseline on 
the monthly average number of migraine days. Pain is a very subjective experience, and its 
perception changes among patients. Therefore, it is most important to capture the individual 
manifestation and perception of migraine in every patient examined. Patients will subjectively 
rate their headaches as mild, moderate, or severe and record this information using the electronic 
headache diary device. This endpoint (decrease from baseline on the monthly average number of 
migraine days) is a classical endpoint used in most prior studies of EM, and it is recommended 
by the IHS (Tfelt-Hansen et al 2012). This is the same primary endpoint used in the adult 
migraine clinical development program, which showed significant results. Consistent with past 
trials in EM and the recommendation of the IHS, migraine day or probable migraine day requires 
meeting the ICHD-3 criteria or days treated with acute migraine therapies (triptans or ergot 
compounds). Teva will follow these guidelines and recommendations. 
2.2. 
Exploratory Objective and Endpoints  
 
 
 
 
 
 
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3. 
STUDY DESIGN  
3.1. 
General Study Design and Study Schematic Diagram  
This is a 4-month, multicenter, randomized, double-blind, placebo-controlled, parallel-group 
study to evaluate the efficacy, safety, and tolerability of 2 different doses (dependent on patients’ 
body weight) of sc fremanezumab and placebo. Enrollment will include male and female patients 
(6 to 17 years of age, inclusive). 
An interim analysis with blinded sample size re-estimation will be conducted by evaluating the 
pooled variability (standard deviation [SD]) of the primary endpoint using the total number of 
patients regardless of the treatment assignment once 50% (±10%) of patients have completed at 
least 3 months of treatment or have withdrawn from the study early. If the pooled SD is <4.8, 
there will be no change in enrollment; if the pooled SD is >5.2, the sample size will increase to 
approximately 400 patients; and if the pooled SD is between 4.8 and 5.2, the sample size will 
increase to approximately 340 patients total. 
The total duration of the study is planned to be 51 months (from Q1 2020 to Q2 2024). 
Patients will be randomly assigned in a 1:1 ratio between fremanezumab and placebo treatment 
groups: 
• monthly sc administration of fremanezumab  
• monthly sc administration of matching placebo 
The dose of fremanezumab to be administered will be determined by the patient’s weight at 
randomization (visit 2): 
• Patients weighing ≥45.0 kg will receive monthly sc administration of fremanezumab 
at 225 mg. 
• Patients weighing <45.0 kg will receive monthly sc administration of fremanezumab 
at 120 mg. 
The enrollment target is approximately 230 EM patients, with a goal of approximately 20% of 
those patients in the 6- through 11-year-old age group. 
The study consists of a screening visit, a 28-day baseline period, and a 12-week (84-day) 
treatment period, including a final evaluation at week 12 (end-of-treatment [EOT] visit, 
approximately 4 weeks [28 days] after the final dose of study drug). 
Blinded treatment will be administered sc once monthly (approximately every 28 days) for a 
total of 3 doses. Randomization and first treatment administration will occur at visit 2 (day 1), 
and additional doses will be administered at visits 3 and 4 (approximately every 28 days) until 
the third dose is completed. Final study assessments will be performed at visit 5 (EOT visit), 
approximately 28 days after the third (last) dose of study drug. Overall, patients will participate 
in the current study for up to 4 months (including a 28-day baseline period and a 12-week, 
double-blind treatment period).  
Patients will be allowed to use acute medications to treat acute migraine attacks, as needed, with 
the exception of medications containing opioids and barbiturates.  
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Upon completion of the final study assessments, all eligible patients will be offered enrollment in 
a long-term safety and tolerability study (Study TV48125-CNS-30084), consisting of 9 months 
(36 weeks) of open-label treatment and 5 months of follow-up commencing from the last study 
drug administration. In the long-term safety extension study, patients rolling over from the 
current study will be weighed at visit 2 and will receive monthly fremanezumab with dose 
adjusted every 3 months per weight category (225 mg in patients ≥45.0 kg or 120 mg in patients 
<45.0 kg). Patients who do not complete this study and patients who complete this study but do 
not wish to continue treatment may enroll in Study TV48125-CNS-30084 for the purpose of 
attending a follow-up visit for safety and ADA assessments approximately 5 months (150 days 
[5 half-lives]) after receiving the last dose of study drug. 
Study procedures and assessments with their time points are shown in Table 1. The study 
schematic diagram is shown in Figure 1. 
The end of study is defined as the date the last patient attends the EOT/early withdrawal visit 
(visit 5). 
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Figure 1: 
Overall Study Schematic Diagram  
 
 
PBO=placebo; SC=subcutaneous; V=visit. 
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3.2. 
Planned Number of Patients and Countries  
The number of evaluable patients is planned to be approximately 220 (110 evaluable patients 
completing the study per treatment group). Details on definition of evaluable patients and sample 
size are given in Section 9. 
The total number of randomized patients planned is approximately 230. 
The study is planned to be conducted in 6 to 10 countries in approximately 85 investigational 
centers. The study is expected to start in Q1 2020 and last until Q2 2024. 
3.3. 
Justification for Study Design and Selection of Population  
A multicenter, randomized, double-blind, placebo-controlled, parallel-group design is 
appropriate, given the objectives of this study. This design is consistent with the 
recommendations of the IHS for controlled trials of preventive drugs in migraine (Tfelt-Hansen 
et al 2012). Furthermore, this study is planned and designed in accordance with International 
Council for Harmonisation (ICH) E11 Guidance - Clinical Investigation of Medicinal Products in 
the Pediatric Population, 2017. 
Migraine is a condition that starts from childhood or adolescence and progresses into adulthood. 
Among populations of children of all ages, migraine prevalence ranges from 8% to 11% 
(Abu-Arafeh et al 2010, Abu-Arefeh and Russell 1994, Laurell et al 2004, Ozge et al 2013, 
Stovner and Andree 2010). Additionally, there is an unmet need for the treatment of migraine in 
pediatric patients as there are limited therapy options available for this patient population. 
Throughout Teva’s development program for adults, fremanezumab had demonstrated 
statistically and clinically significant superior efficacy over placebo. It is also well tolerated in 
the adult migraine population. Given the progression of the disease and the knowledge gained 
from the adult population, it is reasonable and important to evaluate fremanezumab in the 
pediatric population. 
Because headache consortium guidelines recommend preventive therapies for patients with EM 
occurring on 4 or more days per month due to the frequency of headaches and high degree of 
disability, patients using no more than 2 migraine preventive medications for any condition at the 
time of study enrollment will be allowed to remain on the medication if the medication has at 
least moderate evidence of efficacy for migraine (Silberstein et al 2012). Patients on concomitant 
migraine preventive medications must be on a stable dose for at least 2 months prior to screening 
(visit 1), without anticipated changes during the study. A list of migraine preventive medications 
allowed for any condition for the duration of the study for approximately 30% of patients is 
presented in Appendix C. The total number of patients receiving concomitant migraine 
preventive medication during the study will be approximately 30% of the total number of 
patients randomized. Randomization will be stratified by patients with and without preventive 
medications. 
3.4. 
Stopping Rules for the Study  
There are no formal rules for early termination of this study. During the conduct of the study, 
serious adverse events will be reviewed (Section 7.1.7) as they are reported from the 
investigational centers to identify safety concerns. 
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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 the following: 
• new toxicological or pharmacological findings or safety issues that invalidate the 
earlier positive benefit-risk assessment 
• discontinuation of the development of the investigational medicinal product (IMP) 
If the study will be stopped, the patients that are terminated early will be followed according to 
Withdrawal Criteria and Procedures for the Patient (Section 4.3). 
3.5. 
Schedule of Study Procedures and Assessments  
Study procedures and assessments with their time points are presented in Table 1. Detailed 
descriptions of each method of procedures and assessments are provided in Section 6 (efficacy 
assessments), Section 7 (Assessment of Safety), and Section 8 (Assessment of Pharmacokinetics 
and Immunogenicity). Study procedures and assessments by visit, including unscheduled visits, 
are listed in Appendix B. 
 
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Table 1: 
Study Procedures and Assessments  
Study period 
Pretreatment period 
(incl. screening visit 
and baseline period) 
Double-blind treatment period 
Visit number 
V1a        
V2 
V3 
V4 
V5b 
Month number 
Month −1 
Month 0 
Month 1 
Month 2 
Month 3 
Procedures and assessmentsc  
Screening 
Days −28 to −1 
Randomization 
Dose 1 
Day 1d  
(+3 days) 
Dose 2 
Day 29d 
(±3 days) 
Dose 3 
Day 57d 
(±3 days) 
EOT or early 
withdrawal 
Day 85d 
(±3 days) 
Informed consent and assente        
X 
 
 
 
 
Inform patients of study restrictions and compliance 
requirementsf        
X 
 
 
 
 
Medical and psychiatric historyf 
X 
 
 
 
 
Headache historyf 
X 
 
 
 
 
Lifetime prior medication and treatment historyf 
X 
 
 
 
 
Record demographic characteristicsf 
X 
 
 
 
 
Inclusion and exclusion criteria 
X 
Xg        
 
 
 
Physical examination, including weight and heighth        
X 
X 
 
 
X 
Puberty assessmenti,f        
 
X 
 
 
X 
Randomizationj        
 
X 
 
 
 
Triplicate 12-lead ECGk        
X 
X 
X 
X 
X 
Vital signs measurementl        
X 
X 
X 
X 
X 
Adverse eventsm,f        
X 
X 
X 
X 
X 
Concomitant medication inquiryf 
X 
X 
X 
X 
X 
Clinical laboratory testsc,n        
X 
 
X 
 
X 
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Study period 
Pretreatment period 
(incl. screening visit 
and baseline period) 
Double-blind treatment period 
Visit number 
V1a        
V2 
V3 
V4 
V5b 
Month number 
Month −1 
Month 0 
Month 1 
Month 2 
Month 3 
Procedures and assessmentsc  
Screening 
Days −28 to −1 
Randomization 
Dose 1 
Day 1d  
(+3 days) 
Dose 2 
Day 29d 
(±3 days) 
Dose 3 
Day 57d 
(±3 days) 
EOT or early 
withdrawal 
Day 85d 
(±3 days) 
Pregnancy testo         
X 
X 
X 
X 
X 
Electronic headache diary device dispensationp        
X 
 
 
 
 
Review electronic headache diary entriesp,f 
 
X 
X 
X 
X 
Electronic headache diary device returnp 
 
 
 
 
X 
Blood samples for plasma drug concentrationc 
 
X 
X 
 
X 
Blood samples for serum ADA assessmentc 
 
X 
X 
 
X 
C-SSRSq,f        
X 
X 
X 
X 
X 
PedMIDASf 
 
X 
 
 
X 
PedsQLf 
 
X 
X 
X 
X 
PGI-I questionnairef 
 
 
 
 
X 
Administration of study drugr        
 
X 
X 
X 
 
Injection site assessmentc 
 
X 
X 
X 
 
a Patients will complete the screening visit no more than 28 (+3) days before the randomization visit (visit 2 [day 1]). 
b After completing EOT assessments/procedures, all eligible patients will be offered enrollment in the long-term safety and tolerability study (Study TV48125-
CNS-30084). 
c Electrocardiograms will be performed, weight will be recorded (visit 2 only), urine pregnancy tests will be performed at all visits prior to dosing, and blood 
samples will be collected before study drug administration. Assessment of injection site reactions will be performed after administration of each dose of study 
drug, before the patient leaves the investigational site. All other study procedures can be performed at any time during the visit. 
d The date of the next visit will be calculated based on the actual date of the last administration of study drug. 
e Must be performed prior to any study procedure. 
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f This procedure/assessment may be performed remotely for patients who are not able to go to the investigational center or if the investigational center staff are 
not able to see patients at the investigational center due to unforeseen circumstances. 
g Eligibility criteria will be confirmed prior to randomization. 
h Physical examination, including height and weight, will be performed at screening, randomization, and EOT. Body mass index will be calculated at screening 
and randomization. 
i Puberty status (Tanner staging scale, see Section 7.5) will be assessed at randomization (visit 2) and EOT either by patients’ self report or by physical 
examination according to the Tanner staging card provided. 
j Patients will be randomized to receive placebo or 1 of 2 fremanezumab doses (based on body weight). 
k Twelve-lead ECGs will be performed in triplicate at any time during the visit, prior to study drug administration. 
l The method for measuring temperature in an individual patient must be the same at each timepoint. 
m Inquiries about adverse events will be made before and after study drug administration. 
n Serum chemistry, hematology, coagulation, and urinalysis. 
o Females who are postmenarchal or ≥12 years of age only. Serum β-HCG tests will be performed at screening (visit 1) and visit 5; urine β-HCG tests will be 
performed at all visits. Inquire and record start/stop date of menstrual period at each visit. 
p Eligible patients will be given an electronic headache diary device and they or a parent/caregiver will be trained in its use and compliance requirements on the 
day of screening. Patients or parents/caregivers will complete electronic headache diary entries about the previous day daily beginning on day -27 through the 
EOT/early withdrawal visit. If the patient is unable to complete the diary themselves, then a parent/caregiver will complete the diary for them. 
q The C-SSRS will be completed by a qualified rater trained to administer the scale at the investigational center based on discussion with the patient/caregiver at 
the time points described. Any patient who demonstrates suicidal ideation and/or any suicidal behavior at any point during the study should be withdrawn from 
the study and discontinued from study treatment. In addition, if a patient endorses suicidal ideation or behavior at any point during the study (including during 
screening), the investigator must explain to the patient/caregiver the need for follow-up with a mental health professional and make any necessary referrals. 
r The location of the sc injection should be recorded at each administration visit. 
β-HCG=beta-human chorionic gonadotropin; ADA=antidrug antibody; C-SSRS=Columbia-Suicide Severity Rating Scale; ECG=electrocardiogram; 
EOT=end-of-treatment; PedMIDAS=Pediatric Migraine Disability Assessment; PedsQL=Pediatric Quality of Life Inventory; PGI-I=Patient Global Impression 
of Improvement; sc=subcutaneous; V=visit. 
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4. 
SELECTION AND WITHDRAWAL OF PATIENTS  
Prospective waivers (exceptions) from study inclusion and exclusion criteria to allow patients to 
be randomized/enrolled are not granted by Teva (Appendix E). 
4.1. 
Patient Inclusion Criteria  
Patients may be included in this study only if they meet all of the following criteria: 
a. The patient is a male or female between the ages of 6 to 17 years (inclusive) on the 
day of randomization to study drug/IMP. 
b. The patient’s parent(s) or legal guardian(s) must give written informed consent, and 
the patient must give assent (in accordance with local regulations). 
Note: In some countries, patients aged 15 to 17 years (inclusive) may give written 
informed consent; however, the patient’s parent(s) or legal guardian(s) must be 
informed, per local regulations. 
c. The patient has a clinical history of recurrent headache consistent with the diagnosis 
of migraine for at least 6 months before screening, consistent with the ICHD-3 
criteria (Headache Classification Committee of the IHS 2013), and a history of 
≤14 headache days per month in each of the 3 months prior to screening (visit 1). 
d. The patient or parent/caregiver has maintained a prospectively collected headache 
diary during a 28-day baseline period in which at least 4 migraine days and 
≤14 headache days were recorded. Migraine days have at least 1 of the following 
migraine characteristics: 
− head pain of moderate to severe intensity lasting for 2 or more hours in duration 
and accompanied by either throbbing quality, predominantly unilateral location, 
or aggravation with normal activities. 
− headache is accompanied by a migraine-associated symptom, such as 
photophobia, phonophobia, abdominal pain, nausea, or vomiting. 
− headache is preceded by an aura, as described by ICHD-3 criteria. 
− headache was treated by a nonsteroidal anti-inflammatory drug (NSAID), 
paracetamol, triptan, or ergot preparation. 
e. The patient does not have chronic daily headache. For the purposes of this study, 
chronic daily headache is operationally defined as <4 headache-free days during the 
28-day baseline period. 
f. [Revision 01] Not using migraine preventive medications (listed in Appendix C) or 
using no more than 2 migraine preventive medications (listed in Appendix C) for 
migraine or other medical conditions, as long as the dose and regimen have been 
stable for at least 2 months prior to screening (visit 1). A list of migraine preventive 
medications allowed for any condition for the duration of the study for approximately 
30% of patients is presented in Appendix C. 
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Note: A person is considered to be not using migraine preventive medications (listed 
in Appendix C) when at least 5 half-lives have passed since the last use of the 
medication prior to screening (visit 1) or at least 4 months have passed since the last 
use of Onabotulinium toxin A or B prior to screening (visit 1). The use of other 
agents that are not included in Appendix C but used for migraine prevention is 
permitted during the study; however, these patients will not be counted toward the 
approximately 30% patient limit threshold. 
g. Females who are postmenarchal or ≥12 years of age may be included only if they 
have a negative beta-human chorionic gonadotropin (β-HCG) test at baseline or are 
sterile. Definitions of females of childbearing potential and females who are not of 
childbearing potential are given in Appendix G. 
h. Females who are postmenarchal or ≥12 years of age and sexually active must use 
highly effective birth control methods with their male partners for the duration of the 
study (ie, starting at screening) and for 6 months after the last dose of IMP. Males 
who are sexually active with female partners must use a condom for the duration of 
the study and for 6 months after the last administration of IMP. Further details are 
included in Appendix G. 
i. The patient/caregiver has demonstrated compliance with the electronic headache 
diary during the 28-day baseline period by entry of headache data on a minimum of 
21 out of 28 days (approximately 75% diary compliance). 
j. The patient is in good health, as determined by a medical and psychiatric history, 
medical examination, 12-lead ECG, serum chemistry, hematology, coagulation, 
urinalysis, and serology. 
k. The patient/caregiver must be willing and able to comply with study requirements and 
return to the clinic as required for the duration of the study. 
l. The patient weighs at least 17.0 kg on the day of randomization to study drug/IMP. 
m. The patient has a body mass index ranging from the 5th to 120% of the 95th percentile, 
inclusive, at screening, based on the local standard. 
n. The patient has received all recommended age-appropriate vaccines according to 
local standard of care and schedule prior to screening. 
4.2. 
Patient Exclusion Criteria  
Patients will be excluded from participating in this study if they meet any of the following 
criteria: 
a. The patient is using medications containing opioids (including codeine) or 
barbiturates (including Fiorinal®, Fioricet®, or any other combination containing 
butalbital) for the treatment of migraine during the 3 months prior to the day of the 
screening visit. 
b. The patient has used an intervention/device (eg, scheduled nerve block or transcranial 
magnetic stimulation) for the treatment of migraine or in the head or neck area for 
any condition during the 2 months prior to the day of the screening visit. 
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c. The patient has any clinically significant cardiovascular (including congenital cardiac 
anomalies or thromboembolic events), endocrine, gastrointestinal, genitourinary, 
hematologic, hepatic, immunologic, neurologic, ophthalmic, pulmonary, renal 
disease, or complications of an infection, at the discretion of the investigator. 
d. [Revision 01] The patient has a current history of a clinically significant psychiatric 
condition, at the discretion of the investigator. Any prior history of a suicide attempt, 
or a history of suicidal ideation with a specific plan within the past 2 years, must be 
excluded. 
e. The patient has an ongoing infection or a known history of human immunodeficiency 
virus (HIV) infection, tuberculosis, Lyme disease, chronic hepatitis B or C, or a 
known active infection of coronavirus disease 2019 (COVID-19). 
f.  The patient has a past or current history of cancer. 
g. The patient is pregnant or nursing.  
h. The patient has a 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. 
i. The patient has participated in another study of an IMP (or a medical device) within 
the 30 days (or 90 days for biologics) or 5 half-lives previous to the day of the 
screening visit (whichever is longer), or is currently participating in another study of 
an IMP (or a medical device). 
j. The patient has had exposure to a mAb targeting the CGRP pathway (erenumab, 
eptinezumab, galcanezumab, fremanezumab) during the 6 months previous to the day 
of the screening visit. 
k. Previous participation in the Phase 1 pharmacokinetics study 
(Study TV48125-CNS-10141). 
l. In the judgment of the investigator, the patient has an abnormal finding on the 
baseline 12-lead ECG considered clinically significant. 
m. In the judgment of the investigator, the patient has a significantly abnormal finding 
during the 28-day baseline period, including hematology, blood chemistry, 
coagulation tests, or urinalysis values/findings (abnormal tests may be repeated for 
confirmation). 
n. The patient has hepatic enzymes (alanine aminotransferase [ALT], aspartate 
aminotransferase [AST], alkaline phosphatase [ALP]) more than 1.5× the upper limit 
of normal (ULN) during the 28-day baseline period, after confirmation in a repeat 
test, or suspected hepatocellular damage that fulfills the criteria for Hy’s law. 
o. The patient has serum creatinine more than 1.5× the ULN, clinically significant 
proteinuria (urine dipstick +4), an estimated glomerular filtration rate of 
<75 mL/min/1.73m2, as calculated by the revised Schwartz formula 
(eGFR=[0.413×Ht]/serum creatinine), or evidence of renal disease during the 28-day 
baseline period. 
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p. The patient has any history of alcohol or drug abuse. The definition of alcohol or drug 
abuse, including marijuana, is based on the investigator’s clinical judgment. 
q. In the judgment of the investigator, the patient cannot fully participate in or 
successfully complete the study for its full duration for any of the following reasons: 
− The patient is mentally or legally incapacitated, or unable to give assent/consent 
for any reason. 
− The patient is in custody due to an administrative or a legal decision or is in 
residential treatment. 
− The patient/caregiver is unable to be contacted in case of emergency. 
− The patient has any other condition, which, in the opinion of the investigator, 
makes the patient inappropriate for inclusion in the study. 
− The patient is a relative of a study center or sponsor employee who is directly 
involved in the study. 
r. Vulnerable patients (eg, people kept in detention) whose vulnerability is based on a 
condition other than the age required for study eligibility. 
s. The patient received a live attenuated vaccine (eg, intranasal flu vaccine, and measles, 
mumps, and rubella vaccine) within the 12-week period prior to screening. 
Note: If a medical need arises during the study, the patient may receive a live 
attenuated vaccine. 
t. The patient has a known hypersensitivity to the active substance or to any of the 
excipients of the study drug. 
u. The patient has a current or past medical history of hemiplegic migraine. 
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, without 
prejudice to their continued care. Patients must be withdrawn from the study if any of the 
following events occur:  
• Patient withdraws consent or requests discontinuation from the IMP or withdrawal 
from the study for any reason. 
• Patient develops an illness that would interfere with his/her continued participation. 
• Patient is noncompliant with the study procedures and assessments or administration 
of IMPs in the opinion of the investigator. 
• Patient takes prohibited concomitant medications chronically. 
• A female patient has a confirmation of pregnancy during the study from a positive 
pregnancy test.  
• The sponsor requests withdrawal of the patient. 
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• Patient experiences an adverse event or other medical condition indicating to the 
investigator that continued participation is not in the best interest of the patient. 
• Any patient who demonstrates suicidal ideation and/or any suicidal behavior at any 
point during the study should be withdrawn from the study and discontinued from 
study treatment. 
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 H 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 IMP is an adverse event 
and/or clinically significant abnormal laboratory test result, monitoring will be continued as 
applicable (eg, until the event has resolved or stabilized, until the patient is referred to the care of 
a health care professional, or until a determination of a cause unrelated to the IMP [and/or PFS] 
or study procedure is made). The specific event or test result (including repeated test results, as 
applicable) must be recorded both on the source documentation and in the CRF; both the adverse 
events page and the relevant page of the CRF will be completed at that time. 
The patient will be monitored as applicable (eg, until the event has resolved or stabilized, until 
the patient is referred to the care of a health care professional, or until a determination of a cause 
unrelated to the test IMP or study procedure is made). The investigator must inform the Study 
Leader as soon as possible of each patient who is being considered for withdrawal due to adverse 
events. Additional reports must be provided when requested. 
If a patient is withdrawn from the study for multiple reasons that also include adverse events, the 
relevant page of the CRF should indicate that the withdrawal was related to an adverse event. An 
exception to this requirement will be the occurrence of an adverse event that in the opinion of the 
investigator is not severe enough to warrant discontinuation but that requires the use of a 
prohibited medication, thereby requiring discontinuation of the patient. In such a case, the reason 
for discontinuation would be “need to take a prohibited medication,” not the adverse event. 
All protocol-specified procedures/assessments should be performed at the EOT/early withdrawal 
visit (see Table 1). Patients who withdraw from the study or have an early termination will be 
invited to enter the long-term safety extension (within Study TV48125-CNS-30084) for the 
purpose of safety follow-up and evaluating ADA approximately 5 months (150 days 
[5 half-lives]) after receiving the last dose of study drug in this study. 
In the case of patients lost to follow-up, attempts to contact the patient must be made and 
documented in the patient’s medical records and transcribed to the CRF.  
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4.3.1. 
Study-Specific Patient Withdrawal Criteria and Procedures  
In the following circumstances for patients with abnormal hepatic laboratory values (eg, ALT, 
AST, ALP, gamma-glutamyl transpeptidase, total bilirubin, or International Normalized Ratio 
[INR]), IMP should be discontinued immediately:  
1. any increase in ALT or AST to ≥3× the ULN, combined with INR >1.5× the ULN or 
total bilirubin ≥2× the ULN 
2. any increase in ALT or AST to ≥3× the ULN, which is accompanied by symptoms 
clearly associated with impaired liver function (eg, vomiting, nausea, fever, rash, or 
eosinophilia) and not deemed related to other diseases (eg, vomiting or nausea triggered 
by migraine) 
3. any increase in ALT or AST to levels ≥5 but <8× the ULN, which is persistent for 
≥2 weeks of repeated measurements 
4. any increase in ALT or AST to levels ≥8× the ULN 
5. in any case where monitoring of liver enzymes cannot be performed according to the 
protocol guidance 
The patient must be withdrawn from the study drug if the patient experiences a severe 
hypersensitivity reaction or anaphylaxis. 
Additionally, IMP should be discontinued if the patient experiences an adverse event or other 
medical condition indicating to the investigator that continued participation is not in the best 
interest of the patient. 
4.4. 
Replacement of Patients  
A patient who is randomized/enrolled but does not complete the treatment period will not be 
replaced. 
Study enrollment assumes up to a 4% discontinuation rate The number of patients randomized 
(230) was selected to achieve the estimated 220 patients completing the study (110 patients per 
treatment group).  
4.5. 
Rescreening  
A patient who is screened but not enrolled (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. If the history of migraine classification (EM or 
CM) as taken by the investigator differs from the classification determined by the diary data 
(28-day baseline period), the patient may be rescreened one time; this information should be 
recorded in the CRF. 
Patients may have individual parameters retested at the discretion of both the investigator and the 
sponsor. 
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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. A minimal set of screening failure information 
will be entered in the CRF. Minimal information includes but is not limited to demography, 
screening failure details, eligibility criteria, and any serious adverse events. 
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5. 
TREATMENTS  
5.1. 
Investigational Medicinal Products Used in the Study  
Investigational medicinal product is defined as the test IMPs and matching placebo IMPs to the 
respective test IMPs. 
5.1.1. 
Test Investigational Medicinal Product  
The formulation of fremanezumab to be used for clinical investigations in the pediatric 
population will be identical to the sc formulation of fremanezumab that will be used in the 
clinical program for adults. Information on the test IMP and placebo are shown in Table 2.  
Additional details may be found in the IB for fremanezumab. 
5.1.1.1. 
Starting Dose and Dose Levels  
Patients will be randomly assigned in a 1:1 ratio between fremanezumab and placebo treatment 
groups: 
• monthly sc administration of fremanezumab  
• monthly sc administration of matching placebo 
The dose of fremanezumab to be administered will be determined by the patient’s weight at 
randomization (visit 2): 
• Patients weighing ≥45.0 kg at randomization (visit 2) will receive monthly sc 
administration of fremanezumab at 225 mg. 
• Patients weighing <45.0 kg at randomization (visit 2) will receive monthly sc 
administration of fremanezumab at 120 mg. 
(Note: For this study, monthly dosing refers to dosing approximately every 4 weeks [28 days].) 
The recommended sc injection sites follow the National Institutes of Health (NIH) Clinical 
Center Patient Education Materials (NIH Clinical Center Patient Education Materials 2016). The 
suggested injection site locations for sc administration are the following: back of upper arms, 
lower abdomen/belly/waistline, and front of thighs. The sc injection and location will be 
recorded for each administration visit (visits 2, 3, and 4). 
A 1.5 mL volume (patients weighing ≥45.0 kg at randomization [visit 2]) or a 0.8 mL volume 
(patients weighing <45.0 kg at randomization [visit 2]) from each visit kit(s) (the full dose given 
with a PFS or taken from the vials) must be injected sc for administration to be considered 
complete. Patients randomized to the placebo group will receive volume-matched doses of 
placebo. 
5.1.1.2. 
Dose Modification and Dose Stratification  
Not applicable. 
5.1.2. 
Reference Investigational Medicinal Product  
Not applicable. 
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5.1.3. 
Placebo Investigational Medicinal Product  
The placebo will match the test IMP in appearance and volume. See Table 2 for a description of 
the placebo. 
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Table 2: 
Investigational Medicinal Products Used in the Study  
IMP name 
Test IMP 
Placebo IMP 
Trade name and INN, if applicable, or 
company-assigned number 
Fremanezumab 
None 
Formulation 
Sterile, clear to opalescent, colorless to slightly yellow 
solution for injection 
Sterile, clear to opalescent, colorless to slightly yellow 
solution for injection 
Unit dose strength(s)/dosage level(s) 
225 mg monthly in patients with body weight ≥45.0 kg 
at randomization (visit 2) 
120 mg monthly dose in patients with body weight 
<45.0 kg at randomization (visit 2) 
Not applicable 
Route of administration 
Subcutaneous injection 
Subcutaneous injection  
Dosing instructions 
Patients with body weight ≥45.0 kg at randomization 
(visit 2): fremanezumab 225 mg: 1 active injection 
(225 mg/1.5 mL) at visits 2, 3, and 4 
 
Patients with body weight <45.0 kg at randomization 
(visit 2):  
fremanezumab 120 mg: 1 active injection 
(120 mg/0.8 mL) at visits 2, 3, and 4 
Patients with body weight ≥45.0 kg at randomization 
(visit 2):  
Placebo: single 1.5 mL injection at visits 2, 3, and 4  
 
Patients with body weight <45.0 kg at randomization 
(visit 2):  
Placebo: single 0.8 mL injection at visits 2, 3, and 4 
Packaging 
IMP will be provided as follows: 
• 225 mg dose: PFS for single-use administration 
• 120 mg dose: taken from two 2-mL vials each 
containing 0.5 mL of IMP for single-use 
administration 
Placebo will be provided as follows: 
• 1.5 mL injection: PFS for single-use 
administration 
• 0.8 mL injection: taken from two 2-mL vials each 
containing 0.5 mL of placebo for single-use 
administration 
Manufacturer 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
IMP=investigational medicinal product; INN=international nonproprietary name; PFS=pre-filled syringe. 
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5.2. 
Preparation, Handling, Labeling, Storage, and Accountability for 
IMPs  
5.2.1. 
Storage Conditions and Handling  
Fremanezumab should be stored refrigerated at 2°C to 8°C (36°F to 46°F) in the original 
container until it is used. Protect from light. Do not freeze, and do not use if frozen. Do not shake 
vigorously. Refrigerated fremanezumab remains suitable for use until the expiration date printed 
on the primary container and/or carton. Do not use fremanezumab if the liquid is cloudy, 
discolored, or contains visible flakes or particles. Fremanezumab should be equilibrated to room 
temperature for 30 minutes prior to administration. 
The investigator or designee must confirm appropriate temperature conditions have been 
maintained for all IMPs received and any discrepancies are reported and resolved before use of 
the IMPs. 
Further guidance is provided in the Pharmacy Manual. 
5.2.2. 
Labeling  
Supplies of IMPs will be labeled according to the current International Council for 
Harmonisation (ICH) guidelines on Good Clinical Practice (GCP) and Good Manufacturing 
Practice and will include any locally required statements. If necessary, labels will be translated 
into the local language. 
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 Code of Federal Regulations (CFR) or national and/or local regulations, and 
used in accordance with this protocol. 
Only patients enrolled in the study may receive IMPs and only authorized staff at the 
investigational center may supply or 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 staff at the investigational center. 
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for IMP accountability, reconciliation, and record maintenance (ie, receipt, 
reconciliation, and final disposition 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. Empty, partially used, and unused PFS and vials of 
IMP will be destroyed at the investigational center in accordance with investigational center 
Standard Operating Procedures (SOPs) or will be disposed of, retained, or returned to the 
sponsor or designee per sponsor instructions. 
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Further guidance and information are provided in the Study Reference Manual, Pharmacy 
Manual, or other specified location. 
5.3. 
Justification for Investigational Medicinal Products  
5.3.1. 
Justification for Dose of Test Investigational Medicinal Product and/or Device  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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5.3.2. 
Justification for Use of Placebo Investigational Medicinal Product  
A multicenter, randomized, double-blind, placebo-controlled, parallel-group design is 
appropriate, given the objectives of this study. Furthermore, this design is consistent with the 
recommendations of the IHS for controlled trials of preventive drugs in migraine (Tfelt-Hansen 
et al 2012). 
The use of a placebo rather than an active comparator is justified in this study because of the 
limited availability of a suitable comparator. Topiramate is the only migraine preventive 
medication approved for pediatric populations, but it is not approved in all regions of the EU and 
is limited to adolescents ages 12 through 17, so this medication would be off-label for those 
subjects ages 6 through 11.  
5.4. 
Treatment After the End of the Study  
Upon completion of the final study assessments, all eligible patients will be offered enrollment in 
a long-term safety and tolerability study (Study TV48125-CNS-30084), consisting of 9 months 
(36 weeks) of open-label treatment and 5 months of follow-up commencing from the last study 
drug administration. In the long-term safety extension study, patients rolling over from the 
current study will be weighed at visit 2 and will receive monthly fremanezumab with dose 
adjusted per weight category (225 mg in patients ≥45.0 kg or 120 mg in patients <45.0 kg). 
Patients who do not complete this study and patients who complete this study but do not wish to 
continue treatment may enroll in Study TV48125-CNS-30084 for the purpose of attending a 
follow-up visit for safety and ADA assessments approximately 5 months (150 days 
[5 half-lives]) after receiving the last dose of study drug. 
5.5. 
Restrictions  
Medications prohibited before and/or during the study are described in Section 5.6 and the 
exclusion criteria (Section 4.2). Restrictions with regard to pregnancy and required laboratory 
values are provided in the inclusion and exclusion criteria (Section 4.1 and Section 4.2, 
respectively). Restrictions regarding contraception methods are detailed in the inclusion and 
exclusion criteria (Section 4.1 and Section 4.2, respectively) and are also described in 
Appendix G.  
Patients must remain at the site, for safety observation, for at least 30 minutes after injection or 
longer if deemed necessary by medical judgment. 
There are no additional restrictions in this study. 
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5.6. 
Prior and Concomitant Medication or Therapy  
All prior therapy, medication, or procedure (ie, procedures for the treatment of migraine [eg, 
nerve blocks]) for the treatment of migraine a patient has had during their lifetime will be 
recorded on the CRF. In addition, all concomitant medications taken during the study will be 
recorded on the CRF. 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. 
The following medications are prohibited for regular chronic use during the study: opioids 
(including codeine), barbiturates (including Fiorinal®, Fioricet®, or any other combination 
containing butalbital), and lamotrigine. 
Approximately 30% of EM patients will be allowed to remain on no more than 2 migraine 
preventive medications in Appendix C for any condition, provided the medication is recognized 
to have at least moderate evidence of efficacy or is commonly used. Additional details on 
migraine preventive medication information are provided in Appendix C. For chronic use of 
these medications for any indication, patients must have been on a stable, well-tolerated dose of 
this migraine preventive 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 
approximately 70% of EM patients, these medications are not allowed for migraine or for any 
other indications. As-needed (PRN) use of these medications are allowed during the course of 
the study for any indications and do not have to have established dosing regimens. PRN use of 
these medications should be reported in the electronic case report form 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 PRN use of to use acute medications to treat acute migraine attacks, as 
needed, with the exception of regular use of medications containing opioids and barbiturates. 
The chronic use of concomitant therapies not listed in Appendix C for any indication is allowed 
throughout the course of the study. All patients must have been on a stable dose of these 
concomitant medications 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. PRN use of medications for adverse 
events or intercurrent acute situations are allowed. 
Patients must have received all recommended age-appropriate vaccines according to local 
standard of care and schedule prior to screening. Live attenuated vaccines (eg, intranasal flu 
vaccine, and measles, mumps, and rubella vaccine) are disallowed within the 12-week period 
prior to screening. If a medical need arises during the study, the patient may receive a live 
attenuated vaccine. 
All concomitant medications taken during the study, including over-the-counter medications, 
vitamins, or herbal or nutritional supplements, must be recorded with indication, daily dose, and 
start and stop dates of administration. All patients will be questioned about concomitant 
medication use at each visit. 
Concomitant medication and treatment will be recorded until visit 5. 
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5.7. 
Procedures for Monitoring Patient Compliance  
The investigator will be responsible for monitoring patient compliance. If the investigator or the 
sponsor determines that the patient is not in compliance with the study protocol, the investigator 
and the sponsor should determine whether the patient should be withdrawn from the study. The 
Independent Ethics Committee (IEC)/Institutional Review Board (IRB) should be notified. 
5.8. 
Randomization and Blinding  
This is a double-blind study. The sponsor, investigators, study staff (except for staff involved in 
bioanalytical analyses), and patients will be blinded to treatment assignment. A computer-
generated master randomization list will be provided to drug packaging facilities. Packaging 
vendor(s) will package active and placebo into single-visit kits according to Good Manufacturing 
Practice procedures. The active drug and placebo kits for each dose will be identical in 
appearance and will contain 1 PFS (for the 225 mg dose and its matching placebo) or 2 vials (for 
the 120 mg dose and its matching placebo). Adequate kit supply for upcoming study visits will 
be managed by interactive response technology (IRT) and kept (refrigerated at 2°C to 8°C) on 
site.  
This is a randomized study. Randomization will be stratified by country, sex, puberty status, and 
preventive medication use at baseline (Yes/No). Patients will be randomly assigned to treatment 
groups by means of a computer-generated randomization list. The specifications for 
randomization will be under the responsibility and oversight of Teva Global Statistics. Each 
patient will undergo randomization in a 1:1 ratio within the stratum to which he or she belongs to 
receive fremanezumab or placebo, as assigned by the IRT. The IRT will manage initial drug 
supply, maintenance of adequate study drug supplies on site, and study randomization centrally. 
At the time of each study visit, the IRT will be queried, and site personnel will retrieve and 
administer a 1.5 mL volume for patients weighing ≥45.0 kg at randomization (visit 2) or a 
0.8 mL volume for patients weighing <45.0 kg at randomization (visit 2) from each PFS or 
2 vials 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. 
However, if a prioritized sample analysis is needed, bioanalytical and clinical pharmacology 
personnel may be unblinded.  
In the event of an emergency, it will be possible to determine to which treatment group and dose 
the patient has been allocated by accessing the Randomization and Trial Supply Management 
(RTSM) system. All investigational centers will be provided with details of 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. 
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 analysis (after the end of study), after receiving 
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unblinding request from Teva statistician, the service provider will provide the unblinded IMP 
assignment according to the processes defined in the relevant SOP. 
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 test IMP and who 
received 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, pregnancy, or in cases 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. Individual randomization 
codes, indicating the IMP assignment for each randomized patient, will be available to the 
investigator(s) or pharmacist(s) at the investigational center via the RTSM, both via telephone 
and internet. Breaking of the treatment code can always be performed by the investigator without 
prior approval by the sponsor; however, the sponsor should be notified following breaking of the 
treatment code. The patient’s IMP 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 documentation. 
Assignment of IMP should not be recorded in any study documents or source document. 
In blinded studies, for an adverse event defined as a SUSAR (ie, reasonable possibility; see 
Section 7.1.6), Global Patient Safety and Pharmacovigilance (GPSP) may independently request 
that the blind code be broken (on a case-by-case basis) to comply with regulatory requirements. 
The report will be provided in an unblinded manner for regulatory submission. If this occurs, 
blinding will be maintained for the investigator and for other personnel involved in the conduct 
of the study, and analysis and reporting of the data. 
5.9.3. 
Data Monitoring Committee  
There will be no Data Monitoring Committee in this study. 
5.10. 
Total Blood Volume  
The total blood volume to be collected for each patient in this study is approximately 48 mL. See 
Appendix J. 
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6. 
ASSESSMENT OF EFFICACY  
Data from any efficacy assessments performed after the specified time will not be collected on 
the CRF; 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  
The primary efficacy endpoint (and some secondary and exploratory efficacy endpoints as well) 
will be derived from headache variables collected daily using an electronic headache diary 
device. Eligible patients and parents/caregivers will receive comprehensive training from site 
personnel on the use of the electronic headache diary device. Site personnel will also instruct 
patients and parents/caregivers on the requirement for timely and daily completion of the 
electronic diary. Patients will complete an electronic headache diary. If the patient is unable to 
complete the diary themselves then a parent/caregiver will complete the diary for them. 
On each day, the patient or parent/caregiver will be asked to record diary data for the previous 
24-hour period. Patients and parents/caregivers may be asked about their (child’s) performance 
at school and when doing household chores (ie, functional assessments). Patients or 
parents/caregivers who report headache on the previous day will answer questions about the 
headache (ie, the number of hours with headache, headache severity, presence of associated 
symptoms, and use of acute migraine medications). Additional details regarding the questions 
patients or parents/guardians will answer can be found in the electronic headache diary training 
manual.  
If a patient or parent/caregiver fails to complete the diary for the preceding day, the patient will 
be prompted to enter the missed day’s information the next time he/she accesses the electronic 
diary, provided no more than 48 hours have elapsed since the end of the missed day. If more than 
48 hours have elapsed since completion of a diary day, the patient or parent/caregiver will not be 
allowed to enter diary information for that day, and it will be considered a missed day. 
Rating of headache severity and headaches lasting ≥2 hours for each day will be completed in the 
electronic diary.  
If headache is reported, then headache severity will be subjectively rated by the patient or 
parent/caregiver on an 11-point numerical rating scale, where 0 is no pain and 10 is the most 
severe pain. Each headache severity rating from the 11-point numerical rating scale will be 
mapped to mild (1 to 3), moderate (4 to 6), or severe (7 to 10) for endpoint analyses (McCaffery 
and Beebe 1989). Patients or parents/caregivers will also record whether photophobia, 
phonophobia, nausea, and vomiting are present, and they will record any migraine medications 
(name of drug, number of tablets/capsules, and the dose in milligrams per tablet/capsule) taken 
on each day. Diary compliance of less than 75% after the start of treatment will be recorded as a 
protocol deviation. 
6.1.2. 
Pediatric Migraine Disability Assessment  
The PedMIDAS questionnaire is a 6-item instrument to assess migraine-related disability in 
pediatric patients, which can be self-administered by the patient or administered by a caregiver. 
It has been validated in patients aged 4 through 18 years (Hershey et al 2001) and includes 
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questions related to the impact of headache on school performance, disability at home (eg, 
inability to do chores or homework), and social/sport functioning. 
6.1.3. 
Patient Global Impression of Improvement Scale  
The PGI-I scale is a 7-item questionnaire designed to assess the patient’s global impression of 
improvement. It aims at evaluating all aspects of patients’ health and determining if there has 
been an improvement or not. The patient has to select the 1 response that gives the most accurate 
description of his/her state of health (overall status).  
The patient is instructed to select a response option on a 7-point scale in which a score of 1 
indicates that the patient's condition is “very much better,” a score of 4 indicates that the 
participant has experienced “no change,” and a score of 7 indicates that the participant is “very 
much worse.”  
• 1=Very much better 
• 2=Much better 
• 3=A little better 
• 4=No change 
• 5=A little worse 
• 6=Much worse 
• 7=Very much worse 
6.1.4. 
Pediatric Quality of Life Inventory  
The Pediatric Quality of Life Inventory (PedsQL) 4.0 is a brief 23-item health-related quality of 
life instrument that evaluates quality of life in 4 areas of functioning: physical, emotional, social, 
and school functioning. The PedsQL 4.0 has 4 age ranges: toddlers (2 through 4 years), young 
child (5 through 7 years), child (8 through 12 years), and adolescent (13 through 18 years). This 
study will use the young child, child, and adolescent formats. The PedsQL version that will be 
used for the patient for the duration of the study will be based on the age of the patient at visit 2 
and will not change during the course of the study. 
The PedsQL 4.0 asks respondents to indicate how much of a problem each item has been during 
the past month. For the child and adolescent self-report (8 through 18 years of age) and the 
parent report forms, respondents use a 5-point Likert scale to rate the item severity (0=never a 
problem;1=almost never a problem; 2=sometimes a problem; 3=often a problem; 4=almost 
always a problem). For younger children (5 through 7 years of age), a simplified 3-point Likert 
scale, anchored with a happy and a sad face, is used (0=not at all a problem; 2=sometimes a 
problem; 4=a lot of a problem) to increase further the developmental sensitivity of the measure. 
The PedsQL 4.0 yields a total quality of life score and 2 summary scores: Physical Health 
Summary Score and Psychosocial Health Summary Score. To obtain scores, items are reverse 
scored, transformed to a 0 through 100 scale (0=100, 1=75, 2=50, 3=25, 4=0), and averaged; 
total scores near 0 indicate lower quality of life, while scores approaching 100 indicate higher 
quality of life. 
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7. 
ASSESSMENT OF SAFETY  
In this study, safety will be assessed by qualified study personnel by evaluating reported adverse 
events, clinical laboratory test results, vital signs measurements, ECG findings, physical 
examination findings (including body weight and height measurements), suicidal ideation and 
behavior (as suggested by the C-SSRS), and use of concomitant medication. 
7.1. 
Adverse Events  
7.1.1. 
Definition of an Adverse Event  
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have to have a causal relationship with 
this treatment. 
An adverse event can, therefore, be any unfavorable and unintended physical sign, symptom, or 
laboratory parameter that develops or worsens in severity during the course of this study, or 
significant worsening of the disease under study, or of any concurrent disease, whether or not 
considered related to the IMP. 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/drug or drug device interactions 
• events occurring during diagnostic procedures 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 test results at 
the screening visit that preclude a patient from entering the study or receiving study 
drug are not considered adverse events.) 
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. 
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7.1.2. 
Definition of an Adverse Device Effect  
An adverse device effect is an adverse event related to the use of an investigational medical 
device or a combination product. This includes adverse events resulting from insufficient or 
inadequate instructions for use, deployment, implantation, installation, operation, or any 
malfunction of the investigational medical device, including any event resulting from user error 
or from intentional misuse of the investigational medical device. This definition includes events 
related to the procedures involved. For users or other persons, this definition is restricted to 
events related to investigational medical devices. 
7.1.3. 
Recording and Reporting of Adverse Events  
For adverse event recording, the study period is defined for each patient as the time period from 
signature of the ICF through completion of visit 5 or the early withdrawal visit (for patients who 
withdraw from the study for any reason). Adverse events will be collected at each visit via 
adverse event inquiry. 
All adverse events that occur during the defined study period must be recorded on the source 
documentation and transcribed onto the CRF, regardless of the severity of the event or judged 
relationship to the study drug (and/or PFS). For serious adverse events and protocol-defined 
adverse events of special interest for expedited reporting to GPSP, the Serious Adverse Event 
and Protocol-Defined Adverse Events of Special Interest Form must be completed, and the 
serious adverse event and the protocol-defined adverse events of special interest must be 
reported immediately (see Section 7.1.7.4.1). The investigator does not need to actively monitor 
patients for adverse events once the study has ended. Serious adverse events 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 7.1.7.4.1.  
At each contact with the patient, the investigator or designee must question the patient about 
adverse events by asking an open-ended question such as, “Have you had any unusual symptoms 
or medical problems since the last visit? If yes, please describe.” All reported or observed signs 
and symptoms will be recorded individually, except when considered manifestations of a 
medical condition or disease state. A precise diagnosis will be recorded whenever possible. 
When such a diagnosis is made, all related signs, symptoms, and any test findings will be 
recorded collectively as a single diagnosis on the CRF and, if it is a serious adverse event, also 
on the serious adverse event form. 
The clinical course of each adverse event will be monitored at suitable intervals until it resolves, 
stabilizes, or returns to baseline; until the patient is referred for continued care to another health 
care professional; or until a determination of a cause unrelated to the study drug (and/or PFS)or 
study procedure is made. 
The onset and end dates, duration (in case of adverse event duration of less than 24 hours), action 
taken regarding study drug, treatment administered, and outcome for each adverse event must be 
recorded on the source documentation and transcribed onto the CRF.  
The relationship of each adverse event to study drug and study procedures, and the severity and 
seriousness of each adverse event, as judged by the investigator, must be recorded, as described 
below. 
Further details are given in the Safety Monitoring Plan. 
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7.1.4. 
Recording and Reporting of Adverse Device Effect  
Adverse device effects (Figure 2) must be recorded on both the source documentation and the 
CRF.  
The investigator and sponsor will record all relevant information regarding every adverse device 
effect/serious adverse device effect and device deficiency and will categorize each as guided in 
Figure 2. 
The investigator should make an initial determination whether the adverse event may be related 
to a device deficiency. 
Figure 2: 
Decision Tree for Adverse Events and Adverse Device Effects Classification  
 
AE=adverse event; ADE=adverse device effect; CRF=case report form; IEC=Independent Ethics Committee; 
IRB=Institutional Review Board; SADE=serious adverse device effect;SAE=serious adverse event. 
7.1.5. 
Severity of an Adverse Event  
The severity of each adverse event must be recorded as 1 of the following: 
• Mild: No limitation of usual activities 
• Moderate: Some limitation of usual activities 
• Severe: Inability to carry out usual activities 
7.1.6. 
Relationship of an Adverse Event to the Investigational Medicinal Product 
and/or Device  
The relationship of an adverse event to the IMP (and/or PSF) is characterized as described in 
Table 3. 
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Table 3: 
The Relationship of an Adverse Event to the IMP and/or Device  
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 (and/or PFS). 
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 (and/or PFS). 
• 
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 (and/or PFS). 
• 
It does not reappear or worsen when the IMP 
(and/or PFS) 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 
(and/or PFS) 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 (and/or PFS). 
• 
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 (and/or PFS), yet an 
IMP (and/or PFS) relationship clearly exists. 
• 
It follows a known pattern of response to the IMP 
(and/or PFS). 
IMP=investigational medicinal product. 
7.1.7. 
Serious Adverse Events and Serious Adverse Device Effects  
For recording of serious adverse events and serious adverse device effects, the study period is 
defined for each patient as that time period from signature of the ICF to visit 5 (EOT visit). 
Serious adverse events and serious adverse device effects occurring in a patient after the end of 
study should be reported to the sponsor if the investigator occurring in a patient after visit 5 
(EOT visit) should be reported to the sponsor if the investigator becomes aware of them, 
following the procedures described in Section 7.1.7.4.1. 
7.1.7.1. 
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 
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• 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× the ULN 
• total bilirubin increase of >2× ULN 
• absence of initial findings of cholestasis (ie, no substantial increase of ALP) 
An adverse event that does not meet any of the criteria for seriousness listed above will be 
regarded as a nonserious adverse event. 
Refer to Appendix I for guidance regarding monitoring patients with elevated liver function tests.  
7.1.7.2. 
Definition of a Serious Adverse Device Effect  
A serious adverse device effect is an adverse device effect that has resulted in any of the 
consequences characteristic of a serious adverse event (Section 7.1.7.1). 
7.1.7.3. 
Expectedness  
A serious adverse event that is not included in the Adverse Reaction section of the relevant 
reference safety information by its specificity, severity, outcome, or frequency is considered an 
unexpected adverse event. The reference safety information for this study is the IB. 
The sponsor’s Pharmacovigilance Department will determine the expectedness for all serious 
adverse events. 
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For the purpose of SUSAR reporting, the version of the reference safety information document at 
the moment of the occurrence of the SUSAR applies. 
An unanticipated serious adverse device effect is a serious adverse device effect that, by its 
nature, incidence, severity, or outcome, has not been listed in Appendix K (Appendix Table 1 
and Appendix Table 2). 
7.1.7.4. 
Reporting a Serious Adverse Event  
7.1.7.4.1. 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 first dose of IMP 
• date and amount of last administered dose of IMP 
• action taken 
• outcome, if known 
• severity 
• explanation of assessment of relatedness 
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• concomitant medication (including doses, routes of administration, and regimens) and 
treatment of the event 
• pertinent laboratory or other diagnostic test data 
• medical history 
• results of dechallenge/rechallenge, if known 
• 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 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 form/Extensible Markup Language file to the LSO/CRO for submission to 
the competent authorities, IEC/IRBs, 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 the people who are involved directly in the study. Therefore, in 
case of a SUSAR, only the LSO or CRO personnel involved with safety regulatory submissions 
will receive the unblinded report for regulatory submission; the others will receive a blinded 
report.  
Note: Although pregnancy is not a serious adverse event, the process for reporting a pregnancy is 
the same as that for reporting a serious adverse event, but using the pregnancy form (see 
Section 7.2). 
7.1.7.4.2. Sponsor Responsibility  
If a serious unexpected adverse event is believed to be related to the IMP or study procedures, 
the sponsor will take appropriate steps to notify all investigators participating in sponsored 
clinical studies of fremanezumab and the appropriate competent authorities (and IEC/IRB, as 
appropriate). 
In addition to notifying the investigators and competent authorities (and IEC/IRB, as 
appropriate), other action may be required, including the following: 
• altering existing research by modifying the protocol 
• discontinuing or suspending the study 
• modifying the existing consent form and informing all study participants of new 
findings 
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• modifying listings of expected toxicities to include adverse events newly identified as 
related to fremanezumab 
7.1.7.4.3. Reporting a Serious Adverse Device Effect  
The process and contact details for serious adverse device effect reporting are the same as for 
serious adverse event reporting provided in Section 7.1.7.4. 
Events shall be reported to the IEC/IRB by the investigator and to the regulatory authorities by 
the sponsor using the appropriate form according to national and local regulations. 
The investigator should use Appendix K (Appendix Table 1 and Appendix Table 2) to make an 
initial determination whether the serious adverse event may be related to a device deficiency 
7.1.8. 
Protocol-Defined Adverse Events of Special Interest  
Adverse events of special interest for pediatric patients are not listed in the Pediatric 
Investigation Plan or Pediatric Study Plan. 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: ophthalmic-related adverse events of at least moderate severity and severe 
hypersensitivity or anaphylactic reactions. 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 diagnosing anaphylaxis are provided in 
Appendix D. 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 interest is the same as that for 
reporting a serious adverse event (Section 7.1.7.4). 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 7.1.7.1. 
7.1.9. 
Protocol Deviations Because of an Adverse Event  
If a patient experiences an adverse event or medical emergency, deviations from the protocol are 
allowed based on the investigator’s clinical judgment. 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 be withdrawn from the study. 
All pregnancies of females participating in the study and consenting female partners of males 
participating in the study that occur during the study or within 6 months after the last dose of 
study drug in this study 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 
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pregnancy is the same as that for reporting a serious adverse event but using the pregnancy form 
(Section 7.1.7.4). 
The investigator is not required to report patients who are found to be pregnant between 
screening and baseline, provided no protocol-related procedures were applied. 
All female patients (or consenting female partners of male patients participating in the study) 
who become pregnant will be monitored for the outcome of the pregnancy (including 
spontaneous, elective, or voluntary abortion). If the pregnancy continues to term, the outcome 
(health of the infant up to 8 weeks of age), including details of birth and presence or absence of 
any birth defect, congenital abnormalities, or maternal and newborn complications, will be 
reported to the sponsor. Any complication of pregnancy during the study and any complication 
of pregnancy that the investigator becomes aware of after withdrawal from the study will be 
reported as an adverse event or serious adverse event, as appropriate. 
Consenting female partners of men participating in the study who become pregnant will be asked 
to sign an ICF. 
If the pregnancy in the female participating in the study and/or the consenting female partners of 
males participating in the study does not continue to term, 1 of the following actions will be 
taken: 
• For a spontaneous abortion, report as a serious adverse event. 
• For an elective abortion due to developmental anomalies, report as a serious adverse 
event. 
• For an elective abortion not due to developmental anomalies, report on the pregnancy 
form; do not report as an adverse event. 
7.3. 
Medication Error and Special Situations Related to the 
Investigational Medicinal Products  
Any administration of IMP that is not in accordance with the study protocol should be reported 
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 health care 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, reference 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. 
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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 
non-professional occupation. 
7. Breastfeeding: Suspected adverse reactions which occur in infants following exposure to 
a medicinal product from breast milk. 
7.4. 
Clinical Laboratory Tests  
Details on sample handling, storage, shipment, and analysis are given in Appendix N and in the 
Laboratory Manual. 
7.4.1. 
Serum Chemistry, Hematology, Coagulation, and Urinalysis  
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 and monitored as described 
in Section 7.1.2. An adverse event may include a laboratory or diagnostic test abnormality (once 
confirmed by repeated testing) that results in the withdrawal of the patient from the study, the 
temporary or permanent withdrawal of IMP or medical treatment, or further diagnostic work-up. 
(Note: Abnormal laboratory or diagnostic test results at the screening visit that preclude a patient 
from entering the study or receiving IMP are not considered adverse events.) 
In addition, potentially clinically significant values will be predefined by the sponsor for selected 
laboratory parameters and will be detailed in the statistical analysis plan.  
Clinical laboratory tests (serum chemistry, hematology, coagulation, and urinalysis) will be 
performed at the time points detailed in Table 1. In case of suspected hepatitis, HIV, or Lyme 
disease, a blood sample may be taken at screening at the discretion of the investigator. Baseline 
is screening (visit 1). Clinical laboratory tests will be performed using the central laboratory. 
Specific laboratory tests to be performed are listed below (Table 4). Note, reflex tests (eg, red 
blood cell [RBC] shapes, RBC morphology, and other microscopic findings) may be triggered 
automatically. 
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Table 4: 
Clinical Laboratory Tests  
Serum chemistry 
Hematology and coagulation 
Urinalysis 
Calcium 
Phosphate 
Sodium 
Potassium 
Chloride 
Creatinine 
Glucose 
BUN 
ALT 
AST 
LDH 
GGT 
Alkaline phosphatase 
Creatine phosphokinase 
Carbon dioxide 
Magnesium 
Protein 
Albumin 
Bilirubin (total and direct) 
Hemoglobin 
Hematocrit 
RBC count 
RBC indices 
− 
mean corpuscular volume 
− 
mean corpuscular hemoglobin 
concentration 
− 
RBC distribution width 
Platelets 
Leukocytes 
− 
neutrophils 
− 
lymphocytes 
− 
eosinophils 
− 
monocytes 
− 
basophils 
Prothrombin time 
Partial thromboplastin time 
INR 
Color and appearance 
Protein 
Glucose 
Ketones 
Blood 
Leukocyte esterase 
Nitrite 
Bilirubin 
pH 
Specific gravity 
Microscopic tests 
− 
bacteria 
− 
erythrocytes 
− 
leukocytes 
− 
crystals 
− casts 
ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea nitrogen; 
GGT=gamma-glutamyl transpeptidase; INR=International Normalized Ratio; LDH=lactate dehydrogenase; 
RBC=red blood cell. 
7.4.2. 
Other Clinical Laboratory Tests  
7.4.2.1. 
Human Chorionic Gonadotropin Tests  
Serum β-HCG tests will be performed for all female patients who are postmenarchal or 
≥12 years of age at screening (visit 1) and visit 5; urine β-HCG tests will be performed at all 
visits (Table 1). Any patient who becomes pregnant during the study will be withdrawn. 
Procedures for reporting the pregnancy are provided in Section 7.2. 
7.5. 
Physical Examinations  
Physical examinations, including height and weight (to be obtained at the screening visit, 
randomization visit, and EOT only) and puberty status (at randomization and EOT only) will be 
performed at the time points detailed in Table 1. Body mass index will be calculated at screening 
and randomization. 
While the onset of puberty is generally associated with the onset of adolescence, a globally 
accepted age range for the onset of puberty and adolescence cannot be easily defined (World 
Health Organization 1986). Because randomization will be stratified by puberty status, the 
Tanner puberty staging scale (Finegold 1992) will be used to assess puberty status at that time. 
Puberty status will be assessed either by patients’ self report or by physical examination 
according to the Tanner staging card provided. 
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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, recorded on the CRF, and monitored as described in Section 7.1.2. 
7.6. 
Vital Signs  
Vital signs (pulse, systolic and diastolic blood pressure, temperature, and respiratory rate) will be 
measured at any time during the visit, as detailed in Table 1. The method for measuring 
temperature in an individual patient must be the same at each time point. 
Before pulse and blood pressure are measured, the patient must be in a supine or 
semi-erect/seated position and resting for at least 5 minutes. The same position and arm should 
be used each time vital signs are measured for a given patient. For any abnormal vital sign 
finding, the measurement should be repeated as soon as possible. Any vital sign value that is 
judged by the investigator as a clinically significant change (worsening) from a baseline value 
will be considered an adverse event, recorded on the source documentation and transcribed onto 
the CRF, and monitored as described in Section 7.1.2. 
7.7. 
Electrocardiography  
Twelve-lead ECGs will be conducted at any time during the visit, prior to study drug 
administration, as detailed in Table 1. The ECGs should be performed after the patient has been 
supine for at least 5 minutes. The ECGs will be performed in triplicate, with at least 1 minute 
between recordings. 
A qualified physician at a central diagnostic center will be responsible for interpreting the ECG. 
ECGs should be performed and transmitted according to the central ECG reading instructions 
provided in the ECG user manual. ECG equipment will be provided to all clinical sites. 
Although the ECG interpretation will be performed centrally, the clinical evaluation remains 
under the investigator’s responsibility. 
The ECG will be evaluated by the investigator at the time of recording (signed and dated), and 
the printout should be kept in the source documentation file. When potentially clinically 
significant findings are detected by the investigator, a cardiologist should be consulted for a 
definitive interpretation. All communications and diagnoses should be filed in the source 
documentation file. The investigator’s interpretation will be recorded in the CRF regardless of 
the central reading interpretation. Any abnormal findings assessed by the Investigator as 
clinically significant should be recorded in the relevant CRF modules (eg, adverse event, medical 
history). 
Objective alerts are predefined as described in the central ECG reading manual. In these cases, 
the site and the sponsor will be informed immediately. 
Any unscheduled ECGs must also be submitted for central ECG reading. 
Any ECG finding that is judged by the investigator as a potentially clinically significant change 
(worsening) compared with a baseline value will be considered an adverse event, recorded on the 
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source documentation and transcribed onto the CRF, and monitored as described in 
Section 7.1.2. 
7.8. 
Assessment of Local Tolerability and Pain  
Injection site assessment will be performed after administration of each dose of study drug, 
before the patient leaves the investigational site. The injection site will be assessed by site 
personnel for erythema, induration, and ecchymosis and categorized according to measurements: 
5 to ≤50 mm (mild), >50 to ≤100 mm (moderate), and >100 mm (severe). Induration must be 
assessed by careful superficial palpation, avoiding placing pressure on or squeezing the injection 
site. 
Reports of pain will be recorded as adverse events and will be graded using the 11-point 
numerical rating scale according to patient’s self-report of pain intensity and then mapping to 
mild, moderate, or severe. 
Appropriate treatment may be provided if necessary, in which case it must be recorded as 
concomitant medication. 
Injection site reactions will be recorded as adverse events as described in Section 7.1 and 
Section 9.8. 
7.9. 
Assessment of Suicidality  
The C-SSRS, combined with the investigator’s clinical evaluation, will be used to assess whether 
the patient has suicidal ideation or behavior and its severity (Posner et al 2011). The C-SSRS 
will be completed by a qualified rater trained to administer the scale at the investigational center 
based on discussion with the patient/caregiver at the time points described in Table 1. Any 
patient who demonstrates suicidal ideation and/or any suicidal behavior at any point during the 
study should be withdrawn from the study and discontinued from study treatment. In addition, if 
a patient endorses suicidal ideation or behavior at any point during the study (including during 
screening), the investigator must explain to the patient/caregiver the need for follow-up with a 
mental health professional and make any necessary referrals. 
7.10. 
Concomitant Therapy or Medication  
Concomitant therapy or medication usage will be monitored throughout the study. Details of 
prohibited medications are found in Section 5.6. 
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8. 
ASSESSMENT OF PHARMACOKINETICS AND 
IMMUNOGENICITY  
8.1. 
Pharmacokinetic Assessment  
Sampling for pharmacokinetics will be sparse. Thus, the fremanezumab pharmacokinetic 
samples will be analyzed using a population pharmacokinetic approach and will be reported 
separately from the clinical study report.  
Samples from patients who receive active study drug will be analyzed for fremanezumab using a 
validated method. Samples from patients who receive placebo will not be analyzed.  
8.1.1. 
Specimen Sampling, Handling, and Shipment  
Blood samples (2 mL) will be collected via venipuncture or indwelling catheter at the time points 
detailed in Table 1 for plasma concentration measurements of fremanezumab.  
The dates and times of study drug administration and each pharmacokinetic sample will be 
recorded on the source documentation and transcribed onto the CRF.  
Details on sample handling, storage, shipment, and analysis are given in Appendix N and in the 
Laboratory Manual. 
8.2. 
Pharmacodynamics Assessment  
Not applicable. 
8.3. 
Immunogenicity Testing  
Samples from patients who receive active study drug will be analyzed for ADA using a validated 
method. Samples from patients who receive placebo will not be analyzed. 
Blood samples (4 mL) will be collected via venipuncture or indwelling catheter at the time points 
detailed in Table 1 for immunogenicity testing.  
Details on sample handling, storage, shipment, and analysis are given in Appendix N and in the 
Laboratory Manual. 
8.4. 
Assessment of Exploratory Biomarkers  
Not applicable. 
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9. 
STATISTICS  
This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group 
study comparing the efficacy, safety, and tolerability of sc administration of fremanezumab 
versus placebo for preventive treatment of EM in pediatric patients 6 through 17 years of age. 
Eligible patients will be randomized in a 1:1 ratio between fremanezumab and placebo treatment 
groups. Patients weighing ≥45.0 kg at randomization (visit 2) will receive a 225 mg 
administration of fremanezumab or matching placebo. Patients weighing <45.0 kg at 
randomization (visit 2) will receive a 120 mg administration of fremanezumab or matching 
placebo. Randomization will be stratified by country, sex, puberty status, and preventive 
medication use at baseline (Yes/No). 
9.1. 
Sample Size and Power Considerations  
The sample size planned is approximately 220 patients (110 evaluable patients completing the 
study per treatment group). Assuming a treatment difference of 1.8 days (reduction in monthly 
average number of migraine days) and a common SD of 4.31, a sample size of 110 patients per 
treatment group gives at least 87% power for the study to succeed at an alpha level of 0.05. 
Assuming a 4% discontinuation rate, approximately 230 patients (115 patients per treatment 
group) will be randomized. Patients will be randomized to receive either monthly sc 
administration of fremanezumab or placebo.  
The enrollment target is approximately 230 patients in total, with a goal of approximately 20% of 
those patients in the 6- through 11-year-old age group. 
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. 
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. 
9.2.3. 
Full Analysis Set  
The full analysis set (FAS) will include all patients in the ITT population who receive at least 
1 dose of study drug and have at least 10 days of diary entries postbaseline for efficacy 
assessments on the primary endpoint. 
9.2.4. 
Per-Protocol Analysis Set  
The per-protocol analysis set will consist of all patients in the FAS who have completed the 
study without any important deviations, such as important inclusion/exclusion criteria deviations, 
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important deviations or omissions of the IMP administration, or unexpected drug concentration 
findings, and who have at least 75% diary compliance after the start of treatment. 
9.3. 
Data Handling Conventions  
Efficacy variables from patients who do not have their diary completed for the entire study 
period will be imputed. The detailed data imputation rules will be described in the statistical 
analysis plan. 
9.3.1. 
Handling Withdrawals and Missing Data  
Efficacy variables based on diary data will be prorated to monthly rate. Sensitivity analysis for 
primary efficacy endpoint will be conducted using multiple imputation method for missing data. 
9.4. 
Study Population  
The ITT analysis set (Section 9.2) will be used for all study population summaries unless 
otherwise specified. Summaries will be presented by treatment group and for all patients. 
9.4.1. 
Patient Disposition  
Data from patients screened; patients screened but not randomized and reason not randomized; 
patients who are randomized; patients randomized but not treated; patients in the ITT, safety, and 
other analysis sets; patients who complete the study; and patients who withdraw from the study 
will be summarized using descriptive statistics. Data from patients who withdraw from the study 
will also be summarized by reason for withdrawal using descriptive statistics. 
9.4.2. 
Demographic and Baseline Characteristics  
Patient demographic and baseline characteristics, including medical history, prior medications, 
and 12-lead ECG findings, will be summarized by treatment group 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. 
Treatment groups will be compared for all continuous variables, using an analysis of variance 
with treatment group as factors. The categorical variables of patient sex and race will be 
summarized using descriptive statistics for each variable category. Missing categories will be 
presented, if necessary. Treatment groups will be compared for all categorical variables using a 
Pearson’s chi square (or Fisher’s exact test if cell sizes are too small). 
9.5. 
Efficacy Analysis  
For the purpose of this study, a migraine day will be defined as a calendar day where the patient 
reports either of the following:  
• headache pain that lasts ≥2 hours and is accompanied by ≥1 migraine symptom(s) 
• the patient used acute migraine-specific medication (triptans or ergots) to treat a 
headache of any severity or duration  
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The detailed algorithm for deriving migraine days will be described in the statistical analysis 
plan. 
9.5.1. 
Primary Endpoint  
The primary efficacy endpoint is the mean change from baseline (28-day baseline period) in the 
monthly average number of migraine days during the 12-week period after the first dose of study 
drug. 
9.5.1.1. 
Estimand for the Primary Endpoint  
The primary estimand for this study is the difference in means between the fremanezumab group 
and the placebo group in the target population who have received at least 1 dose of study drug 
and have at least 10 days of electronic diary efficacy data for the mean change from baseline in 
the monthly average number of migraine days during the 12-week period after the first dose of 
study drug as if there were no intercurrent events. Data collected after treatment discontinuation 
or prohibited therapy will not be used for assessing the primary estimand. 
9.5.2. 
Secondary Endpoints  
The secondary efficacy endpoints are as follows: 
• mean change from baseline (28-day baseline period) in monthly average number of 
headache days of at least moderate severity during the 12-week period after the first 
dose of study drug 
• proportion of patients reaching at least 50% reduction in the monthly average number 
of migraine days during the 12-week period after the first dose of study drug 
• mean change from baseline (28-day baseline period) in the monthly average number 
of days of use of any acute headache medications during the 12-week period after the 
first dose of study drug 
• mean change from baseline (day 1) in migraine-related disability score, as measured 
by the PedMIDAS questionnaire, at 12 weeks after administration of the first dose of 
study drug 
• mean change from baseline (day 1) in quality of life, as measured by the PedsQL, at 
12 weeks after administration of the first dose of study drug 
• proportion of patients developing ADAs throughout the study. The impact of ADAs 
on safety and efficacy will be analyzed if the number of ADA-positive patients 
allows. 
9.5.3. 
Exploratory/Other Endpoints  
 
 
 
 
 
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9.5.4. 
Planned Method of Analysis  
The FAS (see Section 9.2.3) will be used for all efficacy analyses. Summaries will be presented 
by treatment group.  
9.5.4.1. 
Primary Efficacy Analysis  
The primary efficacy endpoint, the mean change from baseline (28-day baseline period) in the 
monthly average number of migraine days during the 12-week period after the first dose of study 
drug, will be analyzed using an analysis of covariance method. The model will include treatment, 
sex, puberty status, region, baseline weight category (<45.0 kg or ≥45.0 kg), and preventive 
medication use at baseline (Yes/No) as fixed effects and baseline number of migraine days as a 
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covariate. Ninety-five percent confidence intervals will be constructed for the least squares mean 
differences between the fremanezumab group and the placebo group. A hierarchical procedure 
will be used to control Type 1 error rate, as described in Section 9.6. An interim analysis with 
blinded sample size re-estimation will be conducted as described in Section 9.12. 
9.5.4.2. 
Sensitivity and Supplementary Analyses  
A sensitivity analysis for the primary efficacy endpoint will be conducted by using multiple 
imputation method for missing data. Sensitivity analysis using Mixed-Effect Model Repeated 
Measure method also will be conducted for change from baseline to months 1 through 3 in 
migraine days. A supplementary analysis using the ITT population will also be carried out for the 
primary efficacy endpoint. Additional subgroup analyses will be performed to investigate 
treatment effect among relevant sub-populations, such as sex, region, receiving preventive 
migraine therapy or not, receiving 2 preventive medications from Appendix C, and receiving 
alternative preventive medications that belong to the same classes but are not listed in 
Appendix C. The details will be described in the statistical analysis plan. 
9.5.4.3. 
Secondary Efficacy Analysis  
The same analysis used for the primary efficacy endpoint will be performed for the continuous 
secondary efficacy endpoints. For the proportion of responders, defined as at least 50% reduction 
from baseline in the monthly average number of migraine days, a logistic regression model will 
be used with the following factors: treatment, sex, region, puberty status, baseline weight 
category (<45.0 kg or ≥45.0 kg), and preventive medication use at baseline (Yes/No). The odds 
ratio, 95% confidence interval for the odds ratio, and p-value for the treatment comparison will 
be presented.  
9.5.4.4. 
Exploratory Efficacy Analysis  
 
 
9.6. 
Multiple Comparisons and Multiplicity  
A fixed-sequence (hierarchical) testing procedure will be implemented to control the Type 1 
error rate at 0.05. The sequence of comparisons will start with the analysis of the primary 
endpoint and will follow with the secondary efficacy endpoints. 
The order of secondary endpoint analyses will in general follow the sequence listed in 
Section 9.5.2. Final order and details will be confirmed in the statistical analysis plan, which will 
be finalized before database lock. 
9.7. 
Safety Analysis  
Safety analyses will be performed on the safety analysis set. 
Safety assessments and time points are provided in Table 1. 
All adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Each patient will be counted only once in each preferred term or system organ class 
category for the analyses of safety. Summaries will be presented for all adverse events (overall 
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and by severity), adverse events determined by the investigator to be related to test IMP (and/or 
PFS) (ie, reasonable possibility) (defined as related or with missing relationship) (overall and by 
severity), serious adverse events, serious adverse device effects, and adverse events and adverse 
device effects causing withdrawal from the study. Summaries will be presented by treatment 
group and for all patients. Patient listings of serious adverse events and adverse events leading to 
withdrawal will be presented. 
Changes in laboratory, ECG, and vital signs measurements data will be summarized 
descriptively. All values will be compared with predefined criteria to identify potentially 
clinically significant values or changes, and such values will be listed. 
Suicidal ideation and behavior will be measured using the C-SSRS. Data for patients with 
positive findings will be listed. 
The use of concomitant medications will be summarized by therapeutic class using descriptive 
statistics. Concomitant medications will include all medications taken while the patient is treated 
with study drug. 
For continuous variables, descriptive statistics (n, mean, SD, median, minimum, and maximum) 
will be provided for actual values and changes from baseline to each time point. For categorical 
variables, patient counts and percentages will be provided. Descriptive summaries of serious 
adverse events, patient withdrawals due to adverse events, and potentially clinically significant 
abnormal values (clinical laboratory or vital signs) based on predefined criteria will be provided 
as well. 
If any patient dies during the study, a listing of deaths will be provided, and all relevant 
information will be discussed in the patient narrative included in the clinical study report. 
9.8. 
Tolerability Analysis  
Injection site reactions will be recorded as adverse events according to the following severity 
assessment criteria: 
• Assessment 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).  
• Injection site pain will be recorded using the 11-point numerical rating scale and will 
be mapped to mild, moderate, or severe, according to patient’s self-report of pain 
intensity, as described for the recording of headache pain in Section 6.1.1. 
• 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 (day 85, final assessment) 
• the number (%) of patients who fail to complete the study due to adverse events 
Local tolerability findings will be listed and summarized descriptively. 
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9.9. 
Pharmacokinetic Analysis  
Pharmacokinetic plasma concentration results (fremanezumab) will be tabulated descriptively at 
each planned sampling time point by weight cutoff. 
In addition, the most appropriate population pharmacokinetic model will be developed. This 
analysis will be reported separately, as appropriate. 
9.10. 
Pharmacokinetic/Pharmacodynamic Analysis  
The pharmacokinetics/pharmacodynamic relationship may be estimated by compartmental 
techniques. The pharmacokinetic parameters will be based on fremanezumab measurements. The 
pharmacodynamic measures will be the efficacy/safety responses.  
The pharmacokinetic/pharmacodynamic relationship may be estimated using the most 
appropriate model after comparing different candidate models for their quality of fit. If 
performed, this analysis will be reported separately. 
9.11. 
Immunogenicity Analysis  
Summary of immunogenicity results will be provided, and the incidence of immunogenicity will 
be calculated. The impact of immunogenicity on the pharmacokinetic profile, drug efficacy, and 
clinical safety will be evaluated if data allows. This analysis will be reported separately. 
9.12. 
Planned Interim Analysis  
An interim analysis with blinded sample size re-estimation will be conducted by evaluating the 
pooled variability (SD) of the primary endpoint using the total number of patients regardless of 
the treatment assignment once 50% (±10%) of patients have completed at least 3 months of 
treatment or have withdrawn from the study early. If the pooled SD is <4.8, there will be no 
change in enrollment; if the pooled SD is >5.2, the sample size will increase to approximately 
400 patients; and if the pooled SD is between 4.8 and 5.2, the sample size will increase to 
approximately 340 patients total. Details of the interim analysis will be provided in the statistical 
analysis plan. 
9.13. 
Reporting Deviations from the Statistical Plan  
Deviations from the statistical plan, along with the reasons for the deviations, will be described 
in protocol amendments, the statistical analysis plan, the clinical study report, or any 
combination of these, as appropriate, and in accordance with applicable national, local, and 
regional requirements and regulations. 
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10. 
QUALITY CONTROL AND QUALITY ASSURANCE  
Refer to Appendix E 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 K 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 the ICH Harmonised Tripartite Guideline, 
Guideline for Good Clinical Practice E6 and ISO 14155: Clinical investigation of medical 
devices for human subjects – Good clinical practice, and any applicable national and local laws 
and regulations (eg, 21CFR Parts 11, 50, 54, 56, 312, and 314, Directive 2001/20/EC of the 
European Parliament and of the Council on the approximation of the laws, regulations, and 
administrative provisions of the Member States relating to the implementation of good clinical 
practice in the conduct of clinical trials on medicinal products for human use). Any episode of 
noncompliance will be documented. 
The investigator is responsible for performing the clinical study in accordance with this protocol 
and the applicable GCP guidelines referenced above for collecting, recording, and reporting the 
data accurately and properly. Agreement of the investigator to conduct and administer this 
clinical study in accordance with the protocol will be documented in separate clinical study 
agreements with the sponsor and other forms as required by national competent authorities in the 
country where each investigational center is located. 
The investigator is responsible for ensuring the privacy, health, and welfare of the patients during 
and after the clinical study; and must ensure that trained personnel are immediately available in 
the event of a medical emergency. The investigator and the involved clinical study personnel 
must be familiar with the background and requirements of the study and with the properties of 
the IMPs as described in the 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 F for the ethics expectations of informed consent or assent, 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 L 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. 
This clinical study is insured in accordance with the corresponding local legal provisions. The 
policy coverage is subject to the full policy terms, conditions, extensions, and exclusions. 
Excluded from the insurance coverage are inter alia, damages to health, and worsening of 
previous existing disease that would have occurred or continued if the patient had not taken part 
in the clinical study. 
The policy of Clinical Trials Insurance will be provided to the investigational centers by the 
sponsor. 
For covered clinical studies (see 21 CFR 54), the investigator will provide the sponsor with 
financial information required to complete 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 M for information regarding the publication policy. 
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15. 
REFERENCES  
Abu-Arafeh I, Razak S, Sivaraman B, Graham C. Prevalence of headache and migraine in 
children and adolescents: a systematic review of population-based studies. Dev Med Child 
Neurol 2010 Dec;52(12):1088-97. 
Abu-Arefeh I, Russell G. Prevalence of headache and migraine in schoolchildren. BMJ 1994 Sep 
24;309(6957):765-9. 
Armour KL, Clark MR, Hadley AG, Williamson LM. Recombinant human IgG molecules 
lacking Fcgamma receptor I binding and monocyte triggering activities. Eur J Immunol 
1999;29(8):2613–24. 
Barnes NP. Migraine headache in children. BMJ Clin Evid 2015;1-33. 
Burch RC, Loder S, Loder E, Smitherman TA. The prevalence and burden of migraine and 
severe headache in the United States: updated statistics from government health surveillance 
studies. Headache 2015;55(1):21-34. 
Buse DC, Loder EW, Gorman JA, Stewart WF, Reed ML, Fanning KM, et al. Sex differences in 
the prevalence, symptoms, and associated features of migraine, probable migraine and other 
severe headache: results of the American Migraine Prevalence and Prevention (AMPP) Study. 
Headache 2013 Sep;53(8):1278-99. 
Edlund H, Melin J, Parra-Guillen ZP, Kloft C. Pharmacokinetics and pharmacokinetic-
pharmacodynamic relationships of monoclonal antibodies in children. Clin Pharmacokinet 
2015;54(1):35-80. 
Fendrich K, Vennemann M, Pfaffenrath V, Evers S, May A, Berger K, et al. Headache 
prevalence among adolescents—the German DMKG headache study. Cephalalgia 2007 
Apr;27(4):347-54. 
Finegold D. Pediatric endocrinology. In: Zitelli BJ, Davis HW, editors. Atlas of pediatric 
physical diagnosis. 2nd ed. Philadelphia (Pennsylvania): Lippincott Williams & Wilkins, 
1992:16-9. 
Headache Classification Committee of the International Headache Society (IHS). The 
International Classification of Headache Disorders: 3rd Edition (beta version). Cephalalgia 
2013;33(9):629-808. 
Hershey AD, Powers SW, Vockell AL, LeCates S, Kabbouche MA, Maynard MK. PedMIDAS: 
development of a questionnaire to assess disability of migraines in children. Neurology 
2001;57(11):2034-9. 
International Committee of Medical Journal Editors (ICMJE). Recommendations for the 
Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical Journals. Available 
at http://www.icmje.org/recommendations/. Accessed 02 July 2014. 
Kacperski J. Prophylaxis of migraine in children and adolescents. Paediatr Drugs 
2015;17(3):217-26. 
Laurell K, Larsson B, Eeg-Olofsson O. Prevalence of headache in Swedish schoolchildren, with 
a focus on tension-type headache. Cephalalgia 2004 May;24(5):380-8. 
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Lewis DW, Winner P. The pharmacological treatment options for pediatric migraine: an 
evidence-based appraisal. NeuroRx 2006;3(2):181-91. 
Lewis DW. Pediatric migraine. Neurol Clin 2009;27(2):481-501. 
Lipton RB, Silberstein SD. Episodic and chronic migraine headache: breaking down barriers to 
optimal treatment and prevention. Headache 2015;55(S2):103-22. 
Manack A, Buse DC, Serrano D, Turkey CC, Lipton RB. Rates, predictors, and consequences of 
remission from chronic migraine to episodic migraine. Neurology 2011;76(8):711-8. 
McCaffery M and Beebe A. Pain: Clinical manual for nursing practice. St. Louis, MO: Mosby 
1989. Available upon request. 
Momper J, Mulugeta Y, Green D, Karesh A, Krudys K, Sachs H, et al. Adolescent dosing and 
labeling since the Food and Drug Administration amendments act of 2007. JAMA Pediatr 
2013;167(10):926-32. 
National Institutes of Health Clinical Center: Patient Education Materials. Giving a 
Subcutaneous Injection. July 2016. Available at: 
www.cc.nih.gov/ccc/patient_education/pepubs/subq.pdf. 
O’Brien HL, Kabbouche MA, Hershey AD. Treating pediatric migraine: an expert opinion. 
Expert Opin Pharmacother 2012 May;13(7):959-66. 
O’Brien HL, Kabbouche MA, Kacperski J, Hershey AD. Treatment of pediatric migraine. Curr 
Treat Options Neurol 2015;17(1):326. 
Ozge A, Saşmaz T, Buğdaycı R, Cakmak SE, Kurt AÖ, Kaleağası SH, et al. The prevalence of 
chronic and episodic migraine in children and adolescents. Eur J Neurol 2013 Jan;20(1):95-101. 
Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, et al. The Columbia 
Suicide Severity Rating Scale: initial validity and internal consistency findings from three 
multisite studies with adolescents and adults. Am J Psychiatry 2011;168(12):1266-77. 
Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF, Jr., Bock SA, Branum A, et al. 
Second symposium on the definition and management of anaphylaxis: summary report-Second 
National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network 
symposium. [reprint in Ann Emerg Med 2006 Apr;47(4):373-80; PMID:16546624]. J Allergy 
Clin Immunol 2006 Feb;117(2):391-7. 
Silberstein S, Holland S, Freitag F, Dodick DW, Argoff C, Ashma E. Evidence-based guideline 
update: pharmacologic treatment of episodic migraine prevention in adults. Neurology 
2012;78:1337-45. 
Silberstein SD. Practice parameter: evidence-based guidelines for migraine headache (an 
evidence-based review). Neurology 2000;55(6):754-62. 
Stovner LJ, Andree C. Prevalence of headache in Europe: a review for the Eurolight project. J 
Headache Pain 2010;11(4):289-99. 
Tfelt-Hansen P, Pascual J, Ramadan N, Dahlöf C, D’Amico D, Diener H, et al. Guidelines for 
controlled trials of drugs in migraine: third edition. A guide for investigators. Cephalalgia 
2012;32(1):6-38. 
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Unalp A, Dirik E, Kurul S. Prevalence and clinical findings of migraine and tension-type 
headache in adolescents. Pediatr Int 2007 Dec;49(6):943-9. 
Victor TW, Hu X, Campbell JC, Buse DC, Lipton RB. Migraine prevalence by age and sex in 
the United States: a life-span study. Cephalalgia 2010;30(9):1065-72. 
Wang W, Wang EQ, Balthasar JP. Monoclonal antibody pharmacokinetics and 
pharmacodynamics. Clin Pharmacol Ther 2008;84(5):548-58. 
World Health Organization. Young people’s health--a challenge for society. Report of a WHO 
Study Group on young people and “Health for All by the Year 2000”. World Health Organ Tech 
Rep Ser 1986;731:1-117. 
Yang N, Xu M, Yao Z. Evaluation of weight thresholds for pediatric patients to use adult dosage 
of therapeutic monoclonal antibodies. J Clin Pharm 2019;00(0):1-10. 
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 09 Dated 24 September 2023  
The primary reason for this amendment is to reduce the size of the study population and update 
the inclusion criteria in order to help with enrollment and study completion. Text relating to 
device vigilance was also added. All major changes to the protocol body are listed below in the 
table and are reflected in the synopsis, as applicable. Table 1 (Study Procedures and 
Assessments) and Table 3 (The relationship of an adverse event to the IMP and/or Device) have 
been revised to reflect the changes described below. Minor editorial changes (typos, punctuation, 
etc) have been made to the protocol (and protocol synopsis, as appropriate). 
Original text with changes shown 
New wording 
Reason/justification for 
change 
Title page, Investigator Agreement,  and Coordinating Investigator Agreement 
EMA Decision number of Pediatric 
Investigation Plan: P/0411/2019 
P/0378/2023 
EMA Decision number of Pediatric 
Investigation Plan: P/0378/2023 
Alignment with agreed 
modified paediatric 
investigation plan for 
fremanezumab 
1.1. Introduction 
… in CM and EM to evaluate the 
safety and efficacy of fremanezumab. 
One Phase 4 study (Study TV48125-
MH-40142) was conducted to evaluate 
the efficacy and safety of 
fremanezumab in adult patients with 
migraine and comorbid major 
depressive disorder. 
… in CM and EM to evaluate the 
safety and efficacy of fremanezumab. 
One Phase 4 study (Study TV48125-
MH-40142) was conducted to evaluate 
the efficacy and safety of 
fremanezumab in adult patients with 
migraine and comorbid major 
depressive disorder. 
Updated text with info of 
completed Phase 4 Study. 
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Original text with changes shown 
New wording 
Reason/justification for 
change 
1.2.2. Clinical Studies 
Overall in the fremanezumab migraine 
clinical development program, 
25122853 patients with… 
Overall in the fremanezumab migraine 
clinical development program, 2853 
patients with… 
Updated text with info of 
completed Phase 4 Study 
…composed of 14 15 studies…blind, 
placebo-controlled), and 3 Phase 3 
studies (2 double-blind, 
placebo-controlled studies and 1 long-
term, double-blind safety study [Study 
TV48125-CNS-30051], and 1 Phase 4 
study)])…. 
…composed of  15 studies …blind, 
placebo-controlled), 3 Phase 3 studies 
(2 double-blind, placebo-controlled 
studies and 1 long-term, double-blind 
safety study [Study TV48125-CNS-
30051], and 1 Phase 4 study). … 
Updated text with info of 
completed Phase 4 Study. 
SixFive studies in adult migraine 
patients (2 Phase 2b studies, and 3 
Phase 3 studies, and 1 Phase 4 study) 
examining the safety… 
Six studies in adult migraine patients (2 
Phase 2b studies, 3 Phase 3 studies, 
and 1 Phase 4 study) examining the 
safety… 
Updated text with info of 
completed Phase 4 Study. 
…dose regimens of fremanezumab in 
the preventive treatment of migraine 
(CM and EM). The Phase 4 Study 
TV48125-MH-40142 was a 
multicenter, randomized, double-blind, 
placebo-controlled, parallel-group 
study followed by an open-label 
extension to evaluate the efficacy and 
safety of fremanezumab for preventive 
treatment of migraine in patients with 
major depressive disorder. 
…dose regimens of fremanezumab in 
the preventive treatment of migraine 
(CM and EM). The Phase 4 Study 
TV48125-MH-40142 was a 
multicenter, randomized, double-blind, 
placebo-controlled, parallel-group 
study followed by an open-label 
extension to evaluate the efficacy and 
safety of fremanezumab for preventive 
treatment of migraine in patients with 
major depressive disorder. 
Updated text with info of 
completed Phase 4 Study. 
1.2.2.2. Clinical Safety and Efficacy Studies 
…3 Phase 3 studies in patients with 
migraine. Additional studies are the 
Phase 3b FOCUS study [TV48125-
CNS-30068], the Japanese [Otsuka] 
registration studies, and the Phase 4 
UNITE study [TV48125-MH-40142]). 
Safety results from these studies are 
presented in the IB. 
…3 Phase 3 studies in patients with 
migraine. Additional studies are the 
Phase 3b FOCUS study [TV48125-
CNS-30068], the Japanese [Otsuka] 
registration studies, and the Phase 4 
UNITE study [TV48125-MH-40142]). 
Safety results from these studies are 
presented in the IB. 
Update 
None of the identified risks was 
serious or considered as an important 
risk. No serious adverse reactions 
(SARs) are considered expected by the 
sponsor for the purpose of expedited 
reporting of suspected unexpected 
serious adverse reactions (SUSAR). 
None of the identified risks was serious 
or considered as an important risk. 
Statement not relevant for 
protocol as can be quicklu 
outdated. The IB includes 
this information. 
1.3.1. Known and Potential Benefits and Risks of the Test Investigational Medicinal Product(s) and/or 
Device 
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Original text with changes shown 
New wording 
Reason/justification for 
change 
1.3.1. Known and Potential Benefits 
and Risks of the Test Investigational 
Medicinal Product(s) and/or Device 
1.3.1. Known and Potential Benefits 
and Risks of the Test Investigational 
Medicinal Product(s) and/or Device 
Updated according to 
template and added device 
vigilance text throughout 
protocol. 
1.3.1.2. Important Potential Risk 
Severe hypersensitivity reactions are 
regarded as a potential risk for 
fremanezumab. Mild and moderate 
drug hypersensitivity events … 
Mild and moderate drug 
hypersensitivity events… 
Updated as hypersensitivity 
reaction are no longer a 
potential risk 
For additional details, refer to the 
IBcurrent IB, Section 7.5.5. 
For additional details, refer to the IB. 
Update 
2.2. Exploratory Objective and Endpoints 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clarification 
3.1. General Study Design and Study Schematic Diagram 
An interim analysis with blinded 
sample size re-estimation will be 
conducted by evaluating the pooled 
variability (standard deviation [SD]) of 
the primary endpoint using the total 
number of patients regardless of the 
treatment assignment once 50% 
(±10%) of patients have completed… 
An interim analysis with blinded 
sample size re-estimation will be 
conducted by evaluating the pooled 
variability (standard deviation [SD]) of 
the primary endpoint using the total 
number of patients regardless of the 
treatment assignment once 50% 
(±10%) of patients have completed… 
Clarification 
The total duration of the study is 
planned to be 5136 months (from Q1 
2020 to Q2 2024Q4 2022). 
The total duration of the study is 
planned to be 51 months (from Q1 
2020 to Q2 2024). 
Updated study timelines 
according to new projections 
and reduced study 
population. 
The enrollment target is approximately 
230 EM patients,288 patients in total 
with potential increase (up to 
approximately 400 patients total), 
depending on the planned interim 
analysis of blinded sample size re-
estimation (Section 9.12), with a goal 
of approximately 20at least 30% of 
those patients in the 6- through 11-
year-old age group. The goal in the 12- 
through 17-year-old age group is to 
enroll similar numbers of patients who 
are 12 through 14 years old and 15 
through 17 years old. 
 
The enrollment target is approximately 
230 EM patients, with a goal of 
approximately 20% of those patients in 
the 6- through 11-year-old age group. 
 
Updated text to reduce study 
population and study criteria 
in order to aid timely study 
completion.  
3.2. Planned Number of Patients and Countries 
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Original text with changes shown 
New wording 
Reason/justification for 
change 
Approximately 412 patients will be 
screened to achieve 288 randomized 
patients. 
The number of evaluable patients is 
planned to be approximately 220 
(110approximately 244(122 evaluable 
patients completing the study per 
treatment group). Details on definition 
of evaluable patients and sample size 
are given in Section 9. 
The total number of randomized 
patients planned is approximately 
230.288 with potential increase (up to 
approximately 400 patients total), 
depending on the planned interim 
analysis of blinded sample size 
re estimation (Section 9.12). 
… 
The study is expected to start in Q1 
2020 and last until Q2 2024Q4 2022. 
The number of evaluable patients is 
planned to be approximately 220 (110 
evaluable patients completing the study 
per treatment group). Details on 
definition of evaluable patients and 
sample size are given in Section 9. 
 
 
 
 
The total number of randomized 
patients planned is approximatly 230. 
… 
 
 
 
 
 
The study is expected to start in Q1 
2020 and last until Q2 2024.  
Updated text to reflect 
reduced study population, 
projections, and currently 
observed drop-out rate. 
Removed text on interim 
analysis here, as analysis was 
already conducted and based 
on variations sample size 
does not need to be 
increased. 
3.3. Justification for Study Design and Selection of Population 
Patients on concomitant migraine 
preventive medications must be on a 
stable dose for at least 2… 
Patients on concomitant migraine 
preventive medications must be on a 
stable dose for at least 2… 
Clarification 
…A list of migraine preventive 
medications allowed for any condition 
for the duration of the study for 
approximatelyup to 30% of patients is 
presented in Appendix C. The total 
number of patients receiving migraine 
concomitant preventive medication 
during the study will be 
approximatelynot exceed 30% of the 
total number of patients randomized. 
…A list of migraine preventive 
medications allowed for any condition 
for the duration of the study for 
approximately 30% of patients is 
presented in Appendix C. The total 
number of patients receiving 
concomitant preventive medication 
during the study will be approximately 
30% of the total number of patients 
randomized. 
Aid with recruitement and 
clarification 
3.5 Schedule of Study Procedures and Assessments 
Table 1 Study Procedures and Assessments 
d TheIn 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 The date of the next visit will be 
calculated based on the actual date of 
the last administration of study drug. 
 
Clarification that the date of 
the next dosing visit is 
always calculated based on 
the actual date of the last 
investigational medicinal 
product administration; 
regardless of whether the 
visit is out-of-window or not. 
4.1. Patient Inclusion Criteria 
f. [Revision 01] Not using migraine 
preventive medications (listed in 
Appendix C)… no more than 2 
f. [Revision 01] Not using migraine 
preventive medications (listed in 
Appendix C)… no more than 2 
Aid with recruitement and 
clarification 
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Original text with changes shown 
New wording 
Reason/justification for 
change 
migraine preventive medications 
(listed in Appendix C)…A list of 
migraine preventive medications 
allowed for any condition for the 
duration of the study for 
approximatelyup to 30% of patients is 
presented in Appendix C. 
… 
Note: A person is considered to be not 
using migraine preventive medications 
(listed in Appendix C)…but used for 
migraine prevention is permitted 
during the study; however, these 
patients will not be counted toward the 
approximately 30% patient limit 
threshold. 
migraine preventive medications (listed 
in Appendix C)…A list of migraine 
preventive medications allowed for any 
condition for the duration of the study 
for approximately 30% of patients is 
presented in Appendix C. 
… 
 
Note: A person is considered to be not 
using migraine preventive medications 
(listed in Appendix C)… but used for 
migraine prevention is permitted 
during the study; however, these 
patients will not be counted toward the 
approximately 30% patient limit 
threshold. 
4.2. Patient Exclusion Criteria 
d. [Revision 01] The patient has a 
current history of a clinically 
significant psychiatric condition, at the 
discretion of the investigator. Aany 
prior history of a suicide attempt, or a 
history of suicidal ideation with a 
specific plan within the past 2 years, 
must be excludedat the discretion of 
the investigator. 
d. [Revision 01] The patient has a 
current history of a clinically 
significant psychiatric condition, at the 
discretion of the investigator. Any prior 
history of a suicide attempt, or a 
history of suicidal ideation with a 
specific plan within the past 2 years 
must be excluded. 
Clarification 
e. … known active infection of 
coronavirus disease 2019 (COVID-
19). 
e. … known active infection of 
coronavirus disease 2019 (COVID-19). 
Formatting update 
4.3. Withdrawal Criteria and Procedures for the Patient 
… 
• 
Patient takes prohibited 
concomitant medications as defined in 
the protocol chronically. 
…• Any patient who demonstrates 
suicidal ideation and/or any suicidal 
behavior…should be withdrawn from 
the study and discontinued from study 
treatment. 
… 
•Patient takes prohibited concomitant 
medications chronically 
• 
Any patient who demonstrates 
suicidal ideation and/or any suicidal 
behavior…should be withdrawn from 
the study and discontinued from study 
treatment 
Alignment with Section 7.9 
…or until a determination of a cause 
unrelated to the IMP [and/or PFS] or 
study procedure is made). 
…or until a determination of a cause 
unrelated to the IMP [and/or PFS] or 
study procedure is made). 
Updated according to 
template and added device 
vigilance text throughout 
protocol. 
4.4. Replacement of Patients 
Study enrollment assumes up to a 
415% discontinuation rate. The 
number of patients randomized 
(230288) was selected to achieve the 
Study enrollment assumes up to a 4% 
discontinuation rate. The number of 
patients randomized (230) was selected 
to achieve the estimated 220 patients 
Updated text to reflect 
reduced study population and 
currently observed drop-out 
rate. 
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Reason/justification for 
change 
estimated 220244 patients completing 
the study (110122 patients per 
treatment group).  
completing the study (110 patients per 
treatment group).  
5.3.1. Justification for Dose of Test Investigational Medicinal Product and/or Device 
5.3.1. Justification for Dose of Test 
Investigational Medicinal Product 
and/or Device 
5.3.1. Justification for Dose of Test 
Investigational Medicinal Product 
and/or Device 
Updated according to 
template and added device 
vigilance text throughout 
protocol. 
5.6. Prior and Concomitant Medication or Therapy (Other sections affected by this change: Appendix C) 
The following medications are 
prohibited for regular chronic use 
during… 
The following medications are 
prohibited for regular chronic use 
during… 
Clarification 
ApproximatelyUp to 30% of EM 
patients will be allowed to remain on 
no more than 2 migraine preventive 
medications in Appendix C 
…Additional details on concomitant 
migaine preventive medications are 
provided in Appendix C. Patients For 
chronic use of these medications for 
any indication, patients must have 
been on a stable, well-tolerated dose of 
this migraine preventive…For the 
remaining approximately 70% of EM 
patients… 
Approximately 30% of EM patients 
will be allowed to remain on no more 
than 2 migraine preventive medications 
in Appendix C… Additional details on 
migaine preventive medications are 
provided in Appendix C. For chronic 
use of these medications for any 
indication, patients must have must 
have been on a stable, well-tolerated 
dose of this migraine preventive …For 
the remaining approximately 70% of 
EM patients… 
Aid with recruitement 
As-needed (PRN) use of these 
medications are allowed during the 
course of the study for any indications 
and do not have to have established 
dosing regimens. 
As-needed (PRN) use of these 
medications are allowed during the 
course of the study for any indications 
and do not have to have established 
dosing regimens 
Clarification 
Patients will be allowed PRN use of to 
use acute medications to treat acute 
migraine attacks, as needed, with the 
exception of regular use of 
medications… 
Patients will be allowed PRN use of to 
use acute medications to treat acute 
migraine attacks, as needed, with the 
exception of regular use of 
medications… 
Clarification 
The chronic use of concomitant 
therapies not listed in Appendix C for 
any indications other than migraine 
prevention is allowed throughout the 
course of the study, provided they are 
not known to be effective for migraine 
or they meet the criteria for permitted 
concomitant migraine preventive 
medication for any condition for up to 
30% of patients. 
The chronic use of concomitant 
therapies not listed in Appendix C for 
any indication is allowed throughout 
the course of the study. 
Clarification 
All patients must have been on a stable 
dose of these all their concomitant 
medications for at least 2 
All patients must have been on a stable 
dose of these concomitant medications 
for chronic conditions for at least 2 
Clarification 
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change 
months…PRN use of medications for 
adverse events or intercurrent acute 
situations are allowed. 
months…PRN use of medications for 
adverse events or intercurrent acute 
situations are allowed. 
7.1.1. Definition of an Adverse Event 
• 
drug/drug or drug device 
interactions 
• 
drug/drug or drug device 
interactions 
Updated according to 
template and added device 
vigilance text throughout 
protocol. 
7.1.2. Definition of an Adverse Device Effect 
Not applicable 
New Section added 
Updated according to 
template and added device 
vigilance text throughout 
protocol. 
7.1.3. Recording and Reporting of Adverse Events 
…regardless of the severity of the 
event or judged relationship to the 
study drug (and/or PFS). For serious 
adverse events and protocol-defined 
adverse events of special interest for 
expedited reporting to GPSP, the 
serious adverse event Protocol-Defined 
Adverse Events of Special Interest 
Form must be completed, and the 
serious adverse event and the 
protocol-defined adverse events of 
special interest must be reported… 
…regardless of the severity of the 
event or judged relationship to the 
study drug (and/or PFS). For serious 
adverse events and protocol-defined 
adverse events of special interest for 
expedited reporting to GPSP, the 
serious adverse event Protocol-Defined 
Adverse Events of Special Interest 
Form must be completed, and the 
serious adverse event and the 
protocol-defined adverse events of 
special interest must be reported… 
Updated according to 
template and added device 
vigilance text throughout 
protocol. 
…or until a determination of a cause 
unrelated to the study drug (and/or 
PFS) or study procedure is made. 
or until a determination of a cause 
unrelated to the study drug (and/or 
PFS) or study procedure is made. 
Updated according to 
template and added device 
vigilance text throughout 
protocol. 
7.1.4. Recording and Reporting of Adverse Device Effect 
Not applicable 
New Section added (including Figure 
2: Decision Tree for Adverse Events 
and Adverse Device Effects 
Classification). 
Updated according to 
template and added device 
vigilance text throughout 
protocol. 
7.1.6. Relationship of an Adverse Event to the Investigational Medicinal Product and/or Device 
7.1.6. Relationship of an Adverse 
Event to the Investigational Medicinal 
Product and/or Device 
7.1.6. Relationship of an Adverse 
Event to the Investigational Medicinal 
Product and/or Device 
Updated according to 
template and added device 
vigilance text throughout 
protocol. 
The relationship of an adverse event to 
the IMP (and/or PSF) is characterized 
as described in… 
The relationship of an adverse event to 
the IMP (and/or PSF) is characterized 
as described in…. 
Updated according to 
template and added device 
vigilance text throughout 
protocol. 
Table 3: The Relationship of an 
Adverse Event to the IMP and/or 
Table 3: The Relationship of an 
Adverse Event to the IMP and/or 
Updated according to 
template and added device 
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Reason/justification for 
change 
Device 
 
Device 
Text in the table was updated in 
accordance with the title. 
vigilance text throughout 
protocol. 
7.1.7. Serious Adverse Events and Serious Adverse Device Effects 
7.1.7.Serious Adverse Events and 
Serious Adverse Device Effects 
7.1.7. Serious Adverse Events and 
Serious Adverse Device Effects 
Updated according to 
template and added device 
vigilance text throughout 
protocol. 
For recording of serious adverse events 
and serious adverse device effects, the 
study period is defined for each patient 
as that time period from signature of 
the ICF to visit 5 (EOT visit). Serious 
adverse events and serious adverse 
device effects occurring… 
For recording of serious adverse events 
and  serious adverse device effects, the 
study period is defined for each patient 
as that time period from signature of 
the ICF to visit 5 (EOT visit). Serious 
adverse events and serious adverse 
device effects occurring… 
Updated according to 
template and added device 
vigilance text throughout 
protocol. 
7.1.7.2.Definition of a Serious Adverse Device Effect 
Not applicable 
New Section added 
Updated according to 
template and added device 
vigilance text throughout 
protocol. 
7.1.7.3. Expectedness 
An unanticipated serious adverse 
device effect is a serious adverse 
device effect that, by its nature, 
incidence, severity, or outcome, has 
not been listed in Appendix K 
(Appendix Table 1 and Appendix 
Table 2). 
An unanticipated serious adverse 
device effect is a serious adverse 
device effect that, by its nature, 
incidence, severity, or outcome, has not 
been listed in Appendix K (Appendix 
Table 1 and Appendix Table 2). 
Updated according to 
template and added device 
vigilance text throughout 
protocol. 
7.1.7.4.3. Reporting a Serious Adverse Device Effect 
Not applicable 
New Section added 
Updated according to 
template and added device 
vigilance text throughout 
protocol. 
7.1.8. Protocol-Defined Adverse Events of Special Interest 
…anaphylactic reactions. Although 
treatment with fremanezumab is not 
expected to impact the course or 
severity of COVID-19, suspected or 
confirmed COVID-19, based on local 
standard of care, will be considered a 
protocol-defined adverse event of 
special interest to be sent to the 
sponsor’s GPSP for the purpose of 
timely and robust adverse event data 
collection. Hypersensitivity reactions 
will be.. 
…ophthalmic-related adverse events of 
at least moderate severity and severe 
hypersensitivity or anaphylactic 
reactions. Hypersensitivity reactions 
will be… 
COVID-19 is no longer 
adverse event of special 
interest and doesn’t need to 
be reported via same 
procedure as serious adverse 
events. 
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Reason/justification for 
change 
7.4.1. Serum Chemistry, Hematology, Coagulation, and Urinalysis 
…listed below (Table 4). Note, reflex 
tests (eg, red blood cell [RBC] shapes, 
RBC morphology, and other 
microscopic findings) may be 
triggered automatically. 
…listed below (Table 4). Note, reflex 
tests (eg, red blood cell [RBC] shapes, 
RBC morphology, and other 
microscopic findings) may be triggered 
automatically. 
Clarification 
7.4.2.1. Human Chorionic Gonadotropin Tests 
Serum β-HCG tests will be performed 
for all female patients who are 
postmenarchal or ≥12 years of age at 
screening (visit 1) and visit 5; urine β-
HCG tests will be performed at all 
other visits (Table 1). 
Serum β-HCG tests will be performed 
for all female patients who are 
postmenarchal or ≥12 years of age at 
screening (visit 1) and visit 5; urine β-
HCG tests will be performed at all 
visits (Table 1). 
Clarification (and alignment 
with Table 1) that urine 
pregnancy tests are 
performed at all visits. 
9.1. Sample Size and Power Considerations 
The sample size planned is 
approximately 220244 patients 
(110122 evaluable patients 
completing… a sample size of 
110122 patients per treatment group 
gives at least 8790% power for the 
study to succeed at an alpha level of 
0.05. Assuming a 415% 
discontinuation rate, approximately 
230288 patients (115144 patients… 
…  
The enrollment target is approximately 
230288 patients in total, with potential 
increase (up to approximately 400 
patients total), depending on the 
planned interim analysis of blinded 
sample size re-estimation 
(Section 9.12), with a goal of 
approximately 20at least 30% of those 
patients in the 6- through 11-year-old 
age group. The goal in the 12- through 
17-year-old age group is to enroll 
similar numbers of patients who are 12 
through 14 years old and 15 through 
17 years old. 
The sample size planned is 
approximately 220 patients (110 
evaluable patients completing… a 
sample size of 110 patients per 
treatment group gives at least 87% 
power for the study to succeed at an 
alpha level of 0.05. Assuming a 4% 
discontinuation rate, approximately 
230 patients (115 patients… 
…  
The enrollment target is approximately 
230 patients in total, with a goal of 
approximately 20% of those patients in 
the 6- through 11-year-old age group. 
Updated text to reflect 
reduced study population, 
projections, power, and 
currently observed drop-out 
rate. Removed text on 
interim analysis here, as 
analysis was already 
conducted and based on 
variations sample size does 
not need to be increased. 
9.2.4. Per-Protocol Analysis Set 
The per-protocol analysis set will 
consist of all patients in the FAS who 
have completed the study without any 
important deviations, such as 
important violations of the 
inclusion/exclusion criteria deviations, 
important deviationsor any violations 
or omissions of the IMPdrug 
The per-protocol analysis set will 
consist of all patients in the FAS who 
have completed the study without any 
important deviations, such as important 
inclusion/exclusion criteria deviations, 
important deviations or omissions of 
the IMP administration, or unexpected 
drug concentration findings, and who 
Clarification 
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administration, or unexpected drug 
concentration findings, and who have 
at least 75% diary compliance after the 
start of treatment, or who have 
unexpected drug concentration 
findings. 
have at least 75% diary compliance 
after the start of treatment. 
9.5.4.1. Primary Efficacy Analysis 
The model will include treatment, sex, 
puberty status, region, baseline weight 
category (<45.0 kg or ≥45.0 kg), and 
preventive medication use at 
baseline… 
The model will include treatment, sex, 
puberty status, region, baseline weight 
category (<45.0 kg or ≥45.0 kg), and 
preventive medication use at 
baseline… 
Clarification and alignment 
with Statistical Analysis Plan 
9.5.4.3. Secondary Efficacy Analysis 
…region, puberty status, baseline 
weight category (<45.0 kg or ≥45.0 
kg), and preventive medication use at 
baseline (Yes/No). 
…region, puberty status, baseline 
weight category (<45.0 kg or ≥45.0 
kg), and preventive medication use at 
baseline (Yes/No). 
Clarification and alignment 
with Statistical Analysis Plan 
9.7. Safety Analysis 
…adverse events determined by the 
investigator to be related to test IMP 
(and/or PFS) (ie, reasonable 
possibility) (defined as related or with 
missing relationship) (overall and by 
severity), serious adverse events, 
serious adverse device effects, and 
adverse events and adverse device 
effects causing withdrawal from the 
study. 
…adverse events determined by the 
investigator to be related to test IMP 
(and/or PFS) (ie, reasonable 
possibility) (defined as related or with 
missing relationship) (overall and by 
severity), serious adverse events, 
serious adverse device effects, and 
adverse events and adverse device 
effects causing withdrawal from the 
study. 
Updated according to 
template and added device 
vigilance text throughout 
protocol 
9.11. Immunogenecity Analysis 
…The impact of immunogenicity on 
the pharmacokinetic profile, drug 
efficacy, and clinical safety will be 
evaluated if data allows. This analysis 
will be reported separately. 
…The impact of immunogenicity on 
the pharmacokinetic profile, drug 
efficacy, and clinical safety will be 
evaluated if data allows. This analysis 
will be reported separately. 
Clarification 
9.12. Planned Interim Analysis 
… of the primary endpoint using the 
total number of patients regardless of 
the treatment assignment once 50% 
(±10%) of patients… 
… of the primary endpoint using the 
total number of patients regardless of 
the treatment assignment once 50% 
(±10%) of patients… 
Clarification (ie, interim 
analysis was already 
conducted and based on 
variations sample size did 
not need be be increased) 
11. COMPLIANCE STATEMENT 
This study will be conducted in full 
accordance with the ICH Harmonised 
Tripartite Guideline, Guideline for 
Good Clinical Practice E6 and ISO 
14155: Clinical investigation of 
This study will be conducted in full 
accordance with the ICH Harmonised 
Tripartite Guideline, Guideline for 
Good Clinical Practice E6 and ISO 
14155: Clinical investigation of 
Updated according to 
template and added device 
vigilance text throughout 
protocol. 
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Reason/justification for 
change 
medical devices for human subjects – 
Good clinical practice, and any 
applicable… 
medical devices for human subjects – 
Good clinical practice, and any 
applicable… 
APPENDIX A CLINICAL LABORATORIES AND OTHER DEPARTMENTS AND INSTITUTIONS 
 
Global Patient Safety and 
Pharmacovigilance 
Teva PharmaceuticalsPharmaceutical 
Industries Ltd. 
Tel: 
 
Cell: 
 
 
 
 
Global Patient Safety and 
Pharmacovigilance 
Teva Pharmaceuticals 
Cell: 
 
 
Updated contact details for 
Sponsor’s Representative of 
Global Patient Safety and 
Pharmacovigilance 
ClarioeResearch Technology, Inc 
1818 Market Street #1000 
Philadelphia, PA 19103 
United States 
Clario 
1818 Market Street #1000 
Philadelphia, PA 19103 
United States 
Updated contact details for 
Central Electrocardiogram 
Evaluation 
APPENDIX B STUDY PROCEDURES AND ASSESSMENTS BY VISIT 
1. Procedures for Screening (Visit 1, 
Days -28 to -1) 
…• serum beta human chorionic 
gonadotropin (β-HCG) and urine 
pregnancy tests (only female patients 
who are postmenarchal or ≥12 years of 
age); inquire and record start/stop date 
of menstrual period 
… 
1. Procedures for Screening (Visit 1, 
Days -28 to -1) 
…• serum beta human chorionic 
gonadotropin (β-HCG) and urine 
pregnancy tests (only female patients 
who are postmenarchal or ≥12 years of 
age); inquire and record start/stop date 
of menstrual period 
… 
Alignment with Section 
7.4.2.1 
4. End of Treatment/Early 
Withdrawal (Visit 5 [Day 85±3 days]) 
…• serum β-HCG and urine 
pregnancy tests (only female patients 
who are postmenarchal or ≥12 years of 
age); inquire and record start/stop date 
of menstrual period 
… 
4. End of Treatment/Early 
Withdrawal (Visit 5 [Day 85±3 days]) 
…• serum β-HCG and urine pregnancy 
tests (only female patients who are 
postmenarchal or ≥12 years of age); 
inquire and record start/stop date of 
menstrual period 
… 
Alignment with Section 
7.4.2.1 
APPENDIX C. PREVENTIVE MIGRAINE MEDICATIONS FOR ANY CONDITION ALLOWED FOR 
THE DURATION OF THE STUDY FOR APPROXIMATELY 30% OF PATIENTS 
For the remaining approximately 70% 
of EM patients, the chronic use of 
these following medications are not 
allowed… 
For the remaining approximately 70% 
of EM patients, the chronic use of these 
medications are not allowed 
Clarification 
PRN use of the following medications 
are allowed during the course of the 
study for any indication and do not 
have to have established dosing 
regimens. 
PRN use of the following medications 
are allowed during the course of the 
study for any indication and do not 
have to have established dosing 
regimens. 
Clarification 
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Patients will be allowed PRN to use of 
acute medications to treat acute 
migraine attacks, as needed, with the 
exception of regular use of 
medications containing opioids and 
barbiturates. 
Patients will be allowed PRN use of 
acute medications to treat acute 
migraine attacks, as needed, with the 
exception of regular use of medications 
containing opioids and barbiturates 
Clarification 
APPENDIX K. PRODUCT COMPLAINTS 
Clinical Product Complaints/Device 
Deficieny 
Clinical Product Complaints/Device 
Deficieny 
Updated according to 
template and added device 
vigilance text throughout 
protocol. 
For complaints involving a 
device/combination product or other 
retrievable item, it is required that the 
device/combination product (or item) 
be sent 
For complaints involving a 
device/combination product or other 
retrievable item, it is required that the 
device/combination product (or item) 
be sent. 
Updated according to 
template and added device 
vigilance text throughout 
protocol. 
*Please refer to Appendix Table 1 and 
Appendix Table 2. 
*Please refer to Appendix Table 1 and 
Appendix Table 2. 
Updated according to 
template and added device 
vigilance text throughout 
protocol. 
Handling of Investigational Medicinal 
Product(s)/Devices at the 
Investigational Center(s) 
Handling of Investigational Medicinal 
Product(s)/Devices at the 
Investigational Center(s) 
Updated according to 
template and added device 
vigilance text throughout 
protocol. 
If this is necessary, the clinical study 
monitor or designee will provide the 
information needed for returning the 
IMP (and/or PFS). 
If it is determined that the 
investigational center must return all 
IMP (and/or PFS), the sponsor will 
provide the information needed to 
handle the return. 
If this is necessary, the clinical study 
monitor or designee will provide the 
information needed for returning the 
IMP (and/or PFS). 
If it is determined that the 
investigational center must return all 
IMP (and/or PFS), the sponsor will 
provide the information needed to 
handle the return. 
Updated according to 
template and added device 
vigilance text throughout 
protocol. 
The investigator will record in the 
source documentation a description of 
the product complaint, the initial 
determination whether the deficiency 
could have led to a serious adverse 
event (see below: Assessment of 
Device Performance), and any actions 
The investigator will record in the 
source documentation a description of 
the product complaint, the initial 
determination whether the deficiency 
could have led to a serious adverse 
event (see below: Assessment of 
Device Performance), and any actions 
Updated according to 
template and added device 
vigilance text throughout 
protocol. 
Not applicable 
Added new subsection “Assessment of 
Device Performance”. 
Including Appedix Figure 1: Decision 
Tree for Device Deficiencies, 
Appendix Table 1: Potential Use-
Related Deficiencies That Could Lead 
to Serious Adverse Events, and 
Appendix Table 2: Potential Design 
Updated according to 
template and added device 
vigilance text throughout 
protocol. 
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Reason/justification for 
change 
Related Deficiencies That Could Lead 
to Serious Adverse Events. 
APPENDIX O. MANAGEMENT OF STUDY ACTIVITIES DURING COVID-19 
Appendix O and its internal cross refrences were removed thoughout document  
No longer relevant as 
pandemic passed. 
 
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16.2. 
Administrative Letter Dated 21 December 2021  
 
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16.3. 
Amendment 08 Dated 09 December 2021  
The primary reason for this amendment is to revise the protocol to allow combined oral progestin 
and estrogen contraceptives, expand the BMI upper limit to 120% of the 95th percentile in order 
reflect the real-world patient population, and to clarify potential sample size changes subsequent 
to the planned interim analysis. This update and other minor revisions do not impact the study 
design, and the amended protocol remains consistent with the United States FDA Special 
Protocol Assessment and Written Request agreements. 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). 
Original text with changes shown 
New wording 
Reason/justification for 
change 
3.1. General Study Design and Study Schematic (Other sections affected by this change: 3.2, 9.1, and 9.12) 
An interim analysis with blinded 
sample size re-estimation will be 
conducted by evaluating the pooled 
variability (SD) of the primary 
endpoint using the total number of 
patients regardless of the treatment 
assignment once 50% of patients have 
completed at least 3 months of 
treatment or have withdrawn from the 
study early. If the pooled SD is <4.8, 
there will be no change in enrollment; 
if the pooled SD is >5.2, the sample 
size will increase to approximately 400 
patients; and if the pooled SD is 
between 4.8 and 5.2, the sample size 
will increase to approximately 340 
patients total. 
An interim analysis with blinded 
sample size re-estimation will be 
conducted by evaluating the pooled 
variability (SD) of the primary 
endpoint using the total number of 
patients regardless of the treatment 
assignment once 50% of patients have 
completed at least 3 months of 
treatment or have withdrawn from the 
study early. If the pooled SD is <4.8, 
there will be no change in enrollment; 
if the pooled SD is >5.2, the sample 
size will increase to approximately 400 
patients; and if the pooled SD is 
between 4.8 and 5.2, the sample size 
will increase to approximately 
340 patients total. 
Added interim analysis 
language. 
The enrollment target is approximately 
288 patients in total with potential 
increase (up to approximately of 
400 patients total) depending on the 
planned interim analysis of blinded 
sample size re-estimation (Section 
9.12), with a goal of at least 30% of 
those patients in the 6- through 11-
year-old age group. The goal in the 12- 
through 17-year-old age group is to 
enroll similar numbers of patients who 
are 12 through 14 years old and 15 
through 17 years old. 
The enrollment target is approximately 
288 patients in total with potential 
increase (up to approximately of 
400 patients total), depending on the 
planned interim analysis of blinded 
sample size re-estimation (Section 
9.12), with a goal of at least 30% of 
those patients in the 6- through 11-
year-old age group. The goal in the 12- 
through 17-year-old age group is to 
enroll similar numbers of patients who 
are 12 through 14 years old and 15 
through 17 years old. 
Added interim analysis 
language.  
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3.3. Justification for Study Design and Selection of Population (Other sections affected by this change: 4.1) 
A list of migraine preventive 
medications allowed for any condition 
for the duration of the study for up to 
30% of patients is presented in 
Appendix C. 
A list of migraine preventive 
medications allowed for any condition 
for the duration of the study for up to 
30% of patients is presented in 
Appendix C. 
Clarification 
Table 1: Study Procedures and Assessments 
c 
Electrocardiograms will be 
performed, weight will be recorded 
(visit 2 only), urine pregnancy tests 
will be performed at all visits prior to 
dosing, and blood samples will be 
collected before study drug 
administration. Assessment of 
injection site reactions will be 
performed after administration of each 
dose of study drug, before the patient 
leaves the investigational site. All 
other study procedures can be 
performed at any time during the visit. 
c 
Electrocardiograms will be 
performed, weight will be recorded 
(visit 2 only), urine pregnancy tests 
will be performed at all visits prior to 
dosing, and blood samples will be 
collected before study drug 
administration. Assessment of injection 
site reactions will be performed after 
administration of each dose of study 
drug, before the patient leaves the 
investigational site. All other study 
procedures can be performed at any 
time during the visit. 
Clarification. 
4.1. Patient Inclusion Criteria 
d. The patient or parent/caregiver has 
maintained a prospectively collected 
headache diary during a 28-day 
baseline period in which  at least 4 
migraine days and ≤14 headache days 
were recorded on 6 to 14 days 
inclusive. Migraine days have at least 
1 of the following migraine 
characteristics: 
d. The patient or parent/caregiver has 
maintained a prospectively collected 
headache diary during a 28-day 
baseline period in which  at least 
4 migraine days and ≤14 headache 
days were recorded. Migraine days 
have at least 1 of the following 
migraine characteristics: 
Change in the amount of 
migraine days for entry 
criteria 
-headache was treated by a 
nonsteroidal anti-inflammatory drug 
(NSAID), paracetamol, triptan, or 
ergot preparation. 
-headache was treated by a 
nonsteroidal anti-inflammatory drug 
(NSAID), paracetamol, triptan, or ergot 
preparation. 
Paracetamol is added as it is 
a commonly used acute 
medication 
f. 
Note: A person is considered to be 
not using preventive medications when 
at least 5 half-lives have passed since 
the last use of the medication prior to 
screening (visit 1) or at least 4 months 
have passed since the last use of 
Onabotulinum toxin A or B prior to 
screening (visit 1). The use of other 
agents that are not included in 
Appendix C but used for migraine 
prevention is permitted during the 
study; however, these patients will not 
be counted towards the 30% patient 
limit threshold. 
f. 
Note: A person is considered to be 
not using preventive medications when 
at least 5 half-lives have passed since 
the last use of the medication prior to 
screening (visit 1) or at least 4 months 
have passed since the last use of 
Onabotulinum toxin A or B prior to 
screening (visit 1). The use of other 
agents that are not included in 
Appendix C but used for migraine 
prevention is permitted during the 
study; however, these patients will not 
be counted toward the 30% patient 
limit threshold. 
Clarification 
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Reason/justification for 
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m. The patient has a body mass index 
ranging from the 5th to 120% of the 
95th percentile, inclusive, at screening, 
based on the local standard. 
m. The patient has a body mass index 
ranging from the 5th to 120% of the 95th 
percentile, inclusive, at screening, 
based on the local standard. 
Expansion of patient body 
mass index to allow 
representation of real-world 
patient population 
4.2. Patient Exclusion Criteria 
b. The patient has used an 
intervention/device (eg, scheduled 
nerve block or transcranial magnetic 
stimulation) for the treatment of 
migraine or in the head or neck area 
for any condition during the 2 months 
prior to the day of the screening visit. 
b. The patient has used an 
intervention/device (eg, scheduled 
nerve block or transcranial magnetic 
stimulation) for the treatment of 
migraine or in the head or neck area for 
any condition during the 2 months 
prior to the day of the screening visit. 
Clarification 
g. The patient is pregnant, nursing, 
or taking a combined estrogen and 
progestogen hormonal contraceptive or 
nursing. 
g. The patient is pregnant or nursing. 
Changes to reflect allowance 
of combination contraception 
o. The patient has serum creatinine 
more than 1.5× the ULN, clinically 
significant proteinuria (urine dipstick 
+4), an estimated glomerular filtration 
rate of <90 75 mL/min/1.73m2, as 
calculated by the revised Schwartz 
formula (CrCl=[ke 
eGFR=[0.413×Ht]/Serum Creatinine), 
or evidence of renal disease during the 
28-day baseline period. 
o. The patient has serum creatinine 
more than 1.5× the ULN, clinically 
significant proteinuria (urine dipstick 
+4), an estimated glomerular filtration 
rate of <75 mL/min/1.73m2, as 
calculated by the revised Schwartz 
formula (eGFR=[0.413×Ht]/Serum 
Creatinine), or evidence of renal 
disease during the 28-day baseline 
period. 
Clarification of Schwartz 
formula, reflecting the 
administrative letter 
p. The patient has any history of 
alcohol or drug abuse. The definition 
of alcohol or drug abuse, including 
marijuana, is based on investigator's 
clinical judgement. 
p. The patient has any history of 
alcohol or drug abuse. The definition 
of alcohol or drug abuse, including 
marijuana, is based on the 
investigator’s clinical judgment. 
Clarification on alcohol and 
drug abuse, including 
marijuana. 
See New wording column. 
u. The patient has a current or past 
medical history of hemiplegic 
migraine. 
Added an exclusion criterion 
5.1.3. Placebo Investigational Medicinal Product 
Table 2: Investigational Medicinal Products Used in the Study 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
Change updating 
manufacturer name for the 
test and placebo 
investigational medicinal 
products 
5.6. Prior and Concomitant Medication or Therapy 
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change 
All prior therapy, medication, or 
procedure (ie, procedures for the 
treatment of migraine [eg, nerve 
blocks]) for the treatment of migraine 
a patient has had during their lifetime 
will be recorded on the CRF. 
All prior therapy, medication, or 
procedure (ie, procedures for the 
treatment of migraine [eg, nerve 
blocks]) for the treatment of migraine a 
patient has had during their lifetime 
will be recorded on the CRF. 
Clarification 
6.1.4. Pediatric Quality of Life Inventory 
The Pediatric Quality of Life Inventory 
(PedsQL) 4.0 is a brief 23-item 
health-related quality of life instrument 
that evaluates quality of life in 4 areas 
of functioning: physical, emotional, 
social, and school functioning. The 
PedsQL 4.0 has 4 age ranges: toddlers 
(2 through 4 years), young child (5 
through 7 years), child (8 through 12 
years), and adolescent (13 through 18 
years). This study will use the young 
child, child, and adolescent formats. 
The PedsQL version that will be used 
for the patient for the duration of the 
study will be based on the age of the 
patient at visit 2 and will not change 
during the course of the study. 
The Pediatric Quality of Life Inventory 
(PedsQL) 4.0 is a brief 23-item 
health-related quality of life instrument 
that evaluates quality of life in 4 areas 
of functioning: physical, emotional, 
social, and school functioning. The 
PedsQL 4.0 has 4 age ranges: toddlers 
(2 through 4 years), young child (5 
through 7 years), child (8 through 12 
years), and adolescent (13 through 18 
years). This study will use the young 
child, child, and adolescent formats. 
The PedsQL version that will be used 
for the patient for the duration of the 
study will be based on the age of the 
patient at visit 2 and will not change 
during the course of the study. 
Clarification 
9.5.4.2. Sensitivity and Supplementary Analyses 
A sensitivity analysis for the primary 
efficacy endpoint will be conducted by 
using multiple imputation method for 
missing data. Sensitivity analysis using 
Mixed-Effect Model Repeated Measure 
method also will be conducted for 
change from baseline to months 1 
through 3 in headache days of at least 
moderate severity. A supplementary 
analysis using the ITT population will 
also be carried out for the primary 
efficacy endpoint. Additional subgroup 
analyses will be performed to 
investigate treatment effect among 
relevant sub-populations, such as sex, 
region, receiving preventive migraine 
therapy or not, receiving 2 preventive 
medications from Appendix C, and 
receiving alternative preventive 
medications that belong to the same 
classes but are not listed in Appendix 
C. The details will be described in the 
statistical analysis plan. 
A sensitivity analysis for the primary 
efficacy endpoint will be conducted by 
using multiple imputation method for 
missing data. Sensitivity analysis using 
Mixed-Effect Model Repeated 
Measure method also will be 
conducted for change from baseline to 
months 1 through 3 in headache days 
of at least moderate severity. A 
supplementary analysis using the ITT 
population will also be carried out for 
the primary efficacy endpoint. 
Additional subgroup analyses will be 
performed to investigate treatment 
effect among relevant sub-populations, 
such as sex, region, receiving 
preventive migraine therapy or not, 
receiving 2 preventive medications 
from Appendix C, and receiving 
alternative preventive medications that 
belong to the same classes but are not 
listed in Appendix C. The details will 
be described in the statistical analysis 
plan. 
Clarification of additional 
subgroup analyses 
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change 
Appendix C. PREVENTIVE MIGRAINE MEDICATIONS FOR ANY CONDITION ALLOWED FOR 
THE DURATION OF THE STUDY FOR UP TO 30% OF PATIENTS (Other sections affected by this 
change: 3.3, 4.1, 5.6) 
The chronic use of two of the 
following concomitant preventive 
migraine medications are allowed in 
up to 20 30% of patients and should be 
entered in electronic case report form 
(eCRF) pages specific for migraine 
preventive medication. Patients using 
no more than 2 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 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 these medications are not 
allowed for migraine or for any other 
indications. As-needed (PRN) use of 
these 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 
locally approved prescribing 
information or local treatment 
guidelines. 
The chronic use of two of the 
following concomitant medications are 
allowed in up to 30% of patients and 
should be entered in electronic case 
report form (eCRF) pages specific for 
migraine preventive medication. 
Patients using no more than 2 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 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 is not allowed 
for migraine or for any other 
indications. As-needed (PRN) use of 
these medications are allowed during 
the course of the study. PRN use of the 
following 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 
locally approved prescribing 
information or local treatment 
guidelines. 
Clarification of preventative 
migraine medications to 
reflect real-world use 
• 
Other: riboflavin, magnesium 
See Original text with changes shown 
column. 
Removal of riboflavin and 
magnesium from the 
Appendix C as they are not 
prescribed medicines 
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 doubtful evidence 
for migraine prevention and therefore 
are treated the same as other 
concomitant medications and DO NOT 
need to be captured in eCRF pages 
specific for migraine preventive 
medications. 
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 doubtful evidence for migraine 
prevention and therefore are treated the 
same as other concomitant medications 
and DO NOT need to be captured in 
eCRF pages specific for migraine 
preventive medications. 
Clarification 
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change 
APPENDIX G. BIRTH CONTROL METHODS AND PREGNANCY TESTING 
• 
Progestin and estrogen 
contraceptives (oral only) associated 
with inhibition of ovulation; these 
should be initiated at least 1 month 
before the first dose of IMP 
• 
Progestin and estrogen 
contraceptives (oral only) associated 
with inhibition of ovulation; these 
should be initiated at least 1 month 
before the first dose of IMP 
Changes to allow for oral 
progestin and estrogen 
contraceptives. 
Appendix O. 
MANAGEMENT OF STUDY ACTIVITIES DURING COVID-19 
See New wording column. 
Section 5.6 Prior and Concomitant 
Medication or Therapy 
There are currently no data available 
regarding the concomitant use of 
fremanezumab and the new COVID-19 
vaccines. Based on Teva’s knowledge 
of both fremanezumab and what has 
been published about the respective 
vaccines, Teva has no reason to believe 
there would be an interaction. 
However, the investigator should use 
his/her medical judgment regarding 
any concerns related to an individual 
patient. We do recommend not giving 
the 2 injections, the study drug, and the 
vaccines in the same arm if the 
injections are administered close 
together in time, as it would be difficult 
to tell which one caused any potential 
reaction. If logistically possible, we 
would recommend waiting at least 
72 hours between the receipt of the 
vaccine and the subsequent dose of 
fremanezumab in order to allow for 
better attribution of causality should an 
adverse event occur after 
administration. As with any 
concomitant medication, the vaccine 
should be recorded in the source 
documentation and in the electronic 
data capture. 
Clarification regarding the 
COVID-19 vaccination 
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16.4. 
Administrative Letter Dated 10 May 2021  
 
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16.5. 
Administrative Letter Dated 04 February 2021  
 
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16.6. 
Administrative Letter Dated 05 November 2020  
 
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16.7. 
Amendment 07 Dated 20 August 2020  
The primary reason for this amendment is to provide guidance for remote assessments to 
minimize the time that patients and caregivers are required to spend at the study site. This 
consideration was triggered by the COVID-19 pandemic; however, remote assessments can be 
carried out on a regular basis to provide flexibility for patients, caregivers, and site staff. Patient 
reported outcomes assessed in this study, including the PedMIDAS, PedsQL, and PGI-I, as well 
as the C-SSRS, are valid to be conducted remotely, as confirmed by the scale authors. 
Instructions on remote data collection are available in the site operational manual. This update 
and other minor revisions do not impact the study design, and the amended protocol remains 
consistent with the United States FDA Special Protocol Assessment and Written Request 
agreements. 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). 
Additionally, COVID-19 pandemic-related operational updates were added to the study protocol 
as a new appendix (Appendix O). Administrative changes have been applied, including updating 
the Table of Contents.  
Changes to the Protocol 
Original text with changes shown 
New wording 
Reason/justification for 
change 
TITLE PAGE 
See New wording column. 
COVID-19 pandemic-related 
operational updates are provided in 
Appendix O. 
Sentence was added to 
provide a link to the 
operational guidance for 
COVID-19 contained in 
Appendix O. 
1.1. Introduction 
See New wording column. 
In September 2018, fremanezumab was 
approved in the United States of 
America (US) for the preventive 
treatment of migraine in adults and 
marketed under the trade name 
AJOVY®. Fremanezumab has also 
been approved in the European Union 
(EU) and a number of countries 
worldwide. 
Sentences were added to 
provide context regarding the 
regulatory status of 
fremanezumab in the adult 
population. 
3.1. General Study Design and Study Schematic (Other sections affected by this change: 3.5) 
The total duration of the study is 
planned to be 36 months (from 
approximately Q1 2020 to Q4 2022). 
The total duration of the study is 
planned to be 36 months (from Q1 
2020 to Q4 2022). 
Revised as quarter is an 
approximation. 
See New wording column. 
For coronavirus disease 2019 (COVID-
19) updates, see Appendix O. 
Updated sections to cross-
references the addition of 
Appendix O. 
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3.2. Planned Number of Patients and Countries 
The study is expected to start in Q1 
2020 and last until approximately Q4 
2022. 
The study is expected to start in Q1 
2020 and last until Q4 2022. 
Revised as quarter is an 
approximation. 
Table 1 Study Procedures and Assessments 
c 
Electrocardiograms will be 
performed, and blood samples will be 
collected before study drug 
administration. Assessment of 
injection site reactions will be 
performed after administration of each 
dose of study drug, before the patient 
leaves the investigational site. All 
other study procedures can be 
performed at any time during the visit. 
c 
Electrocardiograms will be 
performed, and blood samples will be 
collected before study drug 
administration. Assessment of injection 
site reactions will be performed after 
administration of each dose of study 
drug, before the patient leaves the 
investigational site. All other study 
procedures can be performed at any 
time during the visit. 
Footnote “c” was modified 
to specify that ECGs will be 
performed before study drug 
administration. 
See New wording column. 
f 
This procedure/assessment may be 
performed remotely for patients who 
are not able to go to the investigational 
center or if the investigational center 
staff are not able to see patients at the 
investigational center due to 
unforeseen circumstances. 
Footnote “f” was added to 
identify the 
procedures/assessments that 
may be performed remotely. 
k 
Twelve-lead ECGs will be 
performed in triplicate at any time 
during the visit, prior to study drug 
administration. 
k 
Twelve-lead ECGs will be 
performed in triplicate at any time 
during the visit, prior to study drug 
administration. 
Footnote “k” was modified 
to specify that ECGs will be 
performed before study drug 
administration. 
m Inquiries about adverse events will 
be made before and after study drug 
administration. Postdose inquiries will 
be made before the patient leaves the 
study center. 
m Inquiries about adverse events will 
be made before and after study drug 
administration.  
Revised as adverse event 
inquiries are not mandated to 
occur on site. 
q 
The C-SSRS Baseline/Screening 
version will be completed by a 
qualified rater trained to administer the 
scale at the investigational center the 
physician based on discussion with the 
patient/caregiver at visit 1 (screening 
visit), and the C-SSRS Since Last Visit 
version will be completed by the 
physician based on discussion with the 
patient/caregiver at all other the time 
points described. 
q 
The C-SSRS will be completed by 
a qualified rater trained to administer 
the scale at the investigational center 
based on discussion with the 
patient/caregiver at the time points 
described. 
Revised for simplicity as the 
C-SSRS does not need to be 
completed specifically by a 
physician. 
4.1. Patient Inclusion Criteria 
m. The patient has a body mass index 
ranging from the 5th to the 9095th 
percentile, inclusive, on the day of 
randomizationat screening. 
m. The patient has a body mass index 
ranging from the 5th to the 95th 
percentile, inclusive, at screening. 
This inclusion criterion was 
changed to allow patients at 
a higher BMI percentile to be 
included in the study, for 
greater enrollment.  
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Reason/justification for 
change 
4.2. Patient Exclusion Criteria (Other sections affected by this change: 5.6) 
s. 
The patient received a live 
attenuated vaccine (eg, intranasal flu 
vaccine, and measles, mumps, and 
rubella vaccine) within the 12-week 
period prior to screening or plans to 
receive a live attenuated vaccine at any 
time during the study and for 6 months 
after the last dose of IMP. 
Note: If a medical need arises during 
the study, the patient may receive a 
live attenuated vaccine. 
s. 
The patient received a live 
attenuated vaccine (eg, intranasal flu 
vaccine, and measles, mumps, and 
rubella vaccine) within the 12-week 
period prior to screening. 
Note: If a medical need arises during 
the study, the patient may receive a live 
attenuated vaccine. 
Patient exclusion criterion 
was revised to add leniency 
in the requirements regarding 
live attenuated vaccines 
during the study. 
4.3. Withdrawal Criteria and Procedures for the Patient (Other sections affected by this change: 3.1 and 
5.4) 
Patients who withdraw from the study 
or have an early termination will be 
invited to enter the long-term safety 
extension (within Study TV48125-
CNS-30084) for the purpose of safety 
follow-up and evaluating ADA 
approximately 65 months (180150 
days [more than 5 half-lives]) after 
receiving the last dose of study drug. 
Patients who withdraw from the study 
or have an early termination will be 
invited to enter the long-term safety 
extension (within Study TV48125-
CNS-30084) for the purpose of safety 
follow-up and evaluating ADA 
approximately 5 months (150 days 
[5 half-lives]) after receiving the last 
dose of study drug. 
The duration of the ADA 
follow-up period for patients 
rolling over for ADA 
assessment only in the long-
term safety Study TV48125-
CNS-30084 was changed to 
be approximately 150 days 
(5 half-lives) after the final 
dose of IMP to be in line 
with the duration of the ADA 
follow-up period for patients 
who roll over and continue 
receiving IMP. 
4.3.1. Study-Specific Patient Withdrawal Criteria and Procedures 
The patient must be withdrawn from 
the study drug if the patient 
experiences a severe hypersensitivity 
reaction or anaphylaxis. 
The patient must be withdrawn from 
the study drug if the patient 
experiences a severe hypersensitivity 
reaction or anaphylaxis. 
This was revised as adverse 
events must still be followed 
in these patients and 
therefore, they will not be 
withdrawn from the study, 
rather the study drug. 
7.1.5.1. Definition of a Serious Adverse Event 
An adverse event that does not meet 
any of the criteria for seriousness listed 
above will be regarded as a nonserious 
adverse event. 
Not applicable. 
This sentence was deleted as 
it was inadvertently repeated 
twice in the section. 
7.1.6. Protocol-Defined Adverse Events of Special Interest 
Although treatment with 
fremanezumab is not expected to 
impact the course or severity of 
COVID-19,COVID 19 is not 
suspected to be causally related to 
fremanezumab treatment, suspected or 
confirmed COVID 19, based on local 
Although treatment with 
fremanezumab is not expected to 
impact the course or severity of 
COVID-19, suspected or confirmed 
COVID 19, based on local standard of 
care, will be considered a protocol-
defined adverse event of special 
Clarification. 
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Reason/justification for 
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standard of care, will be considered a 
protocol-defined adverse event of 
special interest to be sent to the 
sponsor’s GPSP for the purpose of 
timely and robust adverse event data 
collection. 
interest to be sent to the sponsor’s 
GPSP for the purpose of timely and 
robust adverse event data collection. 
7.7. Electrocardiography 
Twelve lead ECGs will be conducted 
at any time during the visit, prior to 
study drug administration, as detailed 
in Table 1. 
Twelve lead ECGs will be conducted at 
any time during the visit, prior to study 
drug administration, as detailed in 
Table 1. 
This sentence was modified 
to specify that ECGs will be 
performed before study drug 
administration. 
The ECGs will be performed in 
triplicate, with approximately at least 1 
to 5 minutes between recordings. 
The ECGs will be performed in 
triplicate, with at least 1 minute 
between recordings. 
The time frame between 
ECG recordings was revised 
to allow leniency. 
7.9. Assessment of Suicidality 
The C-SSRS Baseline/Screening 
version will be completed by a 
qualified rater trained to administer the 
scale at the investigational center the 
physician based on discussion with the 
patient/caregiver at visit 1 (screening 
visit), and the C SSRS Since Last Visit 
version will be completed by the 
physician based on discussion with the 
patient/caregiver at all other time 
points, asat the time points described 
in Table 1. 
The C-SSRS will be completed by a 
qualified rater trained to administer the 
scale at the investigational center based 
on discussion with the patient/caregiver 
at the time points described in Table 1. 
Revised for simplicity as the 
C-SSRS does not need to be 
completed specifically by a 
physician. 
Appendix B. Study Procedures and Assessments by Visit 
See New wording column. 
In the case that a patient is not able to 
go to the investigational center or the 
investigational center staff are not able 
to see patients at the investigational 
center, certain assessments/procedures, 
as detailed in Table 1, may be 
performed remotely. 
This sentence was provided 
to add clarity to refer to 
Table 1.  
Appendix O. Management of Study Activities During COVID-19 
New appendix and text. 
Additional text too numerous to 
include in this table; refer to Appendix 
O of this protocol. 
Appendix O has been added 
to describe the management 
of the study during the 
COVID-19 pandemic. 
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16.8. 
Amendment 06 Dated 27 July 2020  
The primary reason for this amendment is to revise the protocol in accordance with the 
conditions for approval of the clinical trial application received from the Voluntary 
Harmonisation Procedure (VHP). This update and other minor revisions do not impact the study 
design, and the amended protocol remains consistent with the United States FDA Special 
Protocol Assessment and Written Request agreements. 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 
2.2. Exploratory Objective and Endpoints (Other sections affected by this change: 9.5.3) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Revision to the exploratory 
endpoint in accordance with 
Protocol Administrative 
Letter 02, which is a 
correction of a typo. 
4.2. Patient Exclusion Criteria 
o. The patient has serum creatinine 
more than 1.5× the ULN, clinically 
significant proteinuria (urine dipstick 
+4), an estimated glomerular filtration 
rate of <90 mL/min/1.73m2, as 
calculated by the Schwartz formula 
(CrCl=[k×Ht]/Serum Creatinine), or 
evidence of renal disease during the 
28-day baseline period. 
o. The patient has serum creatinine 
more than 1.5× the ULN, clinically 
significant proteinuria (urine dipstick 
+4), an estimated glomerular filtration 
rate of <90 mL/min/1.73m2, as 
calculated by the Schwartz formula 
(CrCl=[k×Ht]/Serum Creatinine), or 
evidence of renal disease during the 
28-day baseline period. 
Clarification. 
5.3.1. Justification for Dose of Test Investigational Medicinal Product 
Data from this study (TV48125-CNS-
10141) were used to refine the current 
adult population pharmacokinetic 
model (which was based on adult data 
from 2 Phase 1 studies [Studies LBR-
101-011 and TV48125-PK-10078], 2 
Phase 2b studies [Studies LBR-101-
021 and LBR-101-022], and 3 Phase 3 
Studies [Studies TV48125-CNS-
30049, TV48125-CNS-30050, and 
TV48125-CNS-30051 (cutoff date 30 
May 2018)]), where allometric weight 
exponents for clearance and central 
volume were estimated, and a 2-
compartment model with first-order 
absorption, elimination, and body 
Data from this study (TV48125-CNS-
10141) were used to refine the current 
adult population pharmacokinetic 
model (which was based on adult data 
from 2 Phase 1 studies [Studies LBR-
101-011 and TV48125-PK-10078], 2 
Phase 2b studies [Studies LBR-101-
021 and LBR-101-022], and 3 Phase 3 
Studies [Studies TV48125-CNS-
30049, TV48125-CNS-30050, and 
TV48125-CNS-30051 (cutoff date 30 
May 2018)]), where allometric weight 
exponents for clearance and central 
volume were estimated, and a 2-
compartment model with first-order 
absorption, elimination, and body 
Revised to provide additional 
context for the determination 
of the dose for patients 
weighing <45 kg. 
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Reason/justification for 
change 
weight effect on clearance and central 
volume adequately described the 
fremanezumab concentration-time data 
observed in pediatric patients with 
migraine. 
weight effect on clearance and central 
volume adequately described the 
fremanezumab concentration-time data 
observed in pediatric patients with 
migraine. 
See New wording column. 
Additional simulations of dose 
selection for pediatric patients 
weighing <45 kg was also performed 
with an alternative pediatric population 
pharmacokinetic model with the fixed 
allometric exponents (ie, 0.75 for 
clearance and 1.0 for volume). 
However, the apparent over prediction 
of observed exposures from the Phase 
1 pharmacokinetic pediatric study 
(Study TV48125-CNS-10141) with 
this model led to an under prediction of 
the selected dose needed to achieve 
exposures comparable to those in 
adults receiving 225 mg sc 
fremanezumab. 
Considering the wide safety margin for 
fremanezumab with substantial 
evidence supporting the safety of the 
approved dose of 225 mg sc monthly in 
adults, the expected exposures in 
pediatric patients weighing <45 kg 
after administration of 120 mg sc 
monthly fall well within the exposure 
range of adults receiving doses up to 
900 mg sc monthly; where 675 mg sc 
monthly and 900 mg sc monthly were 
administered in the adult Phase 2b 
studies and were found to be safe and 
well tolerated. Safety margin data from 
a nonclinical study in juvenile rats 
indicate that at the NOAEL dose of 
450 mg/kg/week (see Section 1.2.1), 
calculated safety margins range from 
16- to 22-fold higher than expected 
pediatric clinical exposure based on a 
population pharmacokinetic model. It 
is therefore concluded that in 
nonclinical studies, adequate safety 
margins are calculated even when 
considering higher exposure in the 
pediatric population. 
Additional paragraphs 
detailing the selection of 
dose for patients weighing 
<45 kg have been added to 
inform investigators.  
6.1.3. Patient Global Impression of Improvement Scale 
The PGI-I scale is a 17-item 
questionnaire designed to assess the 
The PGI-I scale is a 7-item 
questionnaire designed to assess the 
Correction of a typo; updated 
in accordance with Protocol 
Administrative Letter 02. 
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Reason/justification for 
change 
patient’s global impression of 
changeimprovement. 
patient’s global impression of 
improvement. 
16. Summary of Changes to Protocol 
See New wording column. 
Section 16.2 Administrative Letter 
02 Dated 07 July 2020 
Updated to include the 
Administrative Letter 02. 
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16.9. 
Administrative Letter 02 Dated 07 July 2020  
 
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16.10. 
Amendment 05 Dated 27 June 2020  
The primary reason for this amendment is to revise the protocol in accordance with the Grounds 
for Non-Acceptance received from the Voluntary Harmonization Procedure (VHP). 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 
3.3. Justification for Study Design and Selection of Population 
Migraine is a condition that starts 
from childhood or adolescence and 
progresses into adulthood. Among 
populations of children of all ages, 
migraine prevalence ranges from 8% 
to 11% (Abu-Arafeh et al 2010, 
Abu-Arefeh and Russell 1994, 
Laurell et al 2004, Ozge et al 2013, 
Stovner and Andree 2010). 
Additionally, there is an unmet need 
for the treatment of migraine in 
pediatric patients as there are limited 
therapy options available for this 
patient population. Throughout 
Teva’s development program for 
adults, fremanezumab had 
demonstrated statistically and 
clinically significant superior 
efficacy over placebo. It is also well 
tolerated in the adult migraine 
population. Given the progression of 
the disease and the knowledge 
gained from the adult population, it 
is reasonable and important to 
evaluate fremanezumab in the 
pediatric population. 
Migraine is a condition that starts 
from childhood or adolescence and 
progresses into adulthood. Among 
populations of children of all ages, 
migraine prevalence ranges from 8% 
to 11% (Abu-Arafeh et al 2010, 
Abu-Arefeh and Russell 1994, 
Laurell et al 2004, Ozge et al 2013, 
Stovner and Andree 2010). 
Additionally, there is an unmet need 
for the treatment of migraine in 
pediatric patients as there are limited 
therapy options available for this 
patient population. Throughout 
Teva’s development program for 
adults, fremanezumab had 
demonstrated statistically and 
clinically significant superior 
efficacy over placebo. It is also well 
tolerated in the adult migraine 
population. Given the progression of 
the disease and the knowledge 
gained from the adult population, it 
is reasonable and important to 
evaluate fremanezumab in the 
pediatric population. 
This paragraph was added to provide 
context for conducting a study in 
vulnerable patients. 
Section 4.1. Patient Inclusion Criteria 
b. The patient’s parent(s) or legal 
guardian(s) must give written 
informed consent, and the patient 
must give assent (in accordance with 
local regulations). 
Note: In some countries, patients 
aged 15 to 17 years (inclusive) may 
give written informed consent; 
however, the patient’s parent(s) or 
legal guardian(s) must be informed, 
per local regulations. 
b. The patient’s parent(s) or legal 
guardian(s) must give written 
informed consent, and the patient 
must give assent (in accordance with 
local regulations). 
Note: In some countries, patients 
aged 15 to 17 years (inclusive) may 
give written informed consent; 
however, the patient’s parent(s) or 
legal guardian(s) must be informed, 
per local regulations. 
Inclusion criterion b was revised to 
specify that some countries may 
allow patients aged 15 to 17 years to 
give written informed consent, per 
local regulations. 
Section 4.2. Patient Exclusion Criteria 
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Reason/justification for change 
d. The patient has a current history 
of a clinically significant psychiatric 
condition, any prior history of a 
suicide attempt, or a history of 
suicidal ideation with a specific plan 
within the past 2 years, at the 
discretion of the investigator. 
d. The patient has a current history 
of a clinically significant psychiatric 
condition, any prior history of a 
suicide attempt, or a history of 
suicidal ideation with a specific plan 
within the past 2 years, at the 
discretion of the investigator. 
Exclusion criterion was revised to 
specify that exclusion of a patient 
based on clinically significant 
psychiatric condition is at the 
discretion of the investigator. 
e. 
The patient has an ongoing 
infection or a known history of 
human immunodeficiency virus 
(HIV) infection, tuberculosis, Lyme 
disease, or chronic hepatitis B or C, 
or a known active infection of 
coronavirus disease 2019 (COVID-
19). 
e. 
The patient has an ongoing 
infection or a known history of 
human immunodeficiency virus 
(HIV) infection, tuberculosis, Lyme 
disease, chronic hepatitis B or C, or 
a known active infection of 
coronavirus disease 2019 (COVID-
19). 
Exclusion criterion was revised to 
exclude those with a known active 
COVID-19 infection. 
g. The patient is pregnant, nursing, 
or taking a combined estrogen and 
progestogen hormonal contraceptive. 
g. The patient is pregnant, nursing, 
or taking a combined estrogen and 
progestogen hormonal contraceptive. 
Revised to exclude patients taking a 
combined estrogen and progestogen 
hormonal contraceptive. 
h. The patient has a 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. 
h. The patient has a 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. 
Revised to exclude patients 
concomitantly using lamotrigine. 
o. The patient has serum creatinine 
more than 1.5× the ULN, clinically 
significant proteinuria (urine 
dipstick +4), an estimated 
glomerular filtration rate of <90 
mL/min/1.73m2, or evidence of 
renal disease during the 28-day 
baseline period. 
o. The patient has serum creatinine 
more than 1.5× the ULN, clinically 
significant proteinuria (urine 
dipstick +4), an estimated 
glomerular filtration rate of <90 
mL/min/1.73m2, or evidence of 
renal disease during the 28-day 
baseline period. 
An exclusion of patients with an 
estimated glomerular filtration rate 
of <90 mL/min/1.73m2 was added as 
another means of evidence of renal 
disease. 
t. 
The patient has a known 
hypersensitivity to the active 
substance or to any of the excipients 
of the study drug. 
t. 
The patient has a known 
hypersensitivity to the active 
substance or to any of the excipients 
of the study drug. 
This exclusion criteria was added to 
ensure patients with a known 
hypersensitivity are not enrolled in 
the study. 
4.3.1. Study-Specific Patient Withdrawal Criteria and Procedures 
The patient must be withdrawn from 
the study if the patient experiences a 
severe hypersensitivity reaction or 
anaphylaxis. 
The patient must be withdrawn from 
the study if the patient experiences a 
severe hypersensitivity reaction or 
anaphylaxis. 
The sentence was added to specify 
that patients must be withdrawn if 
they experience a severe 
hypersensitivity reaction of 
anaphylaxis. 
4.5. Rescreening 
If the history of migraine 
classification (EM or CM) as taken 
by the investigator differs from the 
classification determined by the 
diary data (28- day 
If the history of migraine 
classification (EM or CM) as taken 
by the investigator differs from the 
classification determined by the 
diary data (28- day baseline period), 
Clarification to avoid confusion by 
referencing a screening period. 
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Reason/justification for change 
screeningbaseline period), the 
patient may be rescreened one time; 
this information should be recorded 
in the CRF. 
the patient may be rescreened one 
time; this information should be 
recorded in the CRF. 
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 
screeningbaseline period has 
expired. 
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. 
Clarification to avoid confusion by 
referencing a screening period. 
5.3.1. Justification for Dose of Test Investigational Medicinal Product 
A 2013 investigation by Momper et 
al from the Food and Drug 
Administration (FDA) analyzed 
92 products approved between 2007 
and 2012 with similar adult and 
pediatric indications across different 
therapeutic areas, and 87 (94.5%) 
had equivalent dosing for adults and 
adolescent patients (Momper et al 
2013The formulation of 
fremanezumab to be used for clinical 
investigations in the pediatric 
population will be identical to the sc 
formulation of fremanezumab that 
was used in the clinical program for 
adults.).  
Based on pharmacokinetic 
simulations, a body weight threshold 
of 40 kg can be generally used for 
pediatric patients to receive the same 
fixed adult dosage for mAbs (Yang 
et al 2019). In addition, mAbs tend 
to have wide therapeutic windows 
since they represent more targeted 
therapy with limited off-target 
toxicity; as a result, recommending a 
40 kg threshold for receiving the 
adult dosage, with resultant pediatric 
exposure being within 20% to 30% 
above adult exposure, seems to be 
appropriate (Yang et al 2019). The 
fremanezumab weight cutoff is 
slightly higher (45 kg); hence, this 
reduces the likelihood to be above 
adult exposure. In addition, 
fremanezumab has a wide 
therapeutic dose range that was 
A 2013 investigation by Momper et 
al from the Food and Drug 
Administration (FDA) analyzed 
92 products approved between 2007 
and 2012 with similar adult and 
pediatric indications across different 
therapeutic areas, and 87 (94.5%) 
had equivalent dosing for adults and 
adolescent patients (Momper et al 
2013).  
Based on pharmacokinetic 
simulations, a body weight threshold 
of 40 kg can be generally used for 
pediatric patients to receive the same 
fixed adult dosage for mAbs (Yang 
et al 2019). In addition, mAbs tend 
to have wide therapeutic windows 
since they represent more targeted 
therapy with limited off-target 
toxicity; as a result, recommending a 
40 kg threshold for receiving the 
adult dosage, with resultant pediatric 
exposure being within 20% to 30% 
above adult exposure, seems to be 
appropriate (Yang et al 2019). The 
fremanezumab weight cutoff is 
slightly higher (45 kg); hence, this 
reduces the likelihood to be above 
adult exposure. In addition, 
fremanezumab has a wide 
therapeutic dose range that was 
tested in Phase 2b and Phase 3 
studies in adults of up to 900 mg sc 
monthly. 
Thus, based on considerable data 
available in adult patients with 
migraine weighing ≥45 kg, in 
Additional information on the 
selected weight cutoff for the 
pediatric population has been added 
for investigator awareness. 
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Reason/justification for change 
tested in Phase 2b and Phase 3 
studies in adults of up to 900 mg sc 
monthly. 
Thus, based on considerable data 
available in adult patients with 
migraine weighing ≥45 kg, in 
addition to the evidence supporting 
the lack of expected difference in 
pharmacokinetics between adults 
and adolescent patients, the use of 
225 mg monthly was proposed in 
pediatric patients weighing ≥45 kg. 
addition to the evidence supporting 
the lack of expected difference in 
pharmacokinetics between adults 
and adolescent patients, the use of 
225 mg monthly was proposed in 
pediatric patients weighing ≥45 kg. 
This refined pediatric population 
pharmacokinetic model was used to 
simulate individual estimates of 
exposure for a virtual population of 
pediatric subjects over a range of 
possible fremanezumab doses. 
PediatricA population of 
2400  virtual pediatric patients 
virtual subjects (6 to 17 years of age 
[inclusive]) was generated (200 
patients per year of age) and used 
along with the final pediatric 
pharmacokinetic model estimates to 
simulate concentration-time data for 
monthly sc doses ranging from 60 to 
225 mg. Virtual patients were 
assigned weight values based on a 
uniform distribution of age using 
growth chart data from the Centers 
for Disease Control. TheSimulated 
exposure measures were calculated 
at steady state for the virtual 
pediatric patients and compared to 
exposure measured at steady state in 
the adult population receiving 
fremanezumab 225 mg sc monthly. 
For virtual pediatric patients 6 to 
17 years of age with baseline weight 
<45 kg administered 120 mg sc 
monthly, the simulated area under 
the concentration-time curve from 
time 0 to 28 days distribution was 
nearly identical to the adult patient 
distribution following administration 
of 225 mg sc monthly. Very similar 
patterns were observed for average 
concentration and minimum drug 
concentration. The simulated 
maximum concentration distribution 
following 120 mg sc monthly in the 
pediatric population suggests 
This refined pediatric population 
pharmacokinetic model was used to 
simulate individual estimates of 
exposure for a virtual population of 
pediatric subjects over a range of 
possible fremanezumab doses. A 
population of 2400 virtual pediatric 
patients (6 to 17 years of age 
[inclusive]) was generated 
(200 patients per year of age) and 
used along with the final pediatric 
pharmacokinetic model estimates to 
simulate concentration-time data for 
monthly sc doses ranging from 60 to 
225 mg. Virtual patients were 
assigned weight values based on a 
uniform distribution of age using 
growth chart data from the Centers 
for Disease Control. Simulated 
exposure measures were calculated 
at steady state for the virtual 
pediatric patients and compared to 
exposure measured at steady state in 
the adult population receiving 
fremanezumab 225 mg sc monthly. 
For virtual pediatric patients 6 to 
17 years of age with baseline weight 
<45 kg administered 120 mg sc 
monthly, the simulated area under 
the concentration-time curve from 
time 0 to 28 days distribution was 
nearly identical to the adult patient 
distribution following administration 
of 225 mg sc monthly. Very similar 
patterns were observed for average 
concentration and minimum drug 
concentration. The simulated 
maximum concentration distribution 
following 120 mg sc monthly in the 
pediatric population suggests 
slightly higher maximum 
Additional information on the 
pediatric population 
pharmacokinetic model to determine 
the dose for patients weighing 
<45 kg has been added for 
investigator awareness. 
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Reason/justification for change 
slightly higher maximum 
concentration than that achieved in 
the adult population following 
225 mg sc monthly; however, 
overall, the upper exposure range 
extends only slightly above the 
upper range of the adult exposures.  
Given the wide safety margin of 
fremanezumab with considerable 
evidence supporting the safety of the 
approved dose of 225 mg sc monthly 
in adults, and to minimize the risk of 
decreased efficacy in this pediatric 
population, the 120 mg monthly 
dose level was selected for patients 
aged 6 to 17 years (inclusive) with 
weight values <45.0 kg based on 
targeting the achievement of a 
similar distribution of 
fremanezumab exposure levels 
(following multiple dosing) of 
225 mg monthly in adult patients 
with EM and CM.  
The formulation of fremanezumab to 
be used for clinical investigations in 
the pediatric population will be 
identical to the sc formulation of 
fremanezumab that was used in the 
clinical program for adults. 
concentration than that achieved in 
the adult population following 
225 mg sc monthly; however, 
overall, the upper exposure range 
extends only slightly above the 
upper range of the adult exposures.  
Given the wide safety margin of 
fremanezumab with considerable 
evidence supporting the safety of the 
approved dose of 225 mg sc monthly 
in adults, and to minimize the risk of 
decreased efficacy in this pediatric 
population, the 120 mg monthly 
dose level was selected for patients 
aged 6 to 17 years (inclusive) with 
weight values <45.0 kg based on 
targeting the achievement of a 
similar distribution of 
fremanezumab exposure levels 
(following multiple dosing) of 
225 mg monthly in adult patients 
with EM and CM.  
The formulation of fremanezumab to 
be used for clinical investigations in 
the pediatric population will be 
identical to the sc formulation of 
fremanezumab that was used in the 
clinical program for adults. 
5.5. Restrictions 
Patients must remain at the site, for 
safety observation, for at least 
30 minutes after injection or longer 
if deemed necessary by medical 
judgment. 
Patients must remain at the site, for 
safety observation, for at least 
30 minutes after injection or longer 
if deemed necessary by medical 
judgment. 
This sentence was added to provide 
a minimum time frame that the 
patient must be observed for safety 
evaluation. 
5.6. Prior and Concomitant Medication or Therapy 
The following medications are 
prohibited during the study: opioids 
(including codeine), barbiturates 
(including Fiorinal®, Fioricet®, or 
any other combination containing 
butalbital), combined estrogen and 
progestogen hormonal 
contraceptives, and lamotrigine. 
The following medications are 
prohibited during the study: opioids 
(including codeine), barbiturates 
(including Fiorinal®, Fioricet®, or 
any other combination containing 
butalbital), combined estrogen and 
progestogen hormonal 
contraceptives, and lamotrigine. 
The sentence was added to 
specifically note which medications 
are prohibited during the study. 
5.8. Randomization and Blinding 
Study personnel will be blinded to 
the results of the interim analysis 
other than the need (if any) for an 
adjustment in sample size. 
- 
This sentence was removed as the 
study personnel will not be 
unblinded to the results of the 
interim analysis. 
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7.4. Clinical Laboratory Tests (Other sections affected by this change: 8.1.1, 8.3) 
Details on sample handling, storage, 
shipment, and analysis are given in 
Appendix N and in the Laboratory 
Manual. 
Details on sample handling, storage, 
shipment, and analysis are given in 
Appendix N and in the Laboratory 
Manual. 
Reference to the newly added 
Appendix N has been added as it 
contains information on storage and 
destruction of samples. 
9.5.1.1. Estimand for the Primary Endpoint 
The primary estimand for this study 
is the difference in means between 
the fremanezumab group and the 
placebo group in the target 
population who have received at 
least 1 dose of study drug and have 
at least 10 days of electronic diary 
efficacy data for the mean change 
from baseline in the monthly 
average number of migraine days 
during the 12-week period after the 
first dose of study drug as if there 
were no intercurrent events. Data 
collected after treatment 
discontinuation or prohibited therapy 
will not be used for assessing the 
primary estimand. 
The primary estimand for this study 
is the difference in means between 
the fremanezumab group and the 
placebo group in the target 
population who have received at 
least 1 dose of study drug and have 
at least 10 days of electronic diary 
efficacy data for the mean change 
from baseline in the monthly 
average number of migraine days 
during the 12-week period after the 
first dose of study drug as if there 
were no intercurrent events. Data 
collected after treatment 
discontinuation or prohibited therapy 
will not be used for assessing the 
primary estimand. 
Estimand language has been added 
to the protocol per recent ICH E9 
guidance. 
9.5.4.1. Primary Efficacy Analysis 
The group of patients 6 through 11 
years of age will be analyzed 
descriptively. 
- 
This sentence was removed as 
patients aged 6 through 11 years will 
be analyzed as part of a subgroup 
analysis. 
9.5.4.2. Sensitivity and Supplementary Analyses 
A supplementary analysis using the 
ITT population will also be carried 
out for the primary efficacy 
endpoint. 
A supplementary analysis using the 
ITT population will also be carried 
out for the primary efficacy 
endpoint. 
The sentence was added to provide 
information that a supplementary 
analysis using the ITT population 
will be conducted. 
9.6. Multiple Comparisons and Multiplicity 
The order of secondary endpoint 
analyses will in general follow the 
sequence listed in Section 9.5.2. 
Final order and details will be 
confirmed in the statistical analysis 
plan, which will be finalized before 
database lock. 
The order of secondary endpoint 
analyses will in general follow the 
sequence listed in Section 9.5.2. 
Final order and details will be 
confirmed in the statistical analysis 
plan, which will be finalized before 
database lock. 
This sentence was added to provide 
clarity on the sequence of secondary 
efficacy endpoint comparisons. 
9.8. Tolerability Analysis (Other sections affection by this change: 7.8) 
• 
Injection site pain will be 
recorded as using the 11-point 
numerical rating scale and will be 
mapped to mild, moderate, or 
severe, according to patient’s self-
• 
Injection site pain will be 
recorded using the 11-point 
numerical rating scale and will be 
mapped to mild, moderate, or 
severe, according to patient’s self-
Injection site pain assessments were 
revised to use the 11-point NRS to 
harmonize with the other pain 
assessments in the study. 
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Reason/justification for change 
report of pain intensity, as described 
for the recording of headache pain in 
Section 6.1.1. 
report of pain intensity, as described 
for the recording of headache pain in 
Section 6.1.1. 
9.12. Planned Interim Analysis (Other sections affected by this change: 3.1 and 9.5.4.1) 
An interim analysis forwith blinded 
sample size re-estimation will be 
conducted by an independent 
statistical groupevaluating the 
pooled variability (SD) of the 
primary endpoint using the total 
number of patients regardless of the 
treatment assignment once 50% of 
patients have completed at least 3 
months of treatment or have 
withdrawn from the study early. The 
sample size re estimation will be 
based on the interim analysis result. 
The conditional power for the 
primary efficacy variable will be 
calculated. If the conditional power 
is less than 25% or greater than 
75%, the sample size will not be 
increased. If the conditional power is 
between 25% and 75%, the sample 
size will be increased by up to 25%. 
An interim analysis with blinded 
sample size re-estimation will be 
conducted by evaluating the pooled 
variability (SD) of the primary 
endpoint using the total number of 
patients regardless of the treatment 
assignment once 50% of patients 
have completed at least 3 months of 
treatment or have withdrawn from 
the study early.  
This sentence was revised to ensure 
it is clear that the sample size re-
estimation will be blinded. 
Additionally, the conditional power 
description for the sample size re-
estimation was removed as the 
planned sample size re-assess will 
use a more robust method to be 
described in the statistical analysis 
plan. 
Appendix F. Ethics 
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).), per local 
regulations. 
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).), per local 
regulations. 
This stipulation was added as there 
may be different requirements for 
certain countries. 
The investigator, or a qualified 
person designated by the 
investigator, should fully inform the 
patient and each parent/legally 
acceptable representative of all 
pertinent aspects of the study, 
including the written information 
approved by the IEC/IRB., per local 
regulations. 
The investigator, or a qualified 
person designated by the 
investigator, should fully inform the 
patient and each parent/legally 
acceptable representative of all 
pertinent aspects of the study, 
including the written information 
approved by the IEC/IRB., per local 
regulations. 
This stipulation was added as there 
may be different requirements for 
certain countries. 
Appendix G. Birth Control Methods and Pregnancy Testing 
• 
Combined estrogen and 
progestogen hormonal contraception 
(oral, intravaginal, and transdermal) 
associated with inhibition of 
- 
This bullet was deleted from highly 
effective birth control methods as 
combined estrogen and progestogen 
hormonal contraception has been 
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ovulation; these should be initiated 
at least 1 month before the first dose 
of IMP 
added as prohibited medications 
during the study. 
Appendix L. Data Management and Record Keeping 
These data may also be sent 
electronically to the sponsor (or 
organization performing data 
management). 
- 
This sentence was deleted to avoid 
unintentional unblinding. 
Appendix N. Storage and Destruction of Biological Samples 
Safety Samples 
Safety samples will be stored for a 
short period of time in the central 
laboratory until analysis and 
destruction. Specific details 
regarding central laboratory storage 
and destruction can be found in the 
study Laboratory Manual and the 
central laboratory's standard 
operating procedures (SOPs). 
Pharmacokinetic and 
Immunogenicity Samples 
Pharmacokinetic and 
immunogenicity samples will be 
stored at the sites at a temperature of  
70°C ±20°C (or at/below -20°C if no  
70°C freezer is available) in an 
upright position until they are 
shipped to the central laboratory. 
Samples will be stored at -70°C at 
the central laboratory, until shipped 
to the sponsor or designee for 
analysis, as described in the study 
Laboratory Manual. 
After analysis, the sponsor will store 
the residue (leftovers) from the 
pharmacokinetic and 
immunogenicity samples at  70°C at 
the designated bioanalytical archive 
facility for up to 5 years after the 
study results are submitted to the 
regulatory authorities. Destruction 
will take place at the sponsor's 
bioanalytical laboratory or designee, 
according to the applicable SOPs. 
Safety Samples 
Safety samples will be stored for a 
short period of time in the central 
laboratory until analysis and 
destruction. Specific details 
regarding central laboratory storage 
and destruction can be found in the 
study Laboratory Manual and the 
central laboratory's standard 
operating procedures (SOPs). 
Pharmacokinetic and 
Immunogenicity Samples 
Pharmacokinetic and 
immunogenicity samples will be 
stored at the sites at a temperature of  
70°C ±20°C (or at/below -20°C if no  
70°C freezer is available) in an 
upright position until they are 
shipped to the central laboratory. 
Samples will be stored at -70°C at 
the central laboratory, until shipped 
to the sponsor or designee for 
analysis, as described in the study 
Laboratory Manual. 
After analysis, the sponsor will store 
the residue (leftovers) from the 
pharmacokinetic and 
immunogenicity samples at  70°C at 
the designated bioanalytical archive 
facility for up to 5 years after the 
study results are submitted to the 
regulatory authorities. Destruction 
will take place at the sponsor's 
bioanalytical laboratory or designee, 
according to the applicable SOPs. 
Appendix N has been added to 
describe the storage and destruction 
of biological samples. 
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16.11. 
Amendment 04 Dated 20 April 2020  
The primary reason for this amendment is to revise an exclusion criterion to exclude patients 
with a history of Stevens-Johnson Syndrome or toxic epidermal necrolysis syndrome. This 
update and other minor revisions do not impact the study design, and the amended protocol 
remains consistent with the United States FDA Special Protocol Assessment and Written 
Request agreements. The amendment is considered to be substantial (ie, requires approval by 
competent authorities, IEC, and/or IRB) by the sponsor’s Authorized Representative. Other 
nonsubstantial changes have been made to the protocol (and protocol synopsis, as appropriate). 
These changes are unlikely to affect the safety or rights (physical or mental integrity) of the 
patients in this clinical study or the scientific value of the clinical study. 
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, Investigator Agreement, 
Coordinating Investigator Agreement) 
Protocol with Amendment 04 
Approval Date: 20 April 2020 
Protocol with Amendment 04 
Approval Date: 20 April 2020 
Updated for Amendment 04 
4.2.  Patient Exclusion Criteria  
c. 
The patient has any clinically 
significant cardiovascular (including 
congenital cardiac anomalies or 
thromboembolic events), endocrine, 
gastrointestinal, genitourinary, 
hematologic, hepatic, immunologic, 
neurologic, ophthalmic, pulmonary, 
or renal disease, or complications of 
an infection, at the discretion of the 
investigator. 
e. 
The patient has an ongoing 
infection, or a known history of 
human immunodeficiency virus 
(HIV) infection, tuberculosis, Lyme 
disease, or chronic hepatitis B or C. 
h. The patient has a history of 
hypersensitivity reactions to injected 
proteins, including mAbs, or a 
history of Stevens-Johnson 
Syndrome or toxic epidermal 
necrolysis syndrome. 
c. 
The patient has any clinically 
significant cardiovascular (including 
congenital cardiac anomalies or 
thromboembolic events), endocrine, 
gastrointestinal, genitourinary, 
hematologic, hepatic, immunologic, 
neurologic, ophthalmic, pulmonary, 
renal disease, or complications of an 
infection, at the discretion of the 
investigator. 
e. 
The patient has an ongoing 
infection or a known history of 
human immunodeficiency virus 
(HIV) infection, tuberculosis, Lyme 
disease, or chronic hepatitis B or C. 
h. The patient has a history of 
hypersensitivity reactions to injected 
proteins, including mAbs, or a 
history of Stevens-Johnson 
Syndrome or toxic epidermal 
necrolysis syndrome. 
Updated to specifically exclude 
patients with a history of chronic 
hepatitis B or C, and to exclude 
patients with a history of Stevens-
Johnson Syndrome/toxic epidermal 
necrolysis syndrome from this study. 
It was also specified that patients 
with clinically significant 
complications of an infection may be 
excluded at the discretion of the 
investigator 
4.5.  Rescreening 
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A patient who is screened but not 
enrolled (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. If the history of migraine 
classification (EM or CM) as taken 
by the investigator differs from the 
classification determined by the 
diary data (28-day screening period), 
the patient may be rescreened one 
time; this information should be 
recorded in the CRF. 
A patient who is screened but not 
enrolled (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. If the history of migraine 
classification (EM or CM) as taken 
by the investigator differs from the 
classification determined by the 
diary data (28-day screening period), 
the patient may be rescreened one 
time; this information should be 
recorded in the CRF. 
Clarification as a measure 
implementing to protect study 
participants and manage study 
conduct resulting from the 
COVID-19 or other potential 
pandemic. 
7.1.6. Protocol-Defined Adverse Events of Special Interest 
Although coronavirus disease 2019 
(COVID-19) is not suspected to be 
causally related to fremanezumab 
treatment, suspected or confirmed 
COVID-19, based on local standard 
of care, will be considered a 
protocol-defined adverse event of 
special interest to be sent to the 
sponsor’s GPSP for the purpose of 
timely and robust adverse event data 
collection. 
Although coronavirus disease 2019 
(COVID-19) is not suspected to be 
causally related to fremanezumab 
treatment, suspected or confirmed 
COVID-19, based on local standard 
of care, will be considered a 
protocol-defined adverse event of 
special interest to be sent to the 
sponsor’s GPSP for the purpose of 
timely and robust adverse event data 
collection. 
Suspected or confirmed COVID-19 
was added as an adverse event of 
special interest in order to manage 
study conduct resulting from the 
COVID-19 pandemic. 
16. Summary of Changes to Protocol 
Section 16.2 Administrative Letter 
01 Dated 10 March 2020 
Section 16.2 Administrative Letter 
01 Dated 10 March 2020 
Updated to include the 
Administrative Letter 01. 
Appendix A. Clinical Laboratories and Other Departments and Institutions 
  
 
 
Teva Branded Pharmaceutical 
Products R&D, Inc. 
Tel: 
 
Cell:
 
 
  
 
 
Teva Branded Pharmaceutical 
Products R&D, Inc. 
Tel: 
 
Cell: 
 
 
Updated as outlined in 
Administrative Letter 01. 
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Teva Branded Pharmaceutical 
Products R&D, Inc. 
Tel: 
 
Cell: 
 
 
 
 
  
Teva Branded Pharmaceutical 
Products R&D, Inc. 
Tel:
 
Cell: 
 
 
Updated as outlined in 
Administrative Letter 01. 
 
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16.12. 
Administrative Letter 01 Dated 10 March 2020  
 
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16.13. 
Amendment 03 Dated 03 February 2020  
The primary reason for this amendment is to update the sponsor’s address. This update and other 
minor revisions do not impact the study design, and the amended protocol remains consistent 
with the United States FDA Special Protocol Assessment and Written Request agreements. The 
amendment is considered to be substantial (ie, requires approval by competent authorities, IEC, 
and/or IRB) by the sponsor’s Authorized Representative. Other nonsubstantial changes have 
been made to the protocol (and protocol synopsis, as appropriate). These changes are unlikely to 
affect the safety or rights (physical or mental integrity) of the patients in this clinical study or the 
scientific value of the clinical study.
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Reason/Justification for 
change 
TITLE PAGE (Other sections affected by this change: protocol header, Investigator Agreement, 
Coordinating Investigator Agreement) 
Protocol with Amendment 03 
Approval Date: 03 February 2020 
Protocol with Amendment 03 
Approval Date: 
03 February 2020 
To update for Amendment 03 
Teva Branded Pharmaceutical 
Products R&D, Inc. 
41 Moores Road 
Frazer, Pennsylvania 19355 
145 Brandywine Parkway 
West Chester, Pennsylvania 19380 
United States of America 
Teva Branded Pharmaceutical 
Products R&D, Inc. 
145 Brandywine Parkway 
West Chester, Pennsylvania 
19380 
United States of America 
To update the sponsor’s new 
address. 
© 20192020 Teva Branded 
Pharmaceutical Products R&D, Inc. All 
rights reserved. 
© 2020 Teva Branded 
Pharmaceutical Products R&D, 
Inc. All rights reserved. 
To update for Amendment 03 
3. STUDY DESIGN 
3.5. Schedule of Study Procedures and Assessments (Table 1) (Other sections affected by this change: 
Appendix B) 
Headache history 
Headache history 
Specific study procedure added 
for clarity to collect headache 
history data during screening. 
Clinical laboratory testsc,m 
Clinical laboratory testsc,m 
To clarify that blood samples 
will be collected before study 
drug administration. 
Blood samples for plasma drug 
concentrationcp 
Blood samples for plasma drug 
concentrationc 
Correction to simplify 
footnotes. 
Blood samples for serum ADA 
assessmentcp 
Blood samples for serum ADA 
assessmentc 
Correction to simplify 
footnotes. 
Injection site assessmentsc 
Injection site assessmentsc 
Footnote reference added to the 
injection site assessment row 
for clarity. 
p 
Blood samples for plasma drug 
concentration and serum ADA 
determination must be collected prior 
to dosing as applicable. 
- 
The footnote was deleted as it 
was repetitive with footnote c. 
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change 
4. SELECTION AND WITHDRAWAL OF PATIENTS 
4.1. Patient Inclusion Criteria 
Note: A person is considered to be not 
using preventive medications when at 
least 5 half-lives have passed since the 
last use of the medication prior to 
screening (visit 1) or at least 4 months 
have passed since the last use of 
Onabotulinium toxin A or B prior to 
screening (visit 1). 
Note: A person is considered to be 
not using preventive medications 
when at least 5 half-lives have 
passed since the last use of the 
medication prior to screening (visit 
1) or at least 4 months have passed 
since the last use of Onabotulinium 
toxin A or B prior to screening 
(visit 1). 
This note for inclusion criterion 
f was updated to include 
onabotulinumtoxinB to coincide 
with it being added as a 
preventive migraine medication 
allowed for up to 20% of 
patients during the study as per 
Appendix C. 
4.2. Patient Exclusion Criteria (Other sections affected by this change: 5.6) 
s. 
The patient received a live 
attenuated vaccine (eg, intranasal flu 
vaccine, and measles, mumps, and 
rubella vaccine) within the 12-week 
period prior to screening or plans to 
receive a live attenuated vaccine at any 
time during the study and for 6 months 
after the last dose of IMP. 
s. 
The patient received a live 
attenuated vaccine (eg, intranasal 
flu vaccine, and measles, mumps, 
and rubella vaccine) within the 12-
week period prior to screening or 
plans to receive a live attenuated 
vaccine at any time during the 
study and for 6 months after the 
last dose of IMP. 
Added a clarification to 
describe some potentially 
applicable live attenuated 
vaccines. 
7. ASSESSMENT OF SAFETY 
7.4.1. 
Serum Chemistry, Hematology, Coagulation, and Urinalysis 
Clinical laboratory tests (serum 
chemistry, hematology, coagulation, 
and urinalysis) will be performed at the 
time points detailed in Table 1. In case 
of suspected hepatitis, HIV, or Lyme 
disease, a blood sample may be taken 
at screening at the discretion of the 
investigator. Baseline is screening 
(visit 1). Clinical laboratory tests will 
be performed using the central 
laboratory. Specific laboratory tests to 
be performed are listed below (Table 
4). 
Clinical laboratory tests (serum 
chemistry, hematology, 
coagulation, and urinalysis) will be 
performed at the time points 
detailed in Table 1. In case of 
suspected hepatitis, HIV, or Lyme 
disease, a blood sample may be 
taken at screening at the discretion 
of the investigator. Baseline is 
screening (visit 1). Clinical 
laboratory tests will be performed 
using the central laboratory. 
Specific laboratory tests to be 
performed are listed below (Table 
4). 
To clarify that the investigator 
may take a blood sample at 
screening in case of suspected 
hepatitis. 
Table 4 (urinalysis column) 
Albumin 
- 
Albumin was removed from 
Table 4 as it is included in the 
protein measurement and will 
not be evaluated separately by 
the central laboratory. 
HemoglobinBlood 
Blood 
Correction as the urinalysis will 
specifically assess for blood in 
urine. 
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change 
7.1.5.1. Definition of a Serious Adverse Event 
Refer to Appendix I for guidance 
regarding monitoring patients with 
elevated liver function tests. An 
adverse event that does not meet any of 
the criteria for seriousness listed above 
will be regarded as a nonserious 
adverse event. 
Refer to Appendix I for guidance 
regarding monitoring patients with 
elevated liver function tests. An 
adverse event that does not meet 
any of the criteria for seriousness 
listed above will be regarded as a 
nonserious adverse event. 
Refer to Appendix I for 
guidance regarding monitoring 
patients with elevated liver 
function tests. An adverse event 
that does not meet any of the 
criteria for seriousness listed 
above will be regarded as a 
nonserious adverse event. 
APPENDIX C. PREVENTIVE MIGRAINE MEDICATIONS ALLOWED FOR THE DURATION OF 
THE STUDY FOR UP TO 20% OF PATIENTS 
OnabotulinumtoxinA or B 
OnabotulinumtoxinA or B 
OnabotulinumtoxinB was added 
as a preventive migraine 
medications allowed for the 
duration of the study for up to 
20% of patients as outlined in 
Appendix C. 
APPENDIX I. 
GUIDANCE ON 
SAFETY MONITORING 
APPENDIX I. 
GUIDANCE 
ON SAFETY MONITORING 
Appendix I was newly added to 
provide guidance to the 
investigator on monitoring 
patients with elevated liver 
function tests. 
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16.14. 
Amendment 02 Dated 05 December 2019  
The primary reason for this amendment is to update the protocol with the dose to be used for 
patients <45.0 kg (120 mg sc monthly) following the completion of the Phase 1 pediatric 
pharmacokinetic study (TV48125-CNS-10141). This update and other minor revisions do not 
impact the study design, and the amended protocol remains consistent with the United States 
FDA Special Protocol Assessment agreement. The amendment is considered to be substantial (ie, 
requires approval by competent authorities, IEC, and/or IRB) by the sponsor’s Authorized 
Representative. Other nonsubstantial changes have been made to the protocol (and protocol 
synopsis, as appropriate). These changes are unlikely to affect the safety or rights (physical or 
mental integrity) of the patients in this clinical study or the scientific value of the clinical study.
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Changes to the Protocol 
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Reason/Justification for change 
TITLE PAGE (Other sections affected by this change: protocol header, Amendment History, Investigator Agreement, Coordinating Investigator 
Agreement) 
Clinical Study Protocol with Amendment 0102  
Clinical Study Protocol with Amendment 02 
To update for Amendment 02 
Protocol with Amendment 02 Approval Date: 05 
December 2019 
Protocol with Amendment 02 Approval Date: 05 
December 2019 
To update for Amendment 02 
1.  INTRODUCTION AND BACKGROUND INFORMATION  
1.1. Introduction (Other sections affected by this change: 1.2.2, 1.2.2.1, 1.2.2.2) 
Two completed, randomized, double-blind, placebo-
controlled Phase 3 studies (Studies TV48125-CNS-
30049 in CM and TV48125-CNS-30050 in EM) and 
1 ongoingcompleted, randomized, double-blind 
Phase 3 long-term safety study (Study TV48125-
CNS-30051 in migraine [EM and CM]) were 
conducted to further evaluate the efficacy, safety, 
and tolerability of various dose regimens of 
fremanezumab in the preventive treatment of 
migraine. Study TV48125 CNS 30051 is ongoing, 
and as of the safety cutoff date of 30 May 2018, all 
patients (excluding 2) completed study treatment. 
Additional studies within the migraine development 
program of fremanezumab include the completed 
Phase 3b study (Study TV48125-CNS-30068) in 
patients from the EU and US to evaluate the safety 
and efficacy of fremanezumab in migraine patients 
who have failed multiple preventive medications, 2 
ongoing Phase 2b/3 studies in Japanese and Korean 
EM and CM patients (Studies 406-102-00002 and 
406-102-00001, respectively), and 1 ongoing long-
term safety study (Study 406-102-00003) in CM and 
EM to evaluate the safety and efficacy of 
fremanezumab. 
Two completed, randomized, double-blind, 
placebo-controlled Phase 3 studies (Studies 
TV48125-CNS-30049 in CM and TV48125-CNS-
30050 in EM) and 1 completed, randomized, 
double-blind Phase 3 long-term safety study (Study 
TV48125-CNS-30051 in migraine [EM and CM]) 
were conducted to further evaluate the efficacy, 
safety, and tolerability of various dose regimens of 
fremanezumab in the preventive treatment of 
migraine. Additional studies within the migraine 
development program of fremanezumab include the 
completed Phase 3b study (Study TV48125-CNS-
30068) in patients from the EU and US to evaluate 
the safety and efficacy of fremanezumab in 
migraine patients who have failed multiple 
preventive medications, 2 ongoing Phase 2b/3 
studies in Japanese and Korean EM and CM 
patients (Studies 406-102-00002 and 406-102-
00001, respectively), and 1 ongoing long-term 
safety study (Study 406-102-00003) in CM and EM 
to evaluate the safety and efficacy of 
fremanezumab. 
Updated to reflect that Study TV48125-CNS-
30051 is now complete. 
The pediatric migraine development program 
includes a completed Phase 1, single-dose, open-
The pediatric migraine development program 
includes a completed Phase 1, single-dose, open-
Updated to reflect that Study TV48125-CNS-
10141 is now complete. 
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Reason/Justification for change 
label study with administration of single sc doses of 
75 mg in pediatric migraine patients 6 to 11 years of 
age, inclusive (Study TV48125-CNS-10141). 
label study with administration of single sc doses of 
75 mg in pediatric migraine patients 6 to 11 years 
of age, inclusive (Study TV48125-CNS-10141). 
Fremanezumab is further studied for the preventive 
treatment of cluster headache (CH) and persistent 
posttraumatic headache (PPTH) in the following 
ongoing studies: 1 Phase 2 study (Study TV48125-
CNS-20024) to comparethat is comparing the 
efficacy and safety of the sc dose regimen of 
fremanezumab versus placebo in patients with 
PPTH; 1 Phase 3 study (. Fremanezumab was being 
studied for the preventive treatment of cluster 
headache (CH) in 3 Phase 3 studies: Study 
TV48125-CNS-30056 in patients with episodic 
cluster headache ([ECH]) to evaluate the efficacy 
and safety of various dose regimens of 
fremanezumab in the preventive treatment of ECH; 
and a third study evaluating long term safety of 
fremanezumab (Study TV48125 CNS 30058 in CH). 
As of 15 June 2018, Study TV48125-CNS-30057 in 
patients with chronic cluster headache (CCH) was, 
and a long-term safety Study TV48125-CNS-30058 
in CH. All 3 studies were terminated by Teva, 
because a prespecified futility analysis showed that 
the primary endpoint of mean change from baseline 
in the monthly average number of CH attacks during 
the 12-week treatment period was unlikely to be met. 
At that time, participation in Study TV48125 CNS
30058 was also discontinued for patients with CCH 
who had completed Study TV48125 CNS 30057. 
Fremanezumab is further studied for the preventive 
treatment of persistent posttraumatic headache 
(PPTH) in 1 Phase 2 study (Study TV48125-CNS-
20024) that is comparing the efficacy and safety of 
the sc dose regimen of fremanezumab versus 
placebo in patients with PPTH. Fremanezumab was 
being studied for the preventive treatment of cluster 
headache (CH) in 3 Phase 3 studies: Study 
TV48125-CNS-30056 in patients with episodic CH, 
Study TV48125-CNS-30057 in patients with 
chronic CH, and a long-term safety Study 
TV48125-CNS-30058 in CH. All 3 studies were 
terminated by Teva because a prespecified futility 
analysis showed that the primary endpoint of mean 
change from baseline in the monthly average 
number of CH attacks during the 12-week treatment 
period was unlikely to be met. 
Updated with the status of the 3 chronic 
headache studies. 
1.2.2. 
Clinical Studies 
As of 26 September 2017, 3196 subjects and patients 
(318 healthy subjects and 2878 patients with 
migraine) have been enrolled in 13 studies in the 
fremanezumab migraine clinical development 
program. Overall in the fremanezumab migraine 
clinical development program, 2013 2512 patients 
Overall in the fremanezumab migraine clinical 
development program, 2512 patients with migraine 
and 474 healthy subjects have received at least 1 
dose of fremanezumab in the completed clinical 
studies. In addition, 142 and 380 patients in the 3 
CH Phase 3 blinded studies (TV48125-CNS-30056, 
Update to represent current exposure data. 
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with migraine and 256 474 healthy subjects have 
received at least 1 dose of fremanezumab in the 
completed and ongoing clinical studies. In addition, 
as of 26 September 2018, 138 142 and 380 patients 
in the 3 CH Phase 3 blinded studies (TV48125-CNS-
30056, TV48125-CNS-30057, and TV48125-CNS-
30058) were treated with either placebo orand 
fremanezumab, respectively. 
TV48125-CNS-30057, and TV48125-CNS-30058) 
were treated with placebo and fremanezumab, 
respectively. 
The 89 completed Phase 1 studies include 
administration of single iv doses ranging from 0.2 to 
2000 mg; among these studies are 1 completed Phase 
1 study with administration of 2 doses via iv infusion 
(30 or 300 mg) administered 14 days apart; 1 
completed Phase 1 study testing single iv and sc 
doses of 225 and 900 mg; 1 completed Phase 1 
bioequivalence study comparing the 
pharmacokinetics of 225 mg of fremanezumab 
administered sc using an autoinjector referenced to a 
pre-filled syringe (PFS); and 1 completed Phase 1 
study in Japanese and Caucasian subjects testing 
single sc doses of 225, 675, and 900 mg. 
The 9 completed Phase 1 studies include 
administration of single iv doses ranging from 0.2 
to 2000 mg; among these studies are 1 completed 
Phase 1 study with administration of 2 doses via iv 
infusion (30 or 300 mg) administered 14 days apart; 
1 completed Phase 1 study testing single iv and sc 
doses of 225 and 900 mg; 1 completed Phase 1 
bioequivalence study comparing the 
pharmacokinetics of 225 mg of fremanezumab 
administered sc using an autoinjector referenced to 
a pre-filled syringe (PFS); and 1 completed Phase 1 
study in Japanese and Caucasian subjects testing 
single sc doses of 225, 675, and 900 mg. 
Update for completion of Study TV48125-
CNS-10141. 
FourFive studies in adult migraine patients (2 Phase 
2b studies and 23 Phase 3 studies) examining the 
safety and efficacy of fremanezumab have been 
completed. 
Five studies in adult migraine patients (2 Phase 2b 
studies and 3 Phase 3 studies) examining the safety 
and efficacy of fremanezumab have been 
completed. 
Update for completion of Study TV48125-
CNS-30051. 
1.2.2.1. Clinical Pharmacology Studies 
Two relevant clinical pharmacology studies in the 
pediatric migraine development program have been 
completed: a Phase 1 bioequivalence study 
comparing the pharmacokinetics of 225 mg of 
fremanezumab administered sc using an autoinjector 
referenced to a PFS (TV48125-BE-10145) in healthy 
adult subjects, and a Phase 1, single-dose, open-label 
study with administration of single sc doses of 75 
mg in pediatric migraine patients 6 to 11 years of 
age, inclusive (Study TV48125-CNS-10141). 
Two relevant clinical pharmacology studies have 
been completed: a Phase 1 bioequivalence study 
comparing the pharmacokinetics of 225 mg of 
fremanezumab administered sc using an 
autoinjector referenced to a PFS (TV48125-BE-
10145) in healthy adult subjects, and a Phase 1, 
single-dose, open-label study with administration of 
single sc doses of 75 mg in pediatric migraine 
patients 6 to 11 years of age, inclusive (Study 
TV48125-CNS-10141). 
Update to the clinical pharmacology studies. 
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3.  STUDY DESIGN  
3.1. General Study Design and Study Schematic Diagram (Other sections affected by this change: 3.2, 5.1.1.1, 5.1.3, 5.3.1, 5.4, 5.8, 9, 9.1) 
The total duration of the study is planned to be 48 
months (from approximately Q4 2019Q1 2020 to Q4 
2022). 
The total duration of the study is planned to be 48 
months (from approximately Q1 2020 to Q4 2022). 
Updated the approximate start date of the 
study. 
• Patients weighing <45.0 kg will receive monthly sc 
administration of fremanezumab at a dose to be 
confirmed after pharmacokinetic analyses and safety 
and tolerability results become available from the 
Phase 1 pharmacokinetics study (Study TV48125
CNS 10141). The sponsor will communicate the 
dose selection for patients <45.0 kg when it becomes 
available120 mg. 
• Patients weighing <45.0 kg will receive monthly 
sc administration of fremanezumab at 120 mg. 
Updated dose for patients <45.0 kg. 
The enrollment target is approximately 288 patients 
in total, with a goal of at least 30% of those patients 
in the 6- through 11-year-old age group. The goal in 
the 12- through 17-year-old age group is to enroll 
similar numbers of patients who are 12 through 14 
years old and 15 through 17 years old. The 
enrollment will start with patients weighing ≥45.0 
kg. The enrollment of patients weighing <45.0 kg 
will commence after the dose level is finalized and 
approved by regulatory agencies. 
The enrollment target is approximately 288 patients 
in total, with a goal of at least 30% of those patients 
in the 6- through 11-year-old age group. The goal in 
the 12- through 17-year-old age group is to enroll 
similar numbers of patients who are 12 through 14 
years old and 15 through 17 years old. 
No longer applicable to study enrollment 
3.5. Schedule of Study Procedures and Assessments (Other sections affected by this change: 7.9, Appendix B) 
Lifetime pPrior medication and treatment history 
Lifetime prior medication and treatment history 
Clarification. 
p 
Blood samples for plasma drug concentration 
and serum ADA concentrations determination must 
be collected prior to dosing as applicable. 
p 
Blood samples for plasma drug concentration 
and serum ADA determination must be collected 
prior to dosing as applicable. 
Clarification. 
q 
The C-SSRS Baseline/Screening version will be 
completed by the physician based on discussion with 
the patient/caregiver at visit 1 (screening visit), and 
the C-SSRS Since Last Visit version will be 
completed by the physician based on discussion with 
the patient/caregiver at all other time points. Any 
q 
The C-SSRS Baseline/Screening version will 
be completed by the physician based on discussion 
with the patient/caregiver at visit 1 (screening visit), 
and the C-SSRS Since Last Visit version will be 
completed by the physician based on discussion 
with the patient/caregiver at all other time points. 
Clarified who will be completing the C-SSRS 
and what occurs if there is a positive finding. 
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positive finding on the C SSRS Since Last Visit 
version requires evaluation by a physician or 
doctoral level psychologist. Any patient who 
demonstrates suicidal ideation and/or any suicidal 
behavior at any point during the study should be 
withdrawn from the study and discontinued from 
study treatment. In addition, if a patient endorses 
suicidal ideation or behavior at any point during the 
study (including during screening), the investigator 
must explain to the patient/caregiver the need for 
follow-up with a mental health professional and 
make any necessary referrals. 
Any patient who demonstrates suicidal ideation 
and/or any suicidal behavior at any point during the 
study should be withdrawn from the study and 
discontinued from study treatment. In addition, if a 
patient endorses suicidal ideation or behavior at any 
point during the study (including during screening), 
the investigator must explain to the 
patient/caregiver the need for follow-up with a 
mental health professional and make any necessary 
referrals. 
r 
The location of the sc injection should be 
recorded at each administration visit. 
r 
The location of the sc injection should be 
recorded at each administration visit. 
Clarification. 
4. SELECTION AND WITHDRAWAL OF PATIENTS 
4.3. Withdrawal Criteria and Procedures for the Patient 
All protocol-specified procedures/assessments 
should be performed at the EOT/early withdrawal 
visit (see Table 1). Patients who withdraw from the 
study or have an early termination will be invited to 
enter the long-term safety extension (within Study 
TV48125-CNS-30084) for the purpose of safety 
follow-up and evaluating ADA approximately 6 
months (180 days [more than 5 half-lives]) after 
receiving the last dose of study drug in this study. 
All protocol-specified procedures/assessments 
should be performed at the EOT/early withdrawal 
visit (see Table 1). Patients who withdraw from the 
study or have an early termination will be invited to 
enter the long-term safety extension (within Study 
TV48125-CNS-30084) for the purpose of safety 
follow-up and evaluating ADA approximately 6 
months (180 days [more than 5 half-lives]) after 
receiving the last dose of study drug in this study. 
Clarification. 
5. TREATMENTS (Other sections affected by this change: 5.1.3, 5.8) 
5.1.1.1. Starting Dose and Dose Levels 
A 1.5 mL volume (patients weighing ≥45.0 kg at 
randomization [visit 2]) or a 0.8 mL volume to be 
confirmed (patients weighing <45.0 kg at 
randomization [visit 2]) from each visit kit(s) (the 
full dose given with a PFS or taken from the vials) 
must be injected sc for administration to be 
considered complete. Patients randomized to the 
A 1.5 mL volume (patients weighing ≥45.0 kg at 
randomization [visit 2]) or a 0.8 mL volume 
(patients weighing <45.0 kg at randomization [visit 
2]) from each visit kit(s) (the full dose given with a 
PFS or taken from the vials) must be injected sc for 
administration to be considered complete. Patients 
Updated volume requirements for patients 
<45.0 kg. 
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placebo group will receive volume-matched doses of 
placebo. 
randomized to the placebo group will receive 
volume-matched doses of placebo. 
5.1.3. 
Placebo Investigational Medicinal Product 
dose to be confirmed for patients with body weight 
<45.0 kg120 mg dose: taken from two 2-mL vials 
each containing 0.5 mL of IMP for single-use 
administration 
120 mg dose: taken from two 2-mL vials each 
containing 0.5 mL of IMP for single-use 
administration 
Updated to reflect the dose selected for patients 
<45.0 kg was from the completed Study 
TV48125-CNS-10141. 
0.8-mL injection (volume to be confirmed): taken 
from two 2-mL vials each containing 0.5 mL of 
placebo for single-use administration 
0.8-mL injection: taken from two 2-mL vials each 
containing 0.5 mL of placebo for single-use 
administration 
Updated to reflect the dose selected for patients 
<45.0 kg was from the completed Study 
TV48125-CNS-10141. 
5.3.1. 
Justification for Dose of Test Investigational Medicinal Product 
It should be noted thatThe final dose for patients 
<45.0 kg will be provided during protocol 
development,was determined by taking into account 
observed pharmacokinetic data from Study 
TEV48125-CNS-10141, a Phase 1 study in pediatric 
patients 6 to 11 years of age (inclusive). Data from 
this study (TEV48125-CNS-10141) will be 
incorporated intowere used to refine the pooled 
dataset current adult population pharmacokinetic 
model (currentlywhich was based on adult data from 
2 Phase 1 studies [Studies LBR-101-011 and 
TV48125-PK-10078], 2 Phase 2b studies [Studies 
LBR-101-021 and LBR-101-022], and 3 Phase 3 
Studies [Studies TV48125-CNS-30049, TV48125-
CNS-30050, and TV48125-CNS-30051 (cutoff date 
30 May 2018)]). and used to refine, as appropriate, 
the adult This refined pediatric population 
pharmacokinetic model. This refined population 
pharmacokinetic model, based on adult and pediatric 
data, will then bewas used to simulate individual 
estimates of exposure for a virtual population of 
pediatric subjects over a range of possible 
fremanezumab doses. Pediatric virtual subjects (6 to 
17 years [inclusive]) will bewere assigned weight 
values based on a uniform distribution of age using 
The final dose for patients <45.0 kg was determined 
by taking into account observed pharmacokinetic 
data from Study TV48125-CNS-10141, a Phase 1 
study in pediatric patients 6 to 11 years of age 
(inclusive). Data from this study (TV48125-CNS-
10141) were used to refine the current adult 
population pharmacokinetic model (which was 
based on adult data from 2 Phase 1 studies [Studies 
LBR-101-011 and TV48125-PK-10078], 2 Phase 
2b studies [Studies LBR-101-021 and LBR-101-
022], and 3 Phase 3 Studies [Studies TV48125-
CNS-30049, TV48125-CNS-30050, and TV48125-
CNS-30051 (cutoff date 30 May 2018)]). This 
refined pediatric population pharmacokinetic model 
was used to simulate individual estimates of 
exposure for a virtual population of pediatric 
subjects over a range of possible fremanezumab 
doses. Pediatric virtual subjects (6 to 17 years 
[inclusive]) were assigned weight values based on a 
uniform distribution of age using growth chart data 
from the Centers for Disease Control. The 120 mg 
monthly dose level was selected for patients age 6 
to 17 years (inclusive) with weight values <45.0 kg 
based on targeting the achievement of a similar 
distribution of fremanezumab exposure levels 
Updated to reflect the dose selected for patients 
<45.0 kg was from the completed Study 
TV48125-CNS-10141. 
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Reason/Justification for change 
growth chart data from the Centers for Disease 
Control. A The 120 mg monthly dose level will 
bewas selected for patients age 6 to 17 years 
(inclusive) with weight values <45.0 kg based on 
targeting the achievement of a similar distribution of 
fremanezumab exposure levels (following multiple 
dosing) of 225 mg monthly in adult patients with 
EM and CM. 
(following multiple dosing) of 225 mg monthly in 
adult patients with EM and CM. 
5.10. 
Total Blood Volume 
The total blood volume to be collected for each 
patient in this study is approximately 6648 mL (at 
maximum). See Appendix I. 
The total blood volume to be collected for each 
patient in this study is approximately 48 mL. See 
Appendix I. 
Updated total blood volume. 
6. ASSESSMENT OF EFFICACY 
6.1.1. 
Electronic Headache Diary 
On each day, the patient or parent/caregiver will be 
asked to record diary data for the previous 24-hour 
period. Patients and parents/caregivers may be asked 
about their (child’s) performance at school and when 
doing household chores (ie, functional assessments). 
Patients or parents/caregivers who report headache 
on the previous day will answer questions about the 
headache (ie, the number of hours with headache, 
headache severity, presence of associated symptoms, 
and use of acute migraine medications). Additional 
details regarding the questions patients or 
parents/guardians will answer can be found in the 
electronic headache diary training manual. 
On each day, the patient or parent/caregiver will be 
asked to record diary data for the previous 24-hour 
period. Patients and parents/caregivers may be 
asked about their (child’s) performance at school 
and when doing household chores (ie, functional 
assessments). Patients or parents/caregivers who 
report headache on the previous day will answer 
questions about the headache (ie, the number of 
hours with headache, headache severity, presence 
of associated symptoms, and use of acute migraine 
medications). Additional details regarding the 
questions patients or parents/guardians will answer 
can be found in the electronic headache diary 
training manual. 
Clarification. 
If headache is reported, then headache severity will 
be subjectively rated by the patient or 
parent/caregiver on an 11-point numerical rating 
scale, where 0 is no pain and 10 is the most severe 
pain.as follows: 
• 
mild headache 
If headache is reported, then headache severity will 
be subjectively rated by the patient or 
parent/caregiver on an 11-point numerical rating 
scale, where 0 is no pain and 10 is the most severe 
pain. Each headache severity rating from the 11-
point numerical rating scale will be mapped to mild 
(1 to 3), moderate (4 to 6), or severe (7 to 10) for 
Updated language to clarify how headache 
severity will be assessed. 
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Reason/Justification for change 
• 
moderate headache 
• 
severe headache 
An 11 point numerical scale will be used for the 
patients to rate their headache pain intensity. Each 
headache sSeverity rating from the 11-point 
numerical rating scale will be mapped to mild (1 to 
3), moderate (4 to 6), or severe (7 to 10) for endpoint 
analyses (McCaffery and Beebe 1989). Patients or 
parents/caregivers will also record whether 
photophobia, phonophobia, nausea, and vomiting are 
present, and they will record any migraine 
medications (name of drug, number of 
tablets/capsules, and the dose in milligrams per 
tablet/capsule) taken on each day. Diary compliance 
of less than 75% after the start of treatment will be 
recorded as a protocol deviation. 
endpoint analyses (McCaffery and Beebe 1989). 
Patients or parents/caregivers will also record 
whether photophobia, phonophobia, nausea, and 
vomiting are present, and they will record any 
migraine medications (name of drug, number of 
tablets/capsules, and the dose in milligrams per 
tablet/capsule) taken on each day. Diary 
compliance of less than 75% after the start of 
treatment will be recorded as a protocol deviation. 
7. ASSESSMENT OF SAFETY 
7.4.1. 
Serum Chemistry, Hematology, Coagulation, and Urinalysis 
Clinical laboratory tests (serum chemistry, 
hematology, coagulation, and urinalysis) will be 
performed at the time points detailed in Table 1. In 
case of suspected HIV or Lyme disease, a blood 
sample shouldmay be taken at screening at the 
discretion of the investigator. Baseline is screening 
(visit 1). Clinical laboratory tests will be performed 
using the central laboratory. Specific laboratory tests 
to be performed are listed below (Table 4). 
Clinical laboratory tests (serum chemistry, 
hematology, coagulation, and urinalysis) will be 
performed at the time points detailed in Table 1. In 
case of suspected HIV or Lyme disease, a blood 
sample may be taken at screening at the discretion 
of the investigator. Baseline is screening (visit 1). 
Clinical laboratory tests will be performed using the 
central laboratory. Specific laboratory tests to be 
performed are listed below (Table 4). 
Virology sampling may be done at the 
discretion of the investigator. 
9. STATISTICS 
9.7. Safety Analysis 
Suicidal ideation and behavior will be measured 
using the C-SSRS. Data for patients with positive 
findings will be listed. 
Suicidal ideation and behavior will be measured 
using the C-SSRS. Data for patients with positive 
findings will be listed. 
Clarification. 
9.8. Tolerability Analysis 
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Reason/Justification for change 
Subjective tTolerability will be assessed by the 
following: 
Tolerability will be assessed by the following: 
Clarification. 
15. REFERENCES 
McCaffery M, Beebe A. Pain: Clinical manual for 
nursing practice. St. Louis (MO): Mosby 1989. 
Available upon request. 
McCaffery M, Beebe A. Pain: Clinical manual for 
nursing practice. St. Louis (MO): Mosby 1989. 
Available upon request. 
Added in a reference for the pain severity 
scale. 
APPENDIX A 
CLINICAL LABORATORIES AND OTHER DEPARTMENTS AND INSTITUTIONS 
Legal Representative of the Sponsor in the European 
Union (EU) and Contact Person 
Legal Representative of the Sponsor in the 
European Union (EU) and Contact Person 
Clarification. 
APPENDIX B 
CLINICAL LABORATORIES AND OTHER DEPARTMENTS AND INSTITUTIONS 
• 
review lifetime prior medication and treatment 
history 
• 
review lifetime prior medication and treatment 
history 
Clarification. 
APPENDIX C 
PREVENTIVE MIGRAINE 
MEDICATIONS ALLOWED FOR THE 
DURATION OF THE STUDY FOR UP TO 20% 
OF PATIENTS 
APPENDIX C 
PREVENTIVE MIGRAINE 
MEDICATIONS ALLOWED FOR THE 
DURATION OF THE STUDY FOR UP TO 
20% OF PATIENTS 
Clarification. 
The following concomitant preventive migraine 
medications are allowed in up to 20% of patients and 
should be entered in electronic case report form 
(eCRF) pages specific for migraine preventive 
medication. Patients must have been on a stable, 
well-tolerated dose of this preventive 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 80% of 
patients, these medications are not allowed for 
migraine or for any other indications. 
The following concomitant preventive migraine 
medications are allowed in up to 20% of patients 
and should be entered in electronic case report form 
(eCRF) pages specific for migraine preventive 
medication. Patients must have been on a stable, 
well-tolerated dose of this preventive 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 80% of 
patients, these medications are not allowed for 
migraine or for any other indications. 
Clarification. 
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Reason/Justification for change 
APPENDIX I 
TOTAL BLOOD VOLUME 
Type of 
samples 
Volume 
per 
sample 
(mL) 
Total 
number 
of 
samples 
Total 
volume 
(mL) 
Clinical 
laboratory 
(serum 
chemistry, 
including β-
HCG test, 
hematology, 
coagulation) 
10 
3 
30 
Pharmacoki
netics 
2 
3 
6 
ADA 
4 
3 
12 
Virology 
(hepatitis, 
HIV, Lyme 
disease, and 
tuberculosis
) 
18 
1 
18 
Total 
 
 
6648 
ADA=antidrug antibody; β-HCG=beta-human 
chorionic gonadotropin; HIV=human 
immunodeficiency virus. 
Type of 
samples 
Volume 
per 
sample 
(mL) 
Total 
number 
of 
samples 
Total 
volume 
(mL) 
Clinical 
laboratory 
(serum 
chemistry, 
including β-
HCG test, 
hematology
, 
coagulation
) 
10 
3 
30 
Pharmacoki
netics 
2 
3 
6 
ADA 
4 
3 
12 
Total 
 
 
48 
ADA=antidrug antibody; β-HCG=beta-human 
chorionic gonadotropin. 
Updated blood samples to remove virology 
testing. Virology blood sampling will be done 
at the discretion of the investigator. 
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16.15. 
Amendment 01 Dated 21 June 2019  
The primary reasons for this amendment are to improve the feasibility of the diary compliance 
requirement, clarify the exclusion criterion for nerve stimulation or device, and clarify the timing 
of injection site reaction assessment. None of these revisions impact the study design, and the 
amended protocol remains consistent with the United States FDA Special Protocol Assessment 
agreement. The amendment is considered to be substantial (ie, requires approval by competent 
authorities, IEC, and/or IRB) by the sponsor’s Authorized Representative. Other nonsubstantial 
changes have been made to the protocol (and protocol synopsis, as appropriate). These changes 
are unlikely to affect the safety or rights (physical or mental integrity) of the patients in this 
clinical study or the scientific value of the clinical study.
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Changes to the Protocol 
Table 1 (Study Procedures and Assessments) has been revised to reflect the changes described below. 
Original text with changes shown 
New wording 
Reason/Justification for change 
TITLE PAGE (Other sections affected by this change: Investigator Agreement, Coordinating Investigator Agreement) 
EudraCT number: <TBD>2019-002055-42 
EudraCT number: 2019-002055-42 
This change was made to provide the 
EudraCT number. 
Teva Branded Pharmaceutical Products R&D, Inc. 
145 Brandywine Parkway 
West Chester, PA 19380 
41 Moores Road 
Frazer, Pennsylvania 19355 
United States of America 
Teva Branded Pharmaceutical Products R&D, Inc. 
41 Moores Road 
Frazer, Pennsylvania 19355 
United States of America 
This change was made to update the 
addresses for the Sponsor. 
SELECTION AND WITHDRAWAL OF PATIENTS 
Section 4.1  
i. 
The patient/caregiver has demonstrated 
compliance with the electronic headache diary 
during the 28-day baseline period by entry of 
headache data on a minimum of 2421 out of 28 days 
(approximately 8575% diary compliance). 
i. 
The patient/caregiver has demonstrated 
compliance with the electronic headache diary during 
the 28-day baseline period by entry of headache data 
on a minimum of 21 out of 28 days (approximately 
75% diary compliance). 
This change was made to harmonize the 
required diary compliance during the baseline 
and treatment periods across the 3 Phase 3 
pediatric protocols. The change will not 
impact data quality or accuracy.  
(Not applicable) 
n. The patient has received all recommended age-
appropriate vaccines according to local standard of 
care and schedule. 
This inclusion criterion was added to protect 
study participants from preventable 
childhood illnesses in accordance with 
current medical recommendations for 
pediatric patients and to help prevent the 
spread of communicable infections to others 
at the investigational site. 
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Reason/Justification for change 
Section 4.2 
(Not applicable) 
b. The patient has used an intervention/device (eg, 
scheduled nerve block or transcranial magnetic 
stimulation) for the treatment of migraine during the 
2 months prior to the day of the screening visit. 
This exclusion criterion was added to 
decrease the chances that previous 
nonpharmacologic treatments would 
confound the assessment of safety and 
efficacy of fremanezumab. 
(Not applicable) 
s. 
The patient received a live attenuated vaccine 
within the 12-week period prior to screening or plans 
to receive a live attenuated vaccine at any time during 
the study and for 6 months after the last dose of IMP. 
This exclusion criterion was added to avoid 
an immune response elicited by 
administration of a live attenuated vaccine 
that could interfere with the accurate 
assessment of efficacy and safety of 
fremanezumab. 
ASSESSMENT OF SAFETY 
Section 7.8  
Injection site assessments will be performed 
immediately and 1 hour after administration of each 
dose of study drug, d before patients leave the 
investigational site. 
Injection site assessments will be performed after 
administration of each dose of study drug and before 
patients leave the investigational site. 
This change was made to clarify the 
procedure for assessment of local tolerability 
and pain. 
CLINICAL LABORATORY AND OTHER DEPARTMENTS AND INSTITUTIONS 
Appendix A 
<Name, Degree, Company, Function, Phone, Fax, 
Cell, Email>
  
 
 
Teva Branded Pharmaceutical Products R&D, Inc. 
Tel: 
 
Cell:
 
 
 
 
 
Teva Branded Pharmaceutical Products R&D, Inc. 
Tel:
 
Cell:
 
 
This change was made to add details for the 
Sponsor’s Authorized Representative. 
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Reason/Justification for change 
<Name, Degree, Company, Function, Phone, Fax, 
Cell, Email>
 
 
 
 
Tel: 
 
 
 
 
 
 
Tel: 
 
 
This change was made to add details for the 
Legal Representative of the Sponsor in the 
European Union. 
<Name, Degree, Company, Function, Phone, Fax, 
Cell, Email>
 
  
Teva Branded Pharmaceutical Products R&D, Inc. 
Tel: 
 
Cell: 
 
 
 
  
Teva Branded Pharmaceutical Products R&D, Inc. 
Tel: 
 
Cell: 
 
 
This change was made to add details for the 
Sponsor’s Medical Expert. 
<Name, Degree, Company, Function, Phone, Fax, 
Cell, Email>
 
 
 
 
 
 
 
Tel: 
 
 
 
 
 
 
 
 
Tel: 
 
 
This change was made to add details for the 
Coordinating Investigator. 
<Name, Degree, Company, Function, Phone, Fax, 
Cell, Email>
 
 
Teva Pharmaceutical Industries Ltd. 
Tel: 
 
Cell: 
 
 
 
 
Teva Pharmaceutical Industries Ltd. 
Tel: 
 
Cell: 
 
 
This change was made to add details for the 
Sponsor’s Representative of Global Patient 
Safety and Pharmacovigilance. 
<Name of Company>ICON 
ICON plc 
South County Business Park 
Leopardstown, Dublin 18, Ireland 
This change was made to add the name and 
contact information of the Contract Research 
Organization. 
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Reason/Justification for change 
<Name of Company>Icon Laboratories 
123 Smith Street 
Farmingdale, NY 11735 
United States 
Icon Laboratories 
South County Business Park 
Leopardstown, Dublin 18, Ireland 
Icon Laboratories 
123 Smith Street 
Farmingdale, NY 11735 
United States 
Icon Laboratories 
South County Business Park 
Leopardstown, Dublin 18, Ireland 
This change was made to add the name and 
contact information of the Central Clinical 
Laboratories. 
<Name of Company> eResearch Technology, Inc 
1818 Market Street #1000 
Philadelphia, PA 19103 
United States 
eResearch Technology, Inc 
1818 Market Street #1000 
Philadelphia, PA 19103 
United States 
This change was made to add the name and 
contact information of the Central 
Electrocardiogram Evaluation site. 
<Name of Company> PAREXEL International 
Corp. 
195 West Street 
Waltham, MA 02451 
Tel: 
 
PAREXEL International Corp. 
195 West Street 
Waltham, MA 02451 
Tel:
 
This change was made to add the name and 
contact information of the Randomization 
and Trial Supply Management (RTSM) 
vendor. 
TOTAL BLOOD VOLUME 
Appendix I (Other sections affected by this change: Section 5.10) 
(Not applicable) 
Virology (hepatitis, HIV, Lyme disease, and 
tuberculosis) 
Added virology testing to Total Blood 
Volume table in order to align with exclusion 
criterion e: The patient has an ongoing 
infection, known history of HIV infection, 
tuberculosis, Lyme disease, or hepatitis. 
(Not applicable) 
Virology (hepatitis, HIV, Lyme 
disease, and tuberculosis) 
18 
1 
18 
Total blood draws were adjusted to reflect the 
addition of virology testing.  
Clinical laboratory 
(serum chemistry, 
including β-HCG 
test, hematology, 
coagulation) 
7.5 10 
3 
22.5 30 
Clinical laboratory (serum 
chemistry, including β-HCG test, 
hematology, coagulation) 
10 
3 
30 
Blood draw volumes were adjusted to include 
β-HCG testing. 
Total 
 
 
44.5 5566 
Total 
 
 
66 
Total blood draws were updated to reflect the 
new total based on blood draw adjustments.  
 
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Changes to the Protocol 
Table 1 (Study Procedures and Assessments) has been revised to reflect the changes described below. 
Original text with changes shown 
New wording 
Reason/Justification for change 
TITLE PAGE (Other sections affected by this change: Investigator Agreement, Coordinating Investigator Agreement) 
EudraCT number: <TBD>2019-002055-42 
EudraCT number: 2019-002055-42 
This change was made to provide the 
EudraCT number. 
Teva Branded Pharmaceutical Products R&D, Inc. 
145 Brandywine Parkway 
West Chester, PA 19380 
41 Moores Road 
Frazer, Pennsylvania 19355 
United States of America 
Teva Branded Pharmaceutical Products R&D, Inc. 
41 Moores Road 
Frazer, Pennsylvania 19355 
United States of America 
This change was made to update the 
addresses for the Sponsor. 
SELECTION AND WITHDRAWAL OF PATIENTS 
Section 4.1  
i. 
The patient/caregiver has demonstrated 
compliance with the electronic headache diary 
during the 28-day baseline period by entry of 
headache data on a minimum of 2421 out of 28 days 
(approximately 8575% diary compliance). 
i. 
The patient/caregiver has demonstrated 
compliance with the electronic headache diary during 
the 28-day baseline period by entry of headache data 
on a minimum of 21 out of 28 days (approximately 
75% diary compliance). 
This change was made to harmonize the 
required diary compliance during the baseline 
and treatment periods across the 3 Phase 3 
pediatric protocols. The change will not 
impact data quality or accuracy.  
(Not applicable) 
n. The patient has received all recommended age-
appropriate vaccines according to local standard of 
care and schedule. 
This inclusion criterion was added to protect 
study participants from preventable 
childhood illnesses in accordance with 
current medical recommendations for 
pediatric patients and to help prevent the 
spread of communicable infections to others 
at the investigational site. 
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Original text with changes shown 
New wording 
Reason/Justification for change 
Section 4.2 
(Not applicable) 
b. The patient has used an intervention/device (eg, 
scheduled nerve block or transcranial magnetic 
stimulation) for the treatment of migraine during the 
2 months prior to the day of the screening visit. 
This exclusion criterion was added to 
decrease the chances that previous 
nonpharmacologic treatments would 
confound the assessment of safety and 
efficacy of fremanezumab. 
(Not applicable) 
s. 
The patient received a live attenuated vaccine 
within the 12-week period prior to screening or plans 
to receive a live attenuated vaccine at any time during 
the study and for 6 months after the last dose of IMP. 
This exclusion criterion was added to avoid 
an immune response elicited by 
administration of a live attenuated vaccine 
that could interfere with the accurate 
assessment of efficacy and safety of 
fremanezumab. 
ASSESSMENT OF SAFETY 
Section 7.8  
Injection site assessments will be performed 
immediately and 1 hour after administration of each 
dose of study drug, d before patients leave the 
investigational site. 
Injection site assessments will be performed after 
administration of each dose of study drug and before 
patients leave the investigational site. 
This change was made to clarify the 
procedure for assessment of local tolerability 
and pain. 
CLINICAL LABORATORY AND OTHER DEPARTMENTS AND INSTITUTIONS 
Appendix A 
<Name, Degree, Company, Function, Phone, Fax, 
Cell, Email>
  
 
 
Teva Branded Pharmaceutical Products R&D, Inc. 
Tel: 
 
Cell: 
 
 
 
 
 
Teva Branded Pharmaceutical Products R&D, Inc. 
Tel: 
 
Cell: 
 
 
This change was made to add details for the 
Sponsor’s Authorized Representative. 
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Original text with changes shown 
New wording 
Reason/Justification for change 
<Name, Degree, Company, Function, Phone, Fax, 
Cell, Email>
 
 
 
 
Tel: 
 
 
 
 
 
 
Tel: 
 
 
This change was made to add details for the 
Legal Representative of the Sponsor in the 
European Union. 
<Name, Degree, Company, Function, Phone, Fax, 
Cell, Email>
 
  
Teva Branded Pharmaceutical Products R&D, Inc. 
Tel: 
 
Cell: 
 
 
 
  
Teva Branded Pharmaceutical Products R&D, Inc. 
Tel: 
 
Cell: 
 
 
This change was made to add details for the 
Sponsor’s Medical Expert. 
<Name, Degree, Company, Function, Phone, Fax, 
Cell, Email>
 
 
 
 
 
 
 
Tel: 
 
 
 
 
 
 
 
 
Tel: 
 
 
This change was made to add details for the 
Coordinating Investigator. 
<Name, Degree, Company, Function, Phone, Fax, 
Cell, Email>
 
 
Teva Pharmaceutical Industries Ltd. 
Tel: 
 
Cell: 
 
 
 
 
Teva Pharmaceutical Industries Ltd. 
Tel: 
 
Cell: 
 
 
This change was made to add details for the 
Sponsor’s Representative of Global Patient 
Safety and Pharmacovigilance. 
<Name of Company>ICON 
ICON plc 
South County Business Park 
Leopardstown, Dublin 18, Ireland 
This change was made to add the name and 
contact information of the Contract Research 
Organization. 
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Original text with changes shown 
New wording 
Reason/Justification for change 
<Name of Company>Icon Laboratories 
123 Smith Street 
Farmingdale, NY 11735 
United States 
Icon Laboratories 
South County Business Park 
Leopardstown, Dublin 18, Ireland 
Icon Laboratories 
123 Smith Street 
Farmingdale, NY 11735 
United States 
Icon Laboratories 
South County Business Park 
Leopardstown, Dublin 18, Ireland 
This change was made to add the name and 
contact information of the Central Clinical 
Laboratories. 
<Name of Company> eResearch Technology, Inc 
1818 Market Street #1000 
Philadelphia, PA 19103 
United States 
eResearch Technology, Inc 
1818 Market Street #1000 
Philadelphia, PA 19103 
United States 
This change was made to add the name and 
contact information of the Central 
Electrocardiogram Evaluation site. 
<Name of Company> PAREXEL International 
Corp. 
195 West Street 
Waltham, MA 02451 
Tel: 
 
PAREXEL International Corp. 
195 West Street 
Waltham, MA 02451 
Tel: 
 
This change was made to add the name and 
contact information of the Randomization 
and Trial Supply Management (RTSM) 
vendor. 
TOTAL BLOOD VOLUME 
Appendix I (Other sections affected by this change: Section 5.10) 
(Not applicable) 
Virology (hepatitis, HIV, Lyme disease, and 
tuberculosis) 
Added virology testing to Total Blood 
Volume table in order to align with exclusion 
criterion e: The patient has an ongoing 
infection, known history of HIV infection, 
tuberculosis, Lyme disease, or hepatitis. 
(Not applicable) 
Virology (hepatitis, HIV, Lyme 
disease, and tuberculosis) 
18 
1 
18 
Total blood draws were adjusted to reflect the 
addition of virology testing.  
Clinical laboratory 
(serum chemistry, 
including β-HCG 
test, hematology, 
coagulation) 
7.5 10 
3 
22.5 30 
Clinical laboratory (serum 
chemistry, including β-HCG test, 
hematology, coagulation) 
10 
3 
30 
Blood draw volumes were adjusted to include 
β-HCG testing. 
Total 
 
 
44.5 5566 
Total 
 
 
66 
Total blood draws were updated to reflect the 
new total based on blood draw adjustments.  
 
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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: 
 
 
Legal Representative of the Sponsor in the 
European Union (EU) and Contact Person 
 
 
 
 
Tel: 
 
 
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: 
 
 
Coordinating Investigator 
 
 
 
 
 
 
Tel: 
 
 
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 
ICON plc 
South County Business Park 
Leopardstown, Dublin 18 
Ireland 
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Central Clinical Laboratory 
Icon Laboratories 
123 Smith Street 
Farmingdale, NY 11735 
United States 
Icon Laboratories 
South County Business Park 
Leopardstown, Dublin 18 
Ireland 
Central Electrocardiogram Evaluation 
Clario 
1818 Market Street #1000 
Philadelphia, PA 19103 
United States 
Bioanalytical Pharmacokinetics Evaluation 
Specialty Bioanalytics 
Teva Branded Pharmaceutical Products R&D, Inc. 
610 Brandywine Parkway 
West Chester, PA, 19380  
United States 
Bioanalytical Immunogenicity Evaluation 
Specialty Bioanalytics 
Teva Branded Pharmaceutical Products R&D, Inc. 
610 Brandywine Parkway 
West Chester, PA, 19380  
United States 
Pharmacogenomics/Biomarker Evaluation 
Not Applicable 
Randomization and Trial Supply Management 
(RTSM) vendor 
Calyx  -  Perceptive eClinical Limited 
Castle Wharf, 4 Canal Street, Nottingham 
United Kingdom NG1 7EH 
Tel:
 
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APPENDIX B. STUDY PROCEDURES AND ASSESSMENTS BY VISIT  
1. Procedures for Screening (Visit 1, Days -28 to -1) 
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 from parent(s) or legal guardian(s) and assent 
(according to local regulations) from each patient before any study-related procedures 
are performed 
• inform patients of study restrictions and compliance requirements 
• review medical and psychiatric history 
• review headache history 
• review lifetime prior medication and treatment history 
• review demographic characteristics 
• review inclusion and exclusion criteria 
• full physical examination (including height, weight, and body mass index) 
• triplicate 12-lead electrocardiogram (ECG) 
• vital signs measurements 
• review adverse events 
• review concomitant medications 
• clinical laboratory tests 
• serum beta-human chorionic gonadotropin (β-HCG) and urine pregnancy tests (only 
female patients who are postmenarchal or ≥12 years of age); inquire and record 
start/stop date of menstrual period 
• provide electronic headache diary device and instructions 
• administer Columbia-Suicide Severity Rating Scale (C-SSRS) 
2. Visit 2 (Day 1+3 days) 
Patients who meet the inclusion and exclusion criteria at visit 1 will continue to visit 2. The 
following procedures will be performed at visit 2: 
• review inclusion and exclusion criteria 
• full physical examination (including height, weight, and body mass index) 
• assessment of puberty status (Tanner staging scale) by patient’s self-report or by 
physical examination 
• assign randomization number and enter into case report form (CRF) 
• triplicate 12-lead ECG 
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• vital signs measurements 
• review adverse events 
• review concomitant medications 
• urine β-HCG pregnancy test (only female patients who are postmenarchal or 
≥12 years of age); inquire and record start/stop date of menstrual period 
• review electronic headache diary 
• collect blood samples for plasma drug concentration and serum antidrug antibodies 
(ADA) prior to dosing 
• administer C-SSRS 
• administer Pediatric Migraine Disability Assessment (PedMIDAS) questionnaire 
• administer Pediatric Quality of Life Inventory (PedsQL) 
• administer study drug 
• assess injection site 
3. Visits 3 and 4 (Day 29 [±3 days] and Day 57 [±3 days]) 
The following procedures will be performed at visits 3 and 4: 
• triplicate 12-lead ECG 
• vital signs measurements 
• review adverse events 
• review concomitant medications 
• clinical laboratory tests - visit 3 only 
• collect blood samples for plasma drug concentration and serum ADA prior to dosing 
- visit 3 only 
• urine β-HCG pregnancy test (only female patients who are postmenarchal or 
≥12 years of age); inquire and record start/stop date of menstrual period 
• review electronic headache diary 
• administer C-SSRS 
• administer PedsQL 
• administer study drug 
• assess injection site 
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4. End of Treatment/Early Withdrawal (Visit 5 [Day 85±3 days]) 
The following procedures and assessments will be performed at visit 5 (End of Treatment or 
early withdrawal): 
• full physical examination (including height and weight) 
• assessment of puberty status (Tanner staging scale) by patient’s self-report or by 
physical examination 
• triplicate 12-lead ECG 
• vital signs measurements 
• review adverse events 
• review concomitant medications 
• clinical laboratory tests 
• serum β-HCG and urine pregnancy tests (only female patients who are postmenarchal 
or ≥12 years of age); inquire and record start/stop date of menstrual period  
• review electronic headache diary 
• return electronic headache diary device 
• collect blood samples for plasma drug concentration and serum ADA prior to dosing 
• administer C-SSRS 
• administer PedMIDAS questionnaire 
• administer PedsQL 
• administer Patient Global Impression of Improvement questionnaire 
5. Unscheduled Visits 
An unscheduled procedure or visit may be performed at any time during the study at the 
subject’s request or as deemed necessary by the investigator.  
Unscheduled procedures may include the following: 
• concomitant medication review 
• vital signs measurements 
• inquire and record start/stop date of menstrual period 
• adverse event inquiry 
• study compliance review 
Other procedures may be performed at the discretion of the investigator, who may consult 
with the sponsor. 
In the case that a patient is not able to go to the investigational center or the investigational 
center staff are not able to see patients at the investigational center, certain 
assessments/procedures, as detailed in Table 1, may be performed remotely. 
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APPENDIX C. PREVENTIVE MIGRAINE MEDICATIONS FOR ANY 
CONDITION ALLOWED FOR THE DURATION OF THE 
STUDY FOR APPROXIMATELY 30% OF PATIENTS  
The chronic use of 2 of the following concomitant medications is allowed in approximately 30% 
of EM patients and should be entered in electronic case report form (eCRF) pages specific for 
migraine preventive medication. Patients using no more than 2 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 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 approximately 70% of EM 
patients, the chronic use of these medications are not allowed for migraine or for any other 
indications. PRN use of the following medications are allowed during the course of the study for 
any indications and do not have to have established dosing regimens. 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 PRN use of acute medications to treat acute 
migraine attacks, as needed, with the exception of regular use of medications containing opioids 
and barbiturates. 
• Antidepressants: amitriptyline, nortriptyline, fluoxetine, desipramine, venlafaxine, 
duloxetine 
• Antiepileptics: topiramate, valproic acid, levetiracetam, zonisamide, gabapentin, 
pregabalin 
• Antihistamines: cyproheptadine, pizotifen  
• Beta blockers: propranolol, metoprolol, nadolol, timolol 
• Calcium-channel blockers: flunarizine, verapamil, nimodipine 
• Onabotulinumtoxin A or B 
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 doubtful evidence for migraine 
prevention and therefore are treated the same as other concomitant medications (ie, recorded as 
concomitant medications on the CRF) and DO NOT need to be captured in eCRF pages specific 
for migraine preventive medications. 
Adapted from: 
O’Brien HL, Kabbouche MA, Kacperski J, Hershey AD. Treatment of pediatric migraine. Curr 
Treat Options Neurol 2015;17(1):326. 
Lewis DW, Winner P. The pharmacological treatment options for pediatric migraine: an 
evidence-based appraisal. NeuroRx 2006;3(2):181-91. 
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APPENDIX D. CLINICAL CRITERIA FOR DIAGNOSING 
ANAPHYLAXIS  
Anaphylaxis is highly likely when any one of the following 3 criteria are fulfilled: 
a. Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (eg, generalized hives, pruritus or flushing, swollen 
lips-tongue-uvula) AND AT LEAST ONE OF THE FOLLOWING 
− Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced 
peak expiratory flow [PEF], hypoxemia) 
− Reduced blood pressure (BP) or associated symptoms of end-organ dysfunction 
(eg, hypotonia [collapse], syncope, incontinence) 
b. Two or more of the following that occur rapidly after exposure to a likely allergen for 
that subject (minutes to several hours): 
− Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, swollen 
lips-tongue-uvula) 
− Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced 
PEF, hypoxemia) 
− Reduced BP or associated symptoms (eg, hypotonia [collapse], syncope, 
incontinence) 
− Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting) 
c. Reduced BP after exposure to known allergen for that subject (minutes to several 
hours): 
− Infants and children: low systolic BP (age specific) or greater than 30% decrease 
in systolic BP 
Source: Modified from Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF, Jr., Bock 
SA, Branum A, et al. Second symposium on the definition and management of anaphylaxis: 
summary report-Second National Institute of Allergy and Infectious Disease/Food Allergy and 
Anaphylaxis Network symposium.[reprint in Ann Emerg Med 2006 Apr;47(4):373-80; 
PMID:16546624]. J Allergy Clin Immunol 2006 Feb;117(2):391-7. 
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APPENDIX E. 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/ 
Internal 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; use 
of prohibited medications. Important protocol deviations will be identified and recorded by 
investigational center personnel in the source documents and reported to regulatory authorities as 
applicable. All important protocol deviations will be reported to the responsible IEC/IRB, as 
required. 
When an important protocol deviation is reported, the investigator and 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 the 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. 
Information to Study Personnel 
The investigator is responsible for giving information about the study to all personnel members 
involved in the study or in any element of patient management, both before starting the study and 
during the course of the study (eg, when new personnel become involved). The investigator must 
ensure that all study personnel are qualified by education, experience, and training to perform 
their specific task. These study personnel members must be listed on the investigational center 
authorization form, which includes a clear description of each personnel member’s 
responsibilities. This list must be updated throughout the study, as necessary. 
The study monitor is responsible for explaining the protocol to all study personnel, including the 
investigator, and for ensuring they comply with the protocol. 
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Study Monitoring 
To ensure compliance with GCP guidelines, the study monitor or representative is responsible 
for ensuring that patients have signed the informed consent form and the study is conducted 
according to applicable standard operating procedure (SOPs), the protocol, and other written 
instructions and regulatory guidelines. 
The study monitor is the primary association between the sponsor and the investigator. The main 
responsibilities of the study monitor(s) are to visit the investigator before, during, and after the 
study to ensure adherence to the protocol, that all data are correctly and completely recorded and 
reported, and that informed consent is obtained and recorded for all patients before they 
participate in the study and when changes to the consent form are warranted, in accordance with 
IEC/IRB approvals. 
The study monitor(s) will contact the investigator and visit the investigational center according 
to the monitoring plan. The study monitor will be permitted to review and verify the various 
records (case report forms [CRFs] and other pertinent source data records, including specific 
electronic source document relating to the study) to verify adherence to the protocol and to 
ensure the completeness, consistency, and accuracy of the data being recorded. 
As part of the supervision of study progress, other sponsor personnel may, on request, 
accompany the study monitor on visits to the investigational center. The investigator and 
assisting personnel must agree to cooperate with the study monitor to resolve any problems, 
errors, or possible misunderstandings concerning the findings detected during the course of these 
monitoring visits or provided in follow-up written communication. 
Audit and Inspection 
The sponsor may audit the investigational center to evaluate study conduct and compliance with 
protocols, SOPs, GCP guidelines, and applicable regulatory requirements. The sponsor’s Global 
Clinical Quality Assurance, independent of Global Specialty Development, is responsible for 
determining the need for (and timing of) an investigational center audit. 
The investigator must accept that competent authorities and sponsor representatives may conduct 
inspections and audits to verify compliance with GCP guidelines. 
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APPENDIX F. ETHICS  
Informed Consent/Assent 
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), per local regulations. 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, or a qualified person designated by the investigator, should fully inform the 
patient and each parent/legally acceptable representative of all pertinent aspects of the study, 
including the written information approved by the IEC/IRB, per local regulations. All written 
and oral information about the study will be provided in a language as nontechnical as practical 
to be understood by each parent/legally acceptable representative and the patient. The patient and 
each parent/legally acceptable representative 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. 
A personally signed and dated ICF will be obtained from each parent/legally acceptable 
representative, and a signed and dated assent form will be obtained from each patient (if the 
patient is able) before any study-specific procedures or assessments are done and after the aims, 
methods, anticipated benefits, and potential hazards are explained; according to IEC/IRB 
requirements. The forms will be signed and dated also by the person who conducted the 
informed consent discussion. The investigator will keep the original informed consent and assent 
forms, and copies will be given to the patients (and each parent/legally acceptable 
representative). It will also be explained to the patients (and each parent/legally acceptable 
representative) that they are 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. 
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Personal medical information may be reviewed for the purpose of patient safety or for verifying 
data in the source and the CRF. This review may be conducted by the study monitor, properly 
authorized persons on behalf of the sponsor, Global Quality Assurance (GCA), or competent 
authorities. Personal medical information will always be treated as confidential. 
Registration of the Clinical Study 
In compliance with national and local regulations and in accordance with Teva standard 
procedures, this clinical study will be registered on trials registry websites. 
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APPENDIX G. BIRTH CONTROL METHODS AND PREGNANCY 
TESTING  
Females of childbearing potential are defined as the following: 
• not surgically (documented hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy) or congenitally sterile 
• postmenarchal or ≥12 years of age 
Females who are not of childbearing potential are defined as the following: 
• premenarchal and <12 years of age 
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 are considered. Such methods include the 
following: 
• Progestogen-only hormonal contraception (oral, injectable, and implantable) 
associated with inhibition of ovulation; these should be initiated at least 1 month 
before the first dose of IMP 
• Progestin and estrogen contraceptives (oral only) associated with inhibition of 
ovulation; these should be initiated at least 1 month before the first dose of IMP 
• Intrauterine device and intrauterine hormone-releasing system need to be in place at 
least 2 months before screening 
• Bilateral tubal occlusion 
• Vasectomized partner, provided that he is the sole sexual partner and has received 
medical assessment of the surgical process 
• Sexual abstinence is only considered a highly effective method if defined as 
refraining from heterosexual intercourse in the defined period. The reliability of 
sexual abstinence needs to be evaluated in relation to the duration of the clinical study 
and the preferred and usual lifestyle of the patient. 
Unacceptable birth control methods: 
Periodic abstinence (calendar, symptothermal, and post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and lactational amenorrhea method are not acceptable methods of 
contraception. Female condom and male condom should not be used together. 
Male contraception 
Male patients who are sexually active with female partners must always use a condom for the 
duration of the study and for 6 months after the last administration of IMP. 
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APPENDIX H. LOST TO FOLLOW-UP  
A patient will be considered lost to follow-up if he/she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the investigational center. 
The following actions must be taken if a patient fails to return to the investigational center for a 
required study visit: 
• The investigational center must attempt to contact the patient and reschedule the 
missed visit as soon as possible and counsel the patient on the importance of 
maintaining the assigned visit schedule and ascertain whether or not the patient 
wishes to and/or should continue in the study. 
• In cases in which the patient is deemed lost to follow-up, the investigator or designee 
must make every effort to regain contact with the patient (where possible, 3 telephone 
calls and, if necessary, a certified letter to the patient’s last known mailing address or 
local equivalent methods). These contact attempts should be documented in the 
patient’s medical record and transcribed to the electronic case report forms. 
• 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 I. GUIDANCE ON SAFETY MONITORING  
Guidance on Monitoring Patients with Elevated Liver Function Tests 
Liver enzymes (alanine aminotransferase [ALT], aspartate aminotransferase [AST], gamma 
glutamyl transpeptidase [GGT], and alkaline phosphatase [ALP]) as well as total bilirubin1 will 
be measured at each study visits 1, 3, and 5. 
In any case of elevated ALT or AST to a level exceeding ≥2× the upper limit of normal (ULN) 
(including patients whose baseline ALT or AST levels are ≥2× and ≤3× the ULN, who may be 
enrolled in the study), a thorough medical history and physical examination with a focus on liver 
disease should be undertaken.2 In addition, the patient should be instructed to refrain from 
alcoholic beverages. 
In case of symptoms compatible with drug-induced liver injury during the study, patients will be 
instructed to return to the study center for an unscheduled visit or to go to the emergency room to 
measure liver enzymes as soon as possible. Solitary elevations of total bilirubin, not 
accompanied by elevations of ALT or AST should be managed according to the discretion of the 
treating physician. 
Elevation of Either ALT or AST to ≥3× ULN 
Confirmation is required prior to study drug discontinuation in cases of elevation of either ALT 
or AST ≥3× ULN (Note: In cases of elevation of ALT or AST ≥8× the ULN, no confirmation is 
required prior to study drug discontinuation, but the assessments below should be performed). 
The following procedures should be followed: 
• The day in which the abnormal value is received from the laboratory will be 
considered as day 0.  
• The investigator should repeat the test for confirmation purposes (this may be 
performed in a local laboratory along with complete blood count [CBC] and 
differential to assess for eosinophilia. In general, in case a blood sample is sent to a 
local laboratory, the following assessments [and reference ranges] are mandatory: 
ALT [serum glutamic pyruvic transaminase], AST [serum glutamic oxaloacetic 
transaminase], ALP, total bilirubin, CBC [with differential for eosinophil count, 
separate tube], and International Normalized Ratio [INR] [separate tube; not to be 
sent in a confirmatory test]). The investigator should also question the patient 
regarding symptoms. 
 
 
1 In case total bilirubin is >ULN, then direct bilirubin will be checked. 
2 Thorough medical history with a focus on liver disease: personal or family history of liver disease; personal history 
of a systemic disease with potential liver involvement; exposure to alcohol, medications (prescription or over the 
counter), herbal preparations, dietary supplements, recreational drugs, special diets, or environmental chemical 
agents; potential exposure to infectious agents (eg, travel to developing countries, history of potential exposure to 
blood or blood products, high-risk sexual relations); and any additional information deemed relevant by the 
investigator. Physical examination, including signs of chronic liver disease. 
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The abnormality will be regarded as confirmed in each of the following scenarios: 
• the baseline value was within the normal range and ALT or AST is still ≥3× the ULN 
• the baseline value was above the ULN and ALT or AST is ≥2× the baseline value 
Additional Tests/Evaluations 
Upon confirmation of the abnormality as noted above, the following additional evaluations 
should be performed and results should be recorded in the CRF: 
• serology for hepatitis A (antibody and immunoglobulins M and G), B (core antibody 
total, core immunoglobulin M, and surface antigen), and C viruses (central 
laboratory) 
• serology for autoimmune hepatitis: anti-nuclear antibodies (titer), anti-smooth muscle 
antibodies, and anti-liver kidney microsomal antibodies (central laboratory); further 
testing may be required in case of a positive result for hepatitis B or C 
• ultrasound examination of the liver and biliary tract at the investigator’s discretion 
• other diagnostic tests/consultations as deemed necessary by the investigator (eg, 
serology for hepatitis E virus in case of travel to endemic geography) 
• observation and follow-up (to be performed after the abnormality was confirmed as 
above) 
ALT or AST ≥3× (>3.5× the ULN if the Baseline Value Is >2.5× the ULN) but Less Than 5× 
the ULN 
• In addition to the above procedures required for any elevation to levels >3× the ULN: 
• ALT, AST, GGT, ALP, total and direct bilirubin, CBC and differential (to assess for 
eosinophilia), and INR should be monitored on days 5 (±2 days), 8 (±2 days), 14 (±3 
days), and 28 (±3 days). On at least 1 of these days, the test should be performed 
centrally. (The INR should be sent to a local laboratory only.) 
• In cases where a local laboratory is used, the results should be recorded in the case 
report form, accompanied by the reference range of the relevant measurements. 
• Should the abnormality (≥3× the ULN in case baseline was within the normal range 
or ≥2× the ULN in case the baseline value was above ULN but still <5× the ULN) 
persist further, the patient will be followed according to the investigator’s discretion, 
but a blood sample for ALT, AST, GGT, ALP, and total and direct bilirubin should 
be sent to the central laboratory at least once a month. 
ALT or AST ≥5× but Less Than 8× the ULN 
In addition to the above procedures required for any elevation to levels >3× the ULN: 
• ALT, AST, GGT, ALP, total and direct bilirubin, CBC and differential count (to 
assess for eosinophilia), and INR should be monitored twice a week. 
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• At least for every other measurement, the tests should be sent to the central 
laboratory. The rest of the tests may be sent to a local laboratory. The INR should 
always be sent to a local laboratory. 
ALT or AST ≥8× the ULN 
In addition to the above procedures required for any elevation to levels >3× the ULN: 
• The study drug should be discontinued immediately, and the early withdrawal visit 
should be performed. 
• For follow-up guidance, please see below section “Follow-Up of Liver Enzymes 
After Stopping Rules Are Met.” 
Stopping Rules 
In the following circumstances, the study drug will be discontinued immediately: 
• any increase in ALT or AST to ≥3× the ULN, combined with INR >1.5× the ULN or 
total bilirubin >2× the ULN 
• any increase in ALT or AST to ≥3× the ULN, which is accompanied by symptoms 
clearly associated with impaired liver function (eg, vomiting, nausea, fever, rash, 
eosinophilia) and not deemed related to other diseases (eg, vomiting or nausea 
triggered by migraine) 
• any increase in ALT or AST to levels ≥5 but <8× the ULN, which is persistent for ≥2 
weeks of repeated measurements 
• any increase in ALT or AST to levels ≥8× the ULN 
• in any case where monitoring of liver enzymes cannot be performed according to the 
protocol guidance 
Follow-Up of Liver Enzymes After Stopping Rules Are Met 
• A patient who meets the above criteria for discontinuation of the study drug should be 
invited to the site to return the study drug. Early withdrawal visit activities should be 
performed as soon as possible. 
• Liver enzymes should be monitored until normalization or stabilization of the 
abnormality, according to the discretion of the investigator. 
• In any case, following the early withdrawal visit, the minimal follow-up period will 
be 30 days and will include measurement of liver enzymes at least once weekly (may 
be performed in local laboratory, with at least 1 test being sent to the central 
laboratory). 
• Every effort should be made to complete the additional tests/evaluations, as described 
above. 
• Every effort should be made to ensure that the patient continues to receive ongoing 
evaluation and treatment by their primary care physician after withdrawal from the 
study. 
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APPENDIX J. TOTAL BLOOD VOLUME  
Total blood volume to be collected for each patient in this study is approximately 48 mL. 
Total Blood Volumes 
Type of samples 
Volume per sample (mL) 
Total number of samples 
Total volume (mL) 
Clinical laboratory 
(serum chemistry, 
including β-HCG test, 
hematology, 
coagulation) 
10 
3 
30 
Pharmacokinetics 
2 
3 
6 
ADA 
4 
3 
12 
Total 
 
 
48 
ADA=antidrug antibody; β-HCG=beta-human chorionic gonadotropin. 
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APPENDIX K. PRODUCT COMPLAINTS  
Clinical Product Complaints/Device Deficieny 
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: 
• suspected contamination 
• questionable stability (eg, color change, flaking, crumbling, etc) 
• defective components 
• missing or extra units (eg, primary container is received at the investigational center 
with more or less than the designated number of units inside) 
• incorrect packaging, or incorrect or missing labeling/labels 
• unexpected or unanticipated taste or odor, or both 
• device not working correctly or appears defective in some manner 
Each investigational center will be responsible for reporting a possible clinical product complaint 
by completing the product complaint form provided by Teva and emailing it to 
clinical.productcomplaints@tevapharm.com within 48 hours of becoming aware of the issue. 
For complaints involving a device/combination product or other retrievable item, it is required 
that the device/combination product (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. 
Product Complaint Information Needed from the Investigational Center 
In the event that the product complaint form cannot be completed, the investigator will provide 
the following information, as available: 
• investigational center number and principal investigator name 
• name, phone number, and address of the source of the complaint 
• clinical protocol number 
• patient identifier (patient study number) and corresponding visit numbers, if 
applicable 
• product name and strength for open-label studies 
• patient number, bottle, and kit numbers (if applicable) for double-blind or open-label 
studies 
• product available for return Yes/No 
• product was taken or used according to protocol Yes/No 
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• description or nature of complaint 
• associated serious adverse event Yes/No 
• clinical supplies unblinded (for blinded studies) Yes/No 
• date and name of person receiving the complaint 
Note: Reporting a product complaint must not be delayed even if not all the required information 
can be obtained immediately. Known information must be reported immediately. The sponsor 
will collaborate with the investigator to obtain any outstanding information. 
*Please refer to Appendix Table 1 and Appendix Table 2.  
Handling of Investigational Medicinal Product(s)/Devices 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 (and/or PFS). 
If it is determined that the investigational center must return all IMP (and/or PFS), 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. 
Adverse Events or Serious Adverse Events Associated with a Product Complaint 
If there is an adverse event or serious adverse event due to product complaint, the protocol 
should be followed for recording and reporting (Section 7.1.2 and Section 7.1.7.4, respectively). 
Documenting a Product Complaint 
The investigator will record in the source documentation a description of the product complaint, 
the initial determination whether the deficiency could have led to a serious adverse event (see 
below: Assessment of Device Performance), 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. 
Assessment of Device Performance 
A device deficiency is defined as any inadequacy of an investigational medical device or 
combination product with respect to its identity, quality, durability, reliability, usability, safety, 
or performance (Appendix Figure 1). This definition includes malfunctions, use errors, 
inadequate labeling (eg, unintelligible label, incorrect expiry date), and product complaints that 
are related to the IMP. 
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The investigator should use Appendix Table 1 and Appendix Table 2 to help make an initial 
determination whether the device deficiency could have led to a serious adverse event and 
include this assessment in the product complaint form. 
Device deficiencies with potential serious adverse device effect are defined as deficiencies that 
might have led to a serious adverse device effect if (Appendix Figure 1): 
• suitable action had not been taken (or) 
• intervention had not been made (or) 
• if circumstances had been less fortunate 
These device deficiencies shall be reported to the IEC/IRB by the investigator and to the 
regulatory authorities by the sponsor according to the national and local regulations. 
Appendix Figure 1: Decision Tree for Device Deficiencies 
 
IEC=Independent Ethics Committee; IRB=Institutional Review Board; SAE=serious adverse event. 
Appendix Table 1: Potential Use-Related Deficiencies That Could Lead to Serious Adverse 
Events 
Use step 
Use error 
Potential hazard 
situation 
Potential harm 
Obtain sharps 
container and 
dispose of the 
device 
Syringe not disposed of correctly after use 
Needle stick third 
party 
Third party death 
Check that IMP 
name appears on 
device 
Failure to check IMP information. 
Incorrect 
medicament 
injected 
Patient death 
Store carton 
within the 
refrigerator 
Fail to store product correctly 
Patient exposed to 
toxic substance due 
to degraded drug 
Permanent 
impairment or life 
threatening injury 
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Use step 
Use error 
Potential hazard 
situation 
Potential harm 
Inspect the device 
Fail to perceive or recognize a need to visually 
inspect the device; Incorrect mental model of 
what would be considered to constitute 
'damage'; Expiration date check not completed; 
Misread the expiration date; etc. 
Inject degraded or 
expired IMP 
Toxicity – 
Permanent 
impairment or life 
threatening injury 
IMP=investigational new drug. 
Appendix Table 2: Potential Design Related Deficiencies That Could Lead to Serious 
Adverse Events 
Device component 
Failure mode 
Potential hazard situation 
Potential harm 
PFS components 
(Barrel-needle, RNS, 
plunger rod,  
backstop, syringe 
label) 
PFS components are not 
biocompatible 
User is exposed to an 
irritant, a toxic substance 
and/or a sensitizer 
Toxicity - Permanent 
impairment or life 
threatening injury 
PFS components 
(Barrel-needle, RNS, 
plunger rod,  
backstop, syringe 
label) 
PFS components are not 
compatible with drug 
User injects degraded drug. 
Patient exposed to a toxic 
substance 
Toxicity - Permanent 
impairment or life 
threatening injury 
RNS and syringe 
barrel with needle 
RNS is smaller than needle 
leaving needle exposed 
Needle sterility 
compromised. Drug is 
contaminated 
Infection – Permanent 
impairment or life 
threatening injury 
RNS and syringe 
barrel with needle 
Too much radial clearance 
between needle and inside of 
RNS. RNS comes off easily. 
Needle sterility 
compromised. Drug is 
contaminated. 
Infection – Permanent 
impairment or life 
threatening injury 
Syringe barrel 
Barrel view is occluded 
User is exposed to toxic 
substance 
Toxicity - Permanent 
impairment or life 
threatening injury 
Syringe label 
Label is illegible 
User is exposed to toxic 
substance 
Toxicity - Permanent 
impairment or life 
threatening injury 
Syringe label 
Misinformation or label is 
incorrect. 
User is exposed to toxic 
substance or degraded drug 
Permanent impairment 
or life threatening injury 
Product IFU 
Misinformation or missing 
information. IFU is incorrect 
or incomplete. 
User is exposed to toxic 
substance or degraded drug 
Permanent impairment 
or life threatening injury 
IFU=instructions for use; PFS=pre-filled syringe; RNS=rigid needle shield. 
 
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APPENDIX L. DATA MANAGEMENT AND RECORD KEEPING  
Direct Access to Source Data and Documents 
All patient data must have supportive original source documentation in the medical records, or 
equivalent, before they are transcribed to the case report form (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.  
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, videotapes) for source data verification, provided that patient confidentiality is 
maintained in accordance with national and local requirements. 
The investigator must maintain the original records (ie, source documents) of each patient’s data 
at all times. The investigator must maintain a confidential patient identification list that allows 
the unambiguous identification of each patient. 
Data Collection 
Data will be collected using CRFs that are specifically designed for this study. The data collected 
on the CRFs will be captured in a clinical data management system (CDMS) that meets the 
technical requirements described in 21CFR Part 11 (USA) and documents of other concerned 
competent authorities. Before using the CDMS, it will be fully validated and all users will 
receive training on the system and study-specific training. After they are trained, users will be 
provided with individual system access rights. 
Data will be collected at the investigational center by appropriately designated and trained 
personnel, and CRFs must be completed for each patient who provided informed consent. Patient 
identity should not be discernible from the data provided on the CRF. 
If data are processed from other sources (eg, central laboratory, bioanalytical laboratory, central 
image center, electronic diary data, electronic patient-reported outcome [ePRO] tablet), these 
data will be sent to the investigational center, where they will be retained but not transcribed to 
the CRF, unless otherwise noted in the protocol. All patient data must have supportive original 
source documentation in the medical records, or equivalent, before they are transcribed to the 
CRF. Data may not be recorded directly on the CRF and considered as source data unless the 
sponsor provides written instructions specifying which data are permitted to be recorded directly 
to the CRF. 
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 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. 
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 
• CRFs 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 
• copies of all correspondence with sponsor, the IEC/IRB, and any competent authority 
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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 M. 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 (ICMJE 2014): 
• 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 N. STORAGE AND DESTRUCTION OF BIOLOGICAL 
SAMPLES  
Safety Samples 
Safety samples will be stored for a short period of time in the central laboratory until analysis 
and destruction. Specific details regarding central laboratory storage and destruction can be 
found in the study Laboratory Manual and the central laboratory's standard operating procedures 
(SOPs). 
Pharmacokinetic and Immunogenicity Samples 
Pharmacokinetic and immunogenicity samples will be stored at the sites at a temperature 
of -70°C ±20°C (or at/below -20°C if no -70°C freezer is available) in an upright position until 
they are shipped to the central laboratory. 
Samples will be stored at -70°C at the central laboratory, until shipped to the sponsor or designee 
for analysis, as described in the study Laboratory Manual. 
After analysis, the sponsor will store the residue (leftovers) from the pharmacokinetic and 
immunogenicity samples at -70°C at the designated bioanalytical archive facility for up to 
5 years after the study results are submitted to the regulatory authorities. Destruction will take 
place at the sponsor's bioanalytical laboratory or designee, according to the applicable SOPs. 
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