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 Chronic 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 
Chronic Migraine in Pediatric Patients 6 to 17 Years of Age 
 
 
Study Number TV48125-CNS-30082 
 
 
NCT04464707 
 
 
Protocol with Amendment 09 Approval Date: 24 September 2023 

Clinical Trial Protocol with Amendment 09 
Trial TV48125-CNS-30082 
1 
 
  
Clinical Trial Protocol with Amendment 09  
 
Trial Number TV48125-CNS-30082 
 
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 Chronic Migraine in 
Pediatric Patients 6 to 17 Years of Age 
 
Randomized, Double-Blind, Placebo-Controlled Trial of Fremanezumab in Participants (6 
to 17 Years) with Chronic Migraine 
A Trial to Test if Fremanezumab is Effective in Preventing Chronic Migraine in 
Participants 6 to 17 Years of Age 
 
Efficacy, Safety, and Tolerability Trial (Phase 3) 
 
IND number: 106,533; NDA number: not applicable;  BLA number: 761089; EudraCT 
number: 2019-002053-33; EU CT number: not applicable 
 
EMA Decision Number of Pediatric Investigation Plan: P/0378/2023 
Article 45 or 46 of 1901/2006 applies 
 
EudraVigilance Code for the IMP: SUB181665 
EudraVigilance Code for the Drug Substance: not applicable 
 
Version Date: 24 September 2023 
 
Sponsor 
Teva Branded Pharmaceutical 
Products R&D, Inc. 
145 Brandywine Parkway,  
West Chester, Pennsylvania 19380 
United States of America 
 
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Clinical Trial Protocol with Amendment 09 
Trial TV48125-CNS-30082 
2 
Sponsor’s Authorized Representative 
 
 
Teva Pharmaceutical Industries Ltd. 
 
Name and contact information of the Medical Monitor are provided separately. 
 
This clinical trial will be conducted in accordance with current Good Clinical Practice (GCP) as directed 
by the provisions of the International Council for Harmonisation (ICH); United States (US) Code of 
Federal Regulations (CFR), and European Union (EU) Directives and Regulations (as applicable in the 
region of the trial); national country legislation; the protocol; 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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Clinical Trial Protocol with Amendment 09 
Trial TV48125-CNS-30082 
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INVESTIGATOR AGREEMENT  
Clinical Trial Protocol with Amendment 09 
Version Date: 24 September 2023 
TV48125-CNS-30082 
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 Chronic Migraine in 
Pediatric Patients 6 to 17 Years of Age 
IND number: 106,533; NDA number: not applicable; BLA number: 761089; EudraCT 
number: 2019-002053-33; EU CT number: not applicable 
EMA Decision number of Pediatric Investigation Plan: P/0378/2023 
Article 45 or 46 of 1901/2006 applies 
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 trial. I am qualified by education, experience, and training to conduct this clinical research trial. 
The signature below constitutes agreement with this protocol and attachments, and provides assurance 
that this trial 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 trial personnel reporting to me who 
participate in this trial and will discuss this material with them to ensure that they are fully informed 
regarding the IMP and the conduct of the trial. I agree to keep records on all participant information, IMP 
shipment and return forms, and all other information collected during the trial, in accordance with 
national and local Good Clinical Practice (GCP) regulations as well as all other national and international 
laws and regulations. 
Principal Investigator 
 
Signature 
Date 
Executed signature pages are maintained within the Investigator Site File and the Trial 
Master File 
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Trial TV48125-CNS-30082 
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SPONSOR PROTOCOL APPROVAL  
 
Clinical Trial Protocol with Amendment 09 
Version Date: 24 September 2023 
TV48125-CNS-30082 
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 Chronic Migraine in 
Pediatric Patients 6 to 17 Years of Age 
IND number: 106,533; NDA number: not applicable; BLA number: 761089; EudraCT 
number: 2019-002053-33; EU CT number: not applicable 
 
I have read the protocol with Amendment 09 and approve the design of this trial. 
Sponsor’s Authorized 
Representative 
 
 
Signature 
Date 
Executed signature pages are maintained within the Trial Master File 
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Clinical Trial Protocol with Amendment 09 
Trial TV48125-CNS-30082 
5 
COORDINATING INVESTIGATOR AGREEMENT  
Clinical Trial Protocol with Amendment 09 
Version Date: 24 September 2023 
TV48125-CNS-30082 
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 Chronic Migraine in 
Pediatric Patients 6 to 17 Years of Age 
IND number: 106,533; NDA number: not applicable; BLA number: 761089; EudraCT 
number: 2019-002053-33; EU CT number: not applicable 
EMA Decision number of Pediatric Investigation Plan: P/0378/2023 
Article 45 or 46 of 1901/2006 applies 
I have read the protocol with Amendment 09 and agree that it contains all necessary details for carrying 
out this trial. I am qualified by education, experience, and training to conduct this clinical research trial. 
The signature below constitutes agreement with this protocol and attachments, and provides assurance 
that this trial 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 trial personnel reporting to me who 
participate in this trial and will discuss this material with them to ensure that they are fully informed 
regarding the IMP and the conduct of the trial. I agree to keep records on participant information, IMPs 
shipment and return forms, and other information collected during the trial, in accordance with my 
responsibilities under the function of the Coordinating Investigator and in accordance with national and 
local Good Clinical Practice (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: 
 
Coordinating Investigator 
 
Signature 
Date 
Executed signature page is maintained within the Trial Master File. 
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Clinical Trial Protocol with Amendment 09 
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PROTOCOL AMENDMENT DETAILS  
A total of 8 prior amendments have occurred, as shown in the following table: 
Document History 
Administrative Letter 06 
21 December 2021 
Amendment 08 
09 December 2021 
34 participants randomized/enrolled 
Administrative Letter 05 
10 May 2021 
Administrative Letter 04 
04 February 2021 
Administrative Letter 03 
05 November 2020 
Amendment 07 
20 August 2020 
0 participants randomized/enrolled 
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 
Appendix E. Quality Control and Quality Assurance 
Appendix F. Ethics 
Amendment 06 
27 July 2020 
0 participants randomized/enrolled 
Amendment 05 
27 June 2020 
0 participants randomized/enrolled 
Administrative Letter 02 
07 July 2020 
Amendment 04 
20 April 2020 
0 participants randomized/enrolled 
Administrative Letter 01 
10 March 2020 
Amendment 03 
20 February 2020 
0 participants randomized/enrolled 
Amendment 02 
05 December 2019 
0 participants randomized/enrolled 
Amendment 01 
21 June 2019 
0 participants randomized/enrolled 
Original Protocol 
28 March 2019 
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Current Amendment 09 24 September 2023 
As of 18 September 2023, 180 participants have been randomized/enrolled. 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union.  
The Sponsor took the opportunity of the protocol amendment procedure to already align the 
protocol with the upcoming new Clinical Trial Regulation requirements. This involved updating 
the protocol to a new template. This update may have caused changes and/or relocations to 
specific texts and/or sections, compared to the previous version of the protocol (ie, Protocol 
Amendment 08). An overview of the various relevant sections are presented below.  
Section - Protocol Amendment 08  Section - Protocol Amendment 09 
Comment 
CLINICAL STUDY PROTOCOL 
SYNOPSIS 
1. PROTOCOL SUMMARY 
Alignment with new template 
1. INTRODUCTION AND 
BACKGROUND INFORMATION 
2. INTRODUCTION 
 
Alignment with new template 
 
2. STUDY OBJECTIVES AND 
ENDPOINTS 
3. TRIAL OBJECTIVES, 
ENDPOINTS, AND ESTIMANDS 
Alignment with new template 
3. STUDY DESIGN 
 
3.1. General Study Design and 
Study Schematic Diagram – 
Figure 1: Overall Study Design 
Schematic Diagram 
 
3.4 Stopping Rules for the Study 
 
3.5. Schedule of Study Procedures 
and Assessments 
4. TRIAL DESIGN 
 
Moved Figure 1: Overall Trial 
Schematic Diagram to Section 1.2 
 
 
 
7.4 Trial Stopping Rules 
 
Moved Table 1: Trial Procedures 
and Assessments to Section 1.3  
Alignment with new template 
 
Alignment with new template 
 
 
 
 
Alignment with new template 
 
Alignment with new template 
 
4. SELECTION AND 
WITHDRAWAL OF PATIENTS 
 
4.3. Withdrawal Criteria and 
Procedures for the Patient 
 
4.3.1. 
Study-Specific Patient 
Withdrawal Criteria and Procedures 
 
4.4. Replacement of Patients 
 
4.5. Rescreening 
5. TRIAL POPULATION 
 
 
7.2. Participant Withdrawal from 
the Trial 
 
7.1. Discontinuation of Trial 
Intervention 
 
7.1. Discontinuation of Trial 
Intervention 
Combined with section 5.6.
 
Screen Failures 
Alignment with new template 
 
 
Alignment with new template 
 
 
Alignment with new template 
 
 
Alignment with new template 
 
Alignment with new template 
5. TREATMENTS 
 
 
 
5.5. Restrictions 
 
5.9.3. 
Data Monitoring 
Committee 
6. TRIAL INTERVENTION 
AND CONCOMITANT 
THERAPY  
 
5.5. Lifestyle Considerations 
 
4.1.2. 
Data Monitoring 
Committee/Safety Review 
Alignment with new template. 
 
 
 
Alignment with new template. 
 
Alignment with new template. 
 
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Section - Protocol Amendment 08  Section - Protocol Amendment 09 
Comment 
 
 
 
 
5.10. 
Total Blood Volume 
Committee and 10.3. Informed 
Consent Process 
 
 
8.13. 
Total Blood Volume 
 
 
 
 
Alignment with new template. 
6. ASSESSMENT OF 
EFFICACY 
8. TRIAL ASSESSMENTS AND 
PROCEDURES 
Alignment with new template 
7. ASSESSMENT OF SAFETY 
 
 
7.1. Adverse Events 
 
 
7.2. Pregnancy 
 
 
7.4.1 
Table 4: Clinical 
Laboratory Tests 
8.3. Safety Assessments and 
Procedures 
 
8.4. Adverse Events and Serious 
Adverse Events 
 
8.5. Pregnancy and Postpartum 
Information 
 
13.2. 
Table 7: Clinical 
Laboratory Tests 
Alignment with new template. 
 
 
Alignment with new template. 
 
 
Alignment with new template. 
 
 
Alignment with new template. 
8. ASSESSMENT OF 
PHARMACOKINETICS AND 
IMMUNOGENICITY 
 
8.3. Immunogenicity Testing 
8.7. Pharmacokinetics 
 
 
 
8.11. 
Immunogenicity 
Assessments 
Alignment with new template. 
 
 
 
Alignment with new template. 
9. STATISTICS 
9. STATISTICAL 
CONSIDERATIONS 
Alignment with new template. 
10. QUALITY CONTROL AND 
QUALITY ASSURANCE  
 
11. GENERAL 
CONSIDERATIONS: RISK 
MANAGEMENT AND QUALITY 
ASSURANCE 
Alignment with new template. 
11. COMPLIANCE 
STATEMENT  
10. GENERAL 
CONSIDERATIONS: 
REGULATORY, ETHICAL, AND 
TRIAL OVERSIGHT 
Alignment with new template. 
 
 
12. DATA MANAGEMENT AND 
RECORD KEEPING 
 
11. GENERAL 
CONSIDERATIONS: RISK 
MANAGEMENT AND QUALITY 
ASSURANCE 
Alignment with new template. 
13. FINANCING AND 
INSURANCE 
13.4. 
Financial Disclosure 
Alignment with new template. 
14. PUBLICATION POLICY 
13.7. 
Publication Policy 
Alignment with new template. 
15. REFERENCES 
15. REFERENCES 
Alignment with new template. 
16. SUMMARY OF CHANGES 
TO PROTOCOL 
13.3. 
Prior Protocol 
Amendments 
Alignment with new template. 
APPENDIX A. CLINICAL 
LABORATORIES AND OTHER 
Removed Appendix 
Alignment with new template to 
remove company confidential 
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Section - Protocol Amendment 08  Section - Protocol Amendment 09 
Comment 
DEPARTMENTS AND 
INSTITUTIONS 
information and personal protected 
data.  
APPENDIX B. 
STUDY 
PROCEDURES AND 
ASSESSMENTS BY VISIT 
13.9. 
Trial Procedures and 
Assessments by Visit 
Alignment with new template. 
APPENDIX C. 
PREVENTIVE 
MIGRAINE MEDICATIONS FOR 
ANY CONDITION ALLOWED 
FOR THE DURATION OF THE 
STUDY FOR APPROXIMATELY 
30% OF PATIENTS 
13.8. 
Preventive Migraine 
Medications for Any Condition 
Allowed for the Duration of the 
Trial 
Alignment with new template. 
APPENDIX D. CLINICAL 
CRITERIA FOR DIAGNOSING 
ANAPHYLAXIS 
12.1. 
Further Details and 
Clarifications on the Adverse Event 
Definition 
Alignment with new template. 
APPENDIX E. 
QUALITY 
CONTROL AND QUALITY 
ASSURANCE 
11.2. 
Data Quality Assurance 
Alignment with new template. 
APPENDIX F. 
ETHICS 
10.1. 
Regulatory and Ethical 
Considerations 
10.3. 
Informed Consent Process 
10.4. 
Data Protection 
13.6. 
Dissemination of Clinical 
Trial Data 
Alignment with new template. 
APPENDIX G. BIRTH 
CONTROL METHODS AND 
PREGNANCY TESTING 
13.1. 
Contraception and 
Pregnancy Testing 
Alignment with new template. 
APPENDIX H. LOST TO 
FOLLOW-UP 
7.3. Lost to Follow-Up 
Alignment with new template. 
APPENDIX I. 
GUIDANCE ON 
SAFETY MONITORING 
12.2. 
Further Details and 
Clarifications on the Serious 
Adverse Event Definition 
Alignment with new template. 
APPENDIX J. 
TOTAL BLOOD 
VOLUME 
8.13. 
Total Blood Volume 
Alignment with new template. 
APPENDIX K. PRODUCT 
COMPLAINTS 
8.6. Clinical Product Complaints 
Alignment with new template. 
APPENDIX L. 
DATA 
MANAGEMENT AND RECORD 
KEEPING 
11.2. 
Data Quality Assurance 
11.3. 
Source Data 
Alignment with new template. 
APPENDIX M. PUBLICATION 
POLICY 
13.7. 
Publication Policy 
Alignment with new template. 
APPENDIX N. STORAGE AND 
DESTRUCTION OF 
BIOLOGICAL SAMPLES 
8.3.4. 
Clinical Laboratory Tests 
Handling, storage, and shipping 
details were removed from protocol 
per new template instructions. 
APPENDIX O. MANAGEMENT 
OF STUDY ACTIVITIES 
DURING COVID-19 
Removed Appendix and all cross 
references throughout document 
No longer relevant as pandemic 
passed. 
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Overall Rationale for the Amendment: 
The primary reason for this protocol amendment was to reduce the trial population size and 
relaxation of the inclusion criteria. Consequently, there was reduction in statistical power and a 
removal of the interim analysis. In alignment with the new protocol template, the terms 
“study(ies)” and “patient(s)” were updated to “trial(s)” and “participant(s)”, respectively, 
throughout the document. In addition, where appropriate the term “test IMP” is used for the Teva 
product under study and the term for “placebo” was updated to “placebo IMP”. A high-level 
description of the changes, and a brief rationale are provided in the table below. All changes are 
reflected in the Protocol Synopsis (Section 1.1). Minor editorial changes (typos, punctuation, etc) 
have also been made to the protocol (and Protocol Synopsis, as appropriate). Table 1 (Trial 
Procedures and Assessment), Table 2 (Investigational Medicinal Products Used in the Trial), and 
Table 3 (The Relationship of an Adverse Event to the Investigational Medicinal Product and/or 
Device) have been revised to reflect the changes below. 
Section Number and Name 
Description of Change 
Brief Rationale 
Title page, Investigator 
Agreement, and 
Coordinating Investigator 
Agreement  
Updated paediatric investigation plan 
number from P/0411/2019 to 
P/0378/2023 
Alignment with agreed modified 
paediatric investigation plan for 
fremanezumab  
1.1. Protocol Synopsis 
Protocol Synopsis is reduced to 2 
pages. 
Alignment with new template. 
1.3. Schedule of Activities 
Updated footnote d of Table 1 “The 
date of…administration of IMP”. 
Clarification. 
2. Introduction 
Reduced to 3 pages. For additional 
details the reader is referred to the 
Investigator‘s Brochure.  
 
Added statement about Trial TV48125-
MH-40142. 
Alignment with new template. 
 
 
 
Update. 
2.1.1. 
Known and 
Potential Benefits and Risks 
of the Test Investigational 
Medicinal Product and/or 
Device 
Updating heading to include “and/or 
Device”. 
Alignment with new template. 
2.2.2 Overall Benefit-Risk 
Conclusion 
Removed text “Severe hypersensitivity 
reactions are regarded as a potential 
risk for fremanezumab.” 
Updated as hypersensitivity reactions 
are no longer a potential risk. 
3.1. Primary and Secondary 
Trial Objectives and 
Endpoints 
Primary efficacy endpoint was updated 
from “…headache days of at least 
moderate severity…” to “…migraine 
days…” 
 
First 2 secondary efficacy endpoint 
bullets were updated. Bullet 1: changed 
from “migraine days” to “headache 
days of at least moderate severity”. 
Bullet 2: changed from “headache days 
of at least moderate severity” to 
“migraine days”. 
Updated to align with other pediatric 
and adult trials.  
 
 
 
Updated to align with other pediatric 
and adult trials. 
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Section Number and Name 
Description of Change 
Brief Rationale 
3.1.1.Justification of 
Primary Endpoint 
Aligning with the change to primary 
endpoint from “headache days” to 
“migraine days”. 
Clarification. 
3.2. Primary Estimand 
Update text from headache to migraine 
days: “…number of migraine days 
during…”  
Alignment with objectives. 
3.4. Exploratory/Other 
Objectives and Endpoints 
 
 
 
 
 
 
 
 
 
 
4.1. Description of Trial 
Design  
4.1.1. Planned Number of 
Participants and Countries 
 
Enrollment target was reduced from 
“approximately 418 patients” to 
“approximately 278 patients”. The 
number of evaluable participants is 
planned to be “approximately 266” 
based on the currently observed drop-
out rate of 4%. 
 
In line with the current projections and 
reduced sample size, trial completion 
date was updated from “Q4 2023” to 
“Q3 2026”. Trial start date was updated 
from Q1 2020 to Q2 2020. 
 
Text on interim analysis and/or sample 
size re-estimation was removed.  
Mitigation to the observed recruitment 
constrains and further trial completion 
delays. 
 
 
 
 
 
Mitigation to the observed recruitment 
constrains and further trial completion 
delays. 
 
 
 
Removed due to recruitment 
constraints and to avoid further trial 
completion delays. 
4.4 Start of Trial and End of 
Trial 
Suggested template text added that 
“trial start date is the date on which the 
clinical trial will be open for 
recruitment of participants.” 
Alignment with new template. 
5.3. Inclusion Criteria 
Inclusion criteria c was revised to 
“…history of ≥15 headache days per 
month on average during the 
3 months…” and inclusion criteria e 
was deleted.  
 
Inclusion criteria f was updated to 
specify that “approximately 35% of 
participants” are allowed preventive 
medications. 
Aid with recruitment. 
5.4. Exclusion Criteria 
Inclusion criteria d was revised to 
clarify that the participant’s current 
history of a clinically significant 
psychiatric condition, is at the 
discretion of the Investigator. 
Clarification. 
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Section Number and Name 
Description of Change 
Brief Rationale 
6.1.1. Investigational 
Medicinal Products Used in 
the Trial 
Added line “intervention type” to Table 
2. 
Alignment with template. 
6.2.1. Justification for Test 
Investigational Medicinal 
Product and/or Device and 
Dose 
Updating heading to include “and/or 
Device”. 
Alignment with new template. 
6.8. Prior and Concomitant 
Therapy 
 
Update text to specify that 
“Approximately 35% of participants 
will be allowed to remain on no more 
than 2 migraine preventive medications 
for any condition…” Text in Section 
4.2 was updated accordingly. 
 
Updated text in relation to the PRN and 
chronic use medications. 
Aid with participant retention and 
clarification. 
 
 
 
 
Clarification. 
7.2. Participant Withdrawal 
from the Trial 
Updated format to unnumbered bullets. 
Updated 4th bullet to clarify that 
participants using prohibited 
concomitant medications chronically 
should be withdrawn. Added bullet 
regarding suicidal ideation and/or 
suicidal behavior and trial withdrawal. 
 
In alignment with added device 
vigilance text added “and/or Device” in 
relation relatedness to IMP and 
withdrawal from trial. 
 
Removed duplicate text “The 
participant will be…test IMP or trial 
procedure is made).” 
Clarification. 
 
 
 
 
 
 
 
Alignment with new template. 
 
 
 
 
Clarification. 
7.3. Lost to Follow-Up 
Updated 2nd bullet on effort to regain 
contact with participant deemed lost to 
follow up. 
Alignment with new template. 
8.1. Screening/Baseline 
Assessments and Procedures 
Added new template text. 
Clarification. 
8.3.4.1. Serum Chemistry, 
Hematology, Coagulation, 
and Urinalysis 
Added text that reflex tests may be 
triggered automatically. 
Clarification. 
8.3.4.2.1. Human Chorionic 
Gonadotropin Tests 
Removed word “other” and to clarify 
that “urine β-HCG tests will be 
performed at all visits…” 
Alignment with Table 1. 
8.3.7. Medication Error and 
Special Situations Related to 
the Investigational 
Medicinal Products 
Updated to mandatory template text 
and removed bullets on “off-label use” 
and “breastfeeding” present in protocol 
amendment 08 (Section 7.3). 
 
Added text referencing to Section 8.6 
Alignment with new template. 
 
 
 
 
Alignment with new template. 
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Section Number and Name 
Description of Change 
Brief Rationale 
to evaluate whether the medication 
error or special situation may be due to 
a device deficiency. 
8.4.1.1. Adverse Events 
Added text on medical device 
vigilance. 
Alignment with new template. 
8.4.1.2. Serious Adverse 
Events 
Deleted definitions of Hy’s law 
criteria. 
Alignment with new template. 
8.4.1.3. Adverse Device 
Effects and Serious Adverse 
Device Effects 
Added new section. 
Alignment with new template. 
8.4.2. 
Time Period and 
Frequency for Collecting 
Adverse Event and Serious 
Adverse Event Information 
Added text on treatment-emergent 
adverse events. 
Alignment with new template. 
8.4.4. Recording of Adverse 
Events and Serious Adverse 
Events 
Added text on medical device 
vigilance. 
 
 
Updated text that reporting must occur 
within 24 hours.  
 
Added Figure 2 Decision Tree for 
Adverse Events and Adverse Device 
Effects Classification. 
Alignment with new template. 
 
 
 
Alignment with new template. 
 
 
Alignment with new template. 
8.4.4.2. Relationship of an 
Adverse Event to the 
Investigational Medicinal 
Product and/or Device 
Updated heading and added text on 
medical device vigilance. Also in Table 
3. 
Alignment with new template. 
8.4.4.3. Expectedness of 
Serious Adverse Events 
Added text on medical device 
vigilance.  
Alignment with new template. 
8.4.5. Follow-Up of Adverse 
Events and Serious Adverse 
Events 
Added statements related to devices 
and types of follow-up procedures, 
documentation, and reporting of 
updated data on serious adverse events. 
Alignment with new template. 
8.4.6. Reporting of Serious 
Adverse Events 
Added text on medical device 
vigilance. 
Alignment with new template. 
 
8.4.7. Regulatory Reporting 
Requirements for Serious 
Adverse Events 
Added text on medical device 
vigilance. Added new text on 
submission of SUSARs. Combined 2 
bullets points related to modifying the 
protocol and/or ICF. 
Alignment with new template. 
8.4.8.1. Protocol-Defined 
Adverse Events of Special 
Interest that Require 
Reporting to Sponsor’s 
Global PV 
Removed text on COVID-19.  
 
 
 
 
Added “Protocol-Defined Adverse 
Events of Special Interest Form”. 
COVID-19 is no longer adverse event 
of special interest and does not need to 
be reported via same procedure as 
serious adverse events. 
 
Alignment with new template. 
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Section Number and Name 
Description of Change 
Brief Rationale 
Updated text to “ protocol-defined 
adverse events…that occur before IMP 
(and/or PFS)…”  
8.4.9. Disease-Related 
Events or Outcomes not 
Qualifying as Adverse 
Events or Serious Adverse 
Events 
Added new section. 
Alignment with new template. 
8.5. Pregnancy and 
Postpartum Information 
Added new template text to clarify that 
females who become pregnant during 
trial will be withdrawn from IMP 
(and/or PFS). Added new template text 
clarifying why partners of trial 
participants are requested to sign an 
ICF. 
 
Added number of days and 24 hour 
reporting requirement. 
 
Added clarification that both 
Pregnancy and Serious Adverse Event 
Forms should be completed for a 
spontaneous abortion and for an 
elective abortion due to developmental 
anomalies. 
Clarification and alignment with new 
template. 
 
 
 
 
 
 
Alignment with new template. 
 
 
Clarification and alignment with new 
template. 
8.6.1.Definition of Clinical 
Product Complaints 
Added text on medical device 
vigilance. 
 
Updated text that Product Complaint 
Form should be emailed as soon as 
possible after becoming aware of the 
issue. 
Alignment with new template. 
 
 
Alignment with new template. 
8.6.2. 
Handling the 
IMP/Devices at the 
Investigational Center 
Updated heading and section to also 
include device text. 
Alignment with new template 
8.6.5. Device Deficiency 
that Could Have Led to 
Serious Adverse Event 
Added new section relating to device 
vigilance, including Tables 4 and 5. 
Alignment with new template. 
8.7.1.Pharmacokinetic 
Sampling 
Deleted content on handling, storage 
and shipment and referred to 
Laboratory Manual instead.  
Alignment with new template. 
8.9.  Genetics 
New section added. 
Alignment with new template. 
8.12. Medical Resource 
Utilization and Health 
Economics 
New section added. 
Alignment with new template. 
8.13. 
Total Blood 
Volume 
Table 6: Total Blood Volumes to be 
Collected from an Individual Trial 
Participant was relocated to here (from 
Alignment with new template. 
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Section Number and Name 
Description of Change 
Brief Rationale 
Appendix J in previous version of 
protocol). 
9. STATISTICAL 
CONSIDERATIONS 
New template text added. 
Alignment with new template. 
9.1.4. Per Protocol Analysis 
Set 
Updated text to specify this is a subset 
of the Full Analysis Set. 
Clarification. 
9.2. Analyses Supporting 
Primary Objective(s)  
9.2.1.Primary Endpoint 
9.2.1.1.Estimand for the 
Primary Endpoint  
9.2.2. Secondary Endpoints 
9.2.3.Exploratory/Other 
Endpoints  
9.2.4.1. Primary Efficacy 
Analysis 
9.2.4.2. Sensitivity and 
Supplementary Analyses 
9.3.Analysis Supporting 
Secondary Objective(s) 
In all subsections relevant text referring 
to “headache days of at least moderate 
severity” or “migraine days” was 
updated where needed.  
 
Update the definition of migraine day 
(Section 9.2) 
Alignment with updating the primary 
endpoint. 
 
 
 
Alignment with updating the primary 
endpoint. 
 
9.2.4.1. Primary Efficacy 
Analysis 
9.3. Analysis Supporting 
Secondary Objective(s) 
Added text on weight subgroup 
analysis.” 
Update 
9.5. Safety Analyses 
Added text on medical device 
vigilance. 
Alignment with new template. 
9.6.3. Immunogenicity 
Analysis 
Text updated “…if data allows. This 
analysis will be reported separately.” 
Clarification. 
9.7. Interim Analyses 
Interim analysis for sample size re-
estimation was removed. 
Removed due to recruitment 
constraints and to avoid further trial 
completion delays. 
9.8. Sample Size 
Determination 
Enrollment target was reduced from 
“approximately 418 patients” to 
“approximately 278 patients”. The 
number of evaluable participants is 
planned to be “approximately 266” 
based on the currently observed drop-
out rate of 4%. Statistical power is 
consequently reduced from   “at least 
90% power” to “at least 80%”. 
 
Text on interim analysis and/or sample 
size re-estimation was removed. 
Mitigation to the observed recruitment 
constrains and further trial completion 
delays. 
10.1. Regulatory and Ethical 
Considerations 
Relocated text on ”Competent 
Authorities and Independent Ethics 
Committees/Institutional Review 
Boards”(in Appendix L of previous 
version of protocol) to here.  
 
Alignment with new template. 
 
 
 
 
 
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Section Number and Name 
Description of Change 
Brief Rationale 
Added ISO 14155: Clinical 
investigation of medical devices for 
human subjects – Good Clinical 
Practice in alignment with added text 
on device vigilance. Added template 
text “Regulation [EU] No. 536/2014 
[CTR]” to the statement on applicable 
GCP guidelines for trial conduct. 
Added text to clarify that Investigator 
should conduct and administer the 
clinical trial in accordance with the 
protocol “and applicable regulations”. 
 
Added new template text “The clinical 
trial agreement… and/or protocol.” 
 
Added standard text to include 
multicenter trials.  
Alignment with new template. 
 
 
 
 
 
 
 
 
 
 
 
 
Alignment with new template. 
 
 
Alignment with new template. 
10.3. Informed Consent 
Process 
Added new template text on informed 
consent when a minor reaches the age 
of legal competence. 
Alignment with new template. 
10.4. Data Protection 
Added new template text. 
Alignment with new template. 
10.5. Early Investigational 
Center Closure or Trial 
Termination 
New section and text. 
Alignment with new template. 
11.1. Quality Tolerance 
Limits 
New section added. 
Alignment with new template. 
11.2. Data Quality 
Assurance 
Added new template text concerning 
Investigator responsibilities in relation 
to product complaints, CRF reviews, 
data corrections, important protocol 
deviations, trial monitoring and audit 
and inspection.  
 
Added template text describing the 
main responsibilities of the trial 
monitor(s) “…are to explain… the 
Investigator”… 
Clarification and alignment with new 
template. 
 
 
 
 
 
Clarification and alignment with new 
template. 
11.3. Source Data 
Deleted duplicate text “All participant 
data must … to the CRF.” 
Alignment with new template and lean 
writing. 
13.1.3. Pregnancy Testing 
New section added. 
Clarification and alignment with new 
template. 
13.3. 
Prior Protocol 
Amendments 
Added Administrative letter 06. 
Update. 
13.5. Recruitment Strategy 
 New section added. 
Alignment with new template. 
13.8. 
Preventive 
Migraine Medications for 
Update text to specify that “the chronic 
use of 2 of the following concomitant 
medications is allowed in 
approximately 35% of participants”. 
Aid with participant retention and 
clarification. 
 
 
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Section Number and Name 
Description of Change 
Brief Rationale 
Any Condition Allowed for 
the Duration of the Trial 
 
Updated text in relation to the PRN and 
chronic use medications and updated 
text to clarify that the “regular use” of 
medication containing opioids and 
barbiturates is not allowed. 
 
Update reference to “O’Brien et al 
2015”.. 
 
Clarification. 
 
 
 
 
 
Correction. 
13.9. Trial Procedures and 
Assessments by Visit 
Update bullets to clarify that serum β-
HCG and urine pregnancy tests will be 
conducted.  
1. Procedures for Screening (Visit 1, 
Days -28 to -1): “serum beta-human 
gonadotropin (β-HCG) and 
urine…menstrual period…”  
4. End of Treatment/Early 
Withdrawal (Visit 5 [Day 85±3 days]) 
“serum β-HCG and urine pregnancy 
tests…” 
Alignment with Section 8.3.4.2.1. 
For previous amendments, the Protocol Amendment History including the Summary of Changes 
to the Protocol and the corresponding rationale for each change is provided in Section 13.3. 
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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
INVESTIGATOR AGREEMENT...................................................................................................3 
SPONSOR PROTOCOL APPROVAL ...........................................................................................4 
COORDINATING INVESTIGATOR AGREEMENT ...................................................................5 
PROTOCOL AMENDMENT DETAILS ........................................................................................6 
1. 
PROTOCOL SUMMARY ..........................................................................................25 
1.1. 
Protocol Synopsis .......................................................................................................25 
1.2. 
Trial Schema ...............................................................................................................27 
1.3. 
Schedule of Activities .................................................................................................28 
2. 
INTRODUCTION ......................................................................................................32 
2.1. 
Purpose of Trial ..........................................................................................................34 
2.2. 
Summary of Benefits and Risks .................................................................................34 
2.2.1. 
Known and Potential Benefits and Risks of the Test Investigational 
Medicinal Product and/or Device ...............................................................................34 
2.2.2. 
Overall Benefit-Risk Conclusion ................................................................................34 
3. 
TRIAL OBJECTIVES, ENDPOINTS, AND ESTIMANDS .....................................35 
3.1. 
Primary and Secondary Trial Objectives and Endpoints ............................................35 
3.1.1. 
Justification of Primary Endpoint ...............................................................................36 
3.2. 
Primary Estimand .......................................................................................................36 
3.3. 
Secondary Estimand(s) ...............................................................................................36 
3.4. 
Exploratory/Other Objectives and Endpoints .............................................................36 
4. 
TRIAL DESIGN .........................................................................................................38 
4.1. 
Description of Trial Design ........................................................................................38 
4.1.1. 
Planned Number of Participants and Countries ..........................................................39 
4.1.2. 
Data Monitoring Committee/Safety Review Committee ...........................................39 
4.2. 
Rationale for Trial Design ..........................................................................................39 
4.3. 
Access to Trial Intervention After End of Trial ..........................................................40 
4.4. 
Start of Trial and End of Trial ....................................................................................40 
5. 
TRIAL POPULATION ..............................................................................................41 
5.1. 
Selection of Trial Population ......................................................................................41 
5.2. 
Rationale for Trial Population ....................................................................................41 
5.3. 
Inclusion Criteria ........................................................................................................41 
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5.4. 
Exclusion Criteria .......................................................................................................43 
5.5. 
Lifestyle Considerations .............................................................................................44 
5.6. 
Screen Failures ............................................................................................................45 
6. 
TRIAL INTERVENTION AND CONCOMITANT THERAPY ..............................46 
6.1. 
Description of Trial Intervention(s) ............................................................................46 
6.1.1. 
Investigational Medicinal Products Used in the Trial ................................................46 
6.1.1.1. 
Test Investigational Medicinal Product ......................................................................49 
6.1.1.2. 
Placebo Investigational Medicinal Product ................................................................49 
6.2. 
Rationale for Trial Intervention(s) ..............................................................................49 
6.2.1. 
Justification for Test Investigational Medicinal Product and/or Device and 
Dose ............................................................................................................................49 
6.2.2. 
Justification for Use of Placebo Investigational Medicinal Product ..........................51 
6.3. 
Dosing and Administration .........................................................................................52 
6.4. 
Treatment of Overdose ...............................................................................................52 
6.5. 
Preparation, Handling, Labeling, Storage, and Accountability ..................................52 
6.5.1. 
Storage Conditions and Handling ...............................................................................52 
6.5.2. 
Labeling ......................................................................................................................52 
6.5.3. 
Accountability .............................................................................................................52 
6.6. 
Participant Assignment, Randomization, and Blinding ..............................................53 
6.6.1. 
Participant Assignment and Randomization ...............................................................53 
6.6.2. 
Maintenance of Randomization ..................................................................................54 
6.6.3. 
Blinding and Unblinding ............................................................................................54 
6.7. 
Trial Intervention Compliance ....................................................................................54 
6.8. 
Prior and Concomitant Therapy ..................................................................................55 
7. 
DISCONTINUATION OF TRIAL INTERVENTION AND PARTICIPANT 
WITHDRAWAL FROM TRIAL ...............................................................................56 
7.1. 
Discontinuation of Trial Intervention .........................................................................56 
7.2. 
Participant Withdrawal from the Trial ........................................................................56 
7.3. 
Lost to Follow-Up.......................................................................................................58 
7.4. 
Trial Stopping Rules ...................................................................................................58 
8. 
TRIAL ASSESSMENTS AND PROCEDURES .......................................................59 
8.1. 
Screening/Baseline Assessments and Procedures ......................................................59 
8.2. 
Efficacy Assessments and Procedures ........................................................................59 
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8.2.1. 
Electronic Headache Diary .........................................................................................59 
8.2.2. 
Pediatric Migraine Disability Assessment ..................................................................60 
8.2.3. 
 ......................................................60 
8.2.4. 
Pediatric Quality of Life Inventory .............................................................................60 
8.3. 
Safety Assessments and Procedures ...........................................................................61 
8.3.1. 
Physical Examinations ................................................................................................61 
8.3.2. 
Vital Signs ..................................................................................................................61 
8.3.3. 
Electrocardiograms .....................................................................................................62 
8.3.4. 
Clinical Laboratory Tests ...........................................................................................62 
8.3.4.1. 
Serum Chemistry, Hematology, Coagulation, and Urinalysis ....................................63 
8.3.4.2. 
Other Laboratory Tests ...............................................................................................63 
8.3.5. 
Suicidal Ideation and Behavior Risk Monitoring .......................................................63 
8.3.6. 
Assessment of Local Tolerability and Pain ................................................................64 
8.3.7. 
Medication Error and Special Situations Related to the Investigational 
Medicinal Products .....................................................................................................64 
8.4. 
Adverse Events and Serious Adverse Events .............................................................65 
8.4.1. 
Definitions of Adverse Events and Serious Adverse Events ......................................65 
8.4.1.1. 
Adverse Events ...........................................................................................................65 
8.4.1.2. 
Serious Adverse Events ..............................................................................................66 
8.4.1.3. 
Adverse Device Effects and Serious Adverse Device Effects ....................................66 
8.4.2. 
Time Period and Frequency for Collecting Adverse Event and Serious 
Adverse Event Information .........................................................................................67 
8.4.3. 
Identifying Adverse Events and Serious Adverse Events ..........................................67 
8.4.4. 
Recording of Adverse Events and Serious Adverse Events .......................................67 
8.4.4.1. 
Severity of an Adverse Event .....................................................................................68 
8.4.4.2. 
Relationship of an Adverse Event to the Investigational Medicinal Product 
and/or Device ..............................................................................................................68 
8.4.4.3. 
Expectedness of Serious Adverse Events ...................................................................69 
8.4.5. 
Follow-Up of Adverse Events and Serious Adverse Events ......................................70 
8.4.6. 
Reporting of Serious Adverse Events .........................................................................70 
8.4.7. 
Regulatory Reporting Requirements for Serious Adverse Events .............................71 
8.4.8. 
Adverse Events of Special Interest .............................................................................72 
8.4.8.1. 
Protocol-Defined Adverse Events of Special Interest that Require Reporting 
to Sponsor’s Global PV ..............................................................................................72 
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8.4.9. 
Disease-Related Events or Outcomes not Qualifying as Adverse Events or 
Serious Adverse Events ..............................................................................................72 
8.4.10. 
Protocol Deviations Because of an Adverse Event ....................................................72 
8.5. 
Pregnancy and Postpartum Information .....................................................................73 
8.6. 
Clinical Product Complaints .......................................................................................73 
8.6.1. 
Definition of Clinical Product Complaints .................................................................73 
8.6.2. 
Handling the IMP/Devices at the Investigational Center ...........................................74 
8.6.3. 
Product Complaint Associated with Adverse Events or Serious Adverse 
Events .........................................................................................................................75 
8.6.4. 
Product Complaint Information Needed from the Investigational Center ..................75 
8.6.5. 
Device Deficiency that Could Have Led to Serious Adverse Event ..........................75 
8.7. 
Pharmacokinetics ........................................................................................................77 
8.7.1. 
Pharmacokinetic Sampling .........................................................................................77 
8.8. 
Pharmacodynamics .....................................................................................................77 
8.9. 
Genetics ......................................................................................................................77 
8.10. 
Biomarkers ..................................................................................................................77 
8.11. 
Immunogenicity Assessments ....................................................................................77 
8.12. 
Medical Resource Utilization and Health Economics ................................................78 
8.13. 
Total Blood Volume ...................................................................................................78 
9. 
STATISTICAL CONSIDERATIONS .......................................................................79 
9.1. 
Analysis Sets ...............................................................................................................79 
9.1.1. 
Safety Analysis Set .....................................................................................................79 
9.1.2. 
Intent-to-Treat Analysis Set ........................................................................................79 
9.1.3. 
Full Analysis Set .........................................................................................................79 
9.1.4. 
Per-Protocol Analysis Set ...........................................................................................79 
9.1.5. 
Trial Population ..........................................................................................................79 
9.1.5.1. 
Participant Disposition ................................................................................................79 
9.1.5.2. 
Demographic and Baseline Characteristics ................................................................80 
9.2. 
Analyses Supporting Primary Objective(s) ................................................................80 
9.2.1. 
Primary Endpoint ........................................................................................................80 
9.2.1.1. 
Estimand for the Primary Endpoint ............................................................................80 
9.2.2. 
Secondary Endpoints ..................................................................................................80 
9.2.3. 
Exploratory/Other Endpoints ......................................................................................81 
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9.2.4. 
Planned Method of Analysis .......................................................................................82 
9.2.4.1. 
Primary Efficacy Analysis ..........................................................................................82 
9.2.4.2. 
Sensitivity and Supplementary Analyses ....................................................................82 
9.2.5. 
Data Handling Conventions ........................................................................................82 
9.2.5.1. 
Handling of Withdrawals and Missing Data ..............................................................82 
9.2.6. 
Multiple Comparisons and Multiplicity......................................................................83 
9.3. 
Analysis Supporting Secondary Objective(s) .............................................................83 
9.4. 
Analysis of Exploratory Objective(s) .........................................................................83 
9.5. 
Safety Analyses ..........................................................................................................83 
9.5.1. 
Tolerability Analysis ..................................................................................................84 
9.6. 
Other Analyses ............................................................................................................84 
9.6.1. 
Pharmacokinetic Analysis ..........................................................................................84 
9.6.2. 
Pharmacokinetic/Pharmacodynamic Analysis ............................................................85 
9.6.3. 
Immunogenicity Analysis ...........................................................................................85 
9.7. 
Interim Analyses .........................................................................................................85 
9.8. 
Sample Size Determination ........................................................................................85 
9.9. 
Protocol Deviations ....................................................................................................85 
10. 
GENERAL CONSIDERATIONS: REGULATORY, ETHICAL, AND 
TRIAL OVERSIGHT .................................................................................................86 
10.1. 
Regulatory and Ethical Considerations ......................................................................86 
10.2. 
Committees .................................................................................................................86 
10.3. 
Informed Consent Process ..........................................................................................87 
10.4. 
Data Protection ...........................................................................................................87 
10.5. 
Early Investigational Center Closure or Trial Termination ........................................89 
11. 
GENERAL CONSIDERATIONS: RISK MANAGEMENT AND 
QUALITY ASSURANCE ..........................................................................................90 
11.1. 
Quality Tolerance Limits ............................................................................................90 
11.2. 
Data Quality Assurance ..............................................................................................90 
11.3. 
Source Data .................................................................................................................92 
12. 
APPENDIX: ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS – 
DEFINITIONS, SEVERITY, AND CAUSALITY ....................................................95 
12.1. 
Further Details and Clarifications on the Adverse Event Definition ..........................95 
12.2. 
Further Details and Clarifications on the Serious Adverse Event Definition .............96 
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12.2.1. 
Guidance on Safety Monitoring..................................................................................96 
13. 
APPENDIX: DEFINITIONS AND SUPPORTING OPERATIONAL 
DETAILS ....................................................................................................................99 
13.1. 
Contraception and Pregnancy Testing ........................................................................99 
13.1.1. 
Definitions Related to Childbearing Potential ............................................................99 
13.1.2. 
Contraception ..............................................................................................................99 
13.1.3. 
Pregnancy Testing ....................................................................................................100 
13.2. 
Clinical Laboratory Tests .........................................................................................100 
13.3. 
Prior Protocol Amendments .....................................................................................101 
Administrative Letter 06 Dated 21 December 2021 ....................................................................101 
Amendment 08 Dated 09 December 2021 ...................................................................................104 
Administrative Letter 05 Dated 10 May 2021 .............................................................................110 
Administrative Letter 04 Dated 04 February 2021 ......................................................................112 
Administrative Letter 03 Dated 05 November 2020....................................................................113 
Amendment 07 Dated 20 August 2020 ........................................................................................115 
Amendment 06 Dated 27 July 2020.............................................................................................118 
Administrative Letter 02 Dated 07 July 2020 ..............................................................................122 
Amendment 05 Dated 27 June 2020 ............................................................................................123 
Amendment 04 Dated 20 April 2020 ...........................................................................................130 
Administrative Letter 01 Dated 10 March 2020 ..........................................................................133 
Amendment 03 Dated 03 February 2020 .....................................................................................134 
Amendment 02 Dated 05 December 2019 ...................................................................................138 
Amendment 01 Dated 21 June 2019 ............................................................................................149 
13.4. 
Financial Disclosure .................................................................................................153 
13.5. 
Recruitment Strategy ................................................................................................153 
13.6. 
Dissemination of Clinical Trial Data ........................................................................153 
13.7. 
Publication Policy .....................................................................................................153 
13.8. 
Preventive Migraine Medications for Any Condition Allowed for the 
Duration of the Trial .................................................................................................154 
13.9. 
Trial Procedures and Assessments by Visit ..............................................................155 
14. 
APPENDIX: GLOSSARY OF TERMS ...................................................................159 
15. 
REFERENCES .........................................................................................................162 
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LIST OF TABLES 
Table 1: 
Trial Procedures and Assessments ..............................................................................28 
Table 2: 
Investigational Medicinal Products Used in the Trial ................................................47 
Table 3: 
The Relationship of an Adverse Event to the Investigational Medicinal 
Product and/or Device ................................................................................................69 
Table 4: 
Anticipated Use-Related Deficiencies and Their Potential Hazards and 
Serious Harms .............................................................................................................76 
Table 5: 
Anticipated Design-Related Deficiencies and Their Potential Hazards and 
Serious Harms .............................................................................................................76 
Table 6: 
Total Blood Volumes to be Collected from an Individual Trial Participant ..............78 
Table 7: 
Clinical Laboratory Tests .........................................................................................100 
 
LIST OF FIGURES 
Figure 1: 
Overall Trial Schematic Diagram ...............................................................................27 
Figure 2: 
Decision Tree for Adverse Events and Adverse Device Effects Classification .........68 
 
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1. 
PROTOCOL SUMMARY  
1.1. 
Protocol Synopsis  
Protocol Title: 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 Chronic Migraine in Pediatric 
Patients 6 to 17 Years of Age 
Brief Title: Randomized, Double-Blind, Placebo-Controlled Trial of Fremanezumab in 
Participants (6 to 17 Years) with Chronic Migraine. A Trial to Test if Fremanezumab is Effective 
in Preventing Chronic Migraine in Patients 6 to 17 Years of Age. 
Regulatory Agency Identifier Number(s): IND number: 106,533; NDA number: not 
applicable;  BLA number: 761089; EudraCT number: 2019-002053-33; EU CT number: not 
applicable 
Pediatric Investigation Plan Number: P/0378/2023 
Rationale: 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%. There is an unmet medical need for a safe 
and effective prophylactic treatment for episodic migraine and chronic migraine (CM) in the 
pediatric 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. 
Name of IMP: Fremanezumab 
Intervention Type: Drug (including placebo) 
Primary and Secondary Objectives, Endpoints:  
Objectives 
Endpoints 
The primary objective of the trial is to 
evaluate the efficacy of test investigational 
medicinal product (IMP) as compared to 
placebo IMP for the preventive treatment 
of chronic migraine (CM).  
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 
IMP.  
A secondary objective is to evaluate the 
safety and tolerability of test IMP in the 
preventive treatment of CM. 
The safety and tolerability endpoints are as follows: 
• 
occurrence of adverse events throughout the trial, 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 
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Objectives 
Endpoints 
• 
suicidal ideation and behavior as suggested by the 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
A secondary objective of the trial is to 
further demonstrate the efficacy of test 
IMP as compared to placebo IMP for the 
preventive treatment of CM. 
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 IMP 
• 
proportion of participants reaching at least 50% reduction in 
the monthly average number of migraine days during the 
12-week period after the first dose of IMP 
• 
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 IMP 
• 
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 IMP 
• 
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 IMP 
A secondary objective of the trial is to 
evaluate the immunogenicity of test IMP 
and the impact of antidrug antibodies 
(ADAs) on clinical outcomes in 
participants exposed to test IMP. 
• 
proportion of participants developing ADAs throughout the 
trial. The impact of ADAs on safety and efficacy will be 
analyzed if the number of ADA-positive participants allows. 
Exploratory objectives and endpoints will be assessed as well. 
Overall Design: This is a 4-month, multicenter, randomized, double-blind, placebo-controlled, 
parallel-group trial to evaluate the efficacy, safety, and tolerability of 2 different doses 
(dependent on participants’ body weight) of subcutaneous (sc) test investigational medicinal 
product (IMP) and placebo IMP. Enrollment will include male and female participants (6 to 
17 years of age, inclusive). The dose of test IMP will be determined by the participant’s weight 
at randomization. 
Number of Participants: A planned total of approximately 278 CM participants will be 
randomized. The number of evaluable participants is planned to be approximately 
266 (133 evaluable participants completing the trial per treatment group). 
Trial Arms and Duration: Participants will be randomly assigned in a 1:1 ratio between test 
IMP and placebo IMP treatment groups. The total duration of the trial is planned to be 75 months 
(from quarter [Q]2 2020 to Q3 2026). 
Data Monitoring/Other Committee: Not applicable. 
Ethical Considerations: Based on the current safety profile and the demonstrated efficacy of the 
sc test IMP dosage form as observed in adults, the overall risk and benefit assessment for this 
trial is favorable. 
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1.2. 
Trial Schema  
Figure 1: 
Overall Trial Schematic Diagram  
 
PBO=placebo; SC=subcutaneous; V=visit. 
 
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1.3. 
Schedule of Activities  
Trial 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 8 (Trial Assessments and Procedures) and Section 13.9. 
Table 1: 
Trial Procedures and Assessments  
Trial 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 participants of trial 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 
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Trial 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) 
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 
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 
 
f 
 
 
 
 
X 
Administration of IMPr     
 
X 
X 
X 
 
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Trial 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) 
Injection site assessmentc 
 
X 
X 
X 
 
a Participants 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 participants will be offered enrollment in the long-term safety and tolerability trial (Trial 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 IMP administration. Assessment of injection site reactions will be performed after administration of each dose of IMP, before 
the participant leaves the investigational site. All other trial 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 IMP. 
e Must be performed prior to any trial procedure. 
f 
 
  
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 8.3.1) will be assessed at randomization (visit 2) and EOT either by participants’ self-report or by physical 
examination according to the Tanner staging card provided. 
j Participants will be randomized to receive placebo IMP or 1 of 2 test IMP doses (based on body weight). 
k Twelve-lead ECGs will be performed in triplicate at any time during the visit, prior to IMP administration. 
l The method for measuring temperature in an individual participant must be the same at each timepoint. 
m Inquiries about adverse events will be made before and after IMP 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 participants 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. Participants 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 participant is unable to complete the diary themselves, then a parent/caregiver will complete the diary for them. 
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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 
participant/caregiver at the time points described. Any participant who demonstrates suicidal ideation and/or any suicidal behavior at any point during the trial 
should be withdrawn from the trial and discontinued from trial treatment. In addition, if a patient endorses suicidal ideation or behavior at any point during the 
trial (including during screening), the Investigator must explain to the participant/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; 
 
; sc=subcutaneous; V=visit.
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2. 
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 trials and 3 Phase 3 trials in adult participants with migraine. The 2 Phase 2b trials were 
a randomized, double-blind, placebo-controlled Phase 2b trial 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 participants with chronic migraine (CM) and a 
randomized, double-blind, placebo-controlled Phase 2b trial of 2 sc dosing regimens of 
fremanezumab (monthly fremanezumab at 675 or 225 mg) in participants with episodic migraine 
(EM). 
Two completed, randomized, double-blind, placebo-controlled Phase 3 trials (Trials TV48125-
CNS-30049 in CM and TV48125-CNS-30050 in EM and 1 completed, randomized, double-blind 
Phase 3 long-term safety trial (Trial 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 trials within the migraine 
development program of fremanezumab include the completed Phase 3b trial (Trial TV48125-
CNS-30068) in participants from the EU and US to evaluate the safety and efficacy of 
fremanezumab in migraine participants who have failed multiple preventive medications, 2 
ongoing Phase 2b/3 trials in Japanese and Korean EM and CM participants (Trials 406-102-
00002 and 406-102-00001, respectively), and 1 ongoing long-term safety trial (Trial 
406-102-00003) in CM and EM to evaluate the safety and efficacy of fremanezumab. One Phase 
4 trial (Trial TV48125-MH-40142) was conducted to evaluate the efficacy and safety of 
fremanezumab in adult participants 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 trial with administration of single sc doses of 75 mg in pediatric participants with migraine 
6 to 11 years of age, inclusive (Trial TV48125-CNS-10141). 
Fremanezumab is further studied for the preventive treatment of persistent posttraumatic 
headache (PPTH) in 1 Phase 2 trial (Trial TV48125-CNS-20024) that is comparing the efficacy 
and safety of the sc dose regimen of fremanezumab versus placebo in participants with PPTH. 
Fremanezumab was being studied for the preventive treatment of cluster headache (CH) in 3 
Phase 3 trials: Trial TV48125-CNS-30056 in participants with episodic CH, Trial TV48125-
CNS-30057 in participants with chronic CH, and a long-term safety Trial TV48125-CNS-30058 
in CH. All 3 trials 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 all 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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Detailed information on the test investigational medicinal product (IMP) (fremanezumab), 
nonclinical pharmacokinetics, toxicology studies, and clinical trials/studies are provided in the 
Investigator’s Brochure (IB). 
2.1. 
Purpose of Trial  
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 trial is to determine whether the test IMP is safe and effective in the 
preventive treatment of migraine in pediatric participants with CM. 
2.2. 
Summary of Benefits and Risks  
2.2.1. 
Known and Potential Benefits and Risks of the Test Investigational Medicinal 
Product and/or Device  
Known risks that do not impact the risk-benefit profile: 
• Injection site induration 
• Injection site erythema 
• Injection site pruritus 
• Injection site rash 
• Injection site pain 
2.2.2. 
Overall Benefit-Risk Conclusion  
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. Additional information regarding benefits and risks to participants may 
be found in the IB. 
In summary, the benefit and risk assessment for fremanezumab is favorable following review of 
the observed clinical adult data. 
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3. 
TRIAL OBJECTIVES, ENDPOINTS, AND ESTIMANDS  
3.1. 
Primary and Secondary Trial Objectives and Endpoints  
The primary and secondary trial objectives and endpoints are as follows: 
Objectives 
Endpoints 
The primary objective of the trial is to 
evaluate the efficacy of test investigational 
medicinal product (IMP) as compared to 
placebo IMP for the preventive treatment 
of chronic migraine (CM).  
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 
IMP.  
A secondary objective is to evaluate the 
safety and tolerability of test IMP in the 
preventive treatment of CM. 
The safety and tolerability endpoints are as follows: 
• 
occurrence of adverse events throughout the trial, 
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 trial is to 
further demonstrate the efficacy of test 
IMP as compared to placebo IMP for the 
preventive treatment of CM. 
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 IMP 
• 
proportion of participants reaching at least 50% 
reduction in the monthly average number of migraine 
days during the 12-week period after the first dose of 
IMP 
• 
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 IMP 
• 
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 IMP 
• 
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 IMP 
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Objectives 
Endpoints 
A secondary objective of the trial is to 
evaluate the immunogenicity of test IMP 
and the impact of antidrug antibodies 
(ADAs) on clinical outcomes in 
participants exposed to test IMP. 
• 
proportion of participants developing ADAs 
throughout the trial. The impact of ADAs on safety 
and efficacy will be analyzed if the number of 
ADA-positive participants allows. 
3.1.1. 
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 CM include patients that suffer ≥15 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. This requirement is consistent with 
migraine preventive treatment guidelines and also with the Teva adult CM trial inclusion criteria. 
As per the guidelines for controlled trials of preventive treatment of CM 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 (change from baseline on the monthly average number of 
migraine days) is a classical endpoint used in most prior studies of CM, 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 CM 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. 
3.2. 
Primary Estimand  
The primary estimand for this trial 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 IMP and have 
at least 10 days of electronic diary (eDiary) 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 
IMP as if there were no intercurrent events. Data collected after treatment discontinuation or 
prohibited therapy will not be used for assessing the primary estimand. 
3.3. 
Secondary Estimand(s)  
Not applicable. 
3.4. 
Exploratory/Other Objectives and Endpoints  
 
 
 
 
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4. 
TRIAL DESIGN  
4.1. 
Description of Trial Design  
This is a 4-month, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial 
to evaluate the efficacy, safety, and tolerability of 2 different doses (dependent on participants’ 
body weight) of test IMP and placebo IMP. Enrollment will include male and female participants 
(6 to 17 years of age, inclusive). 
The total duration of the trial is planned to be 75 months (from quarter [Q]2 2020 to Q3 2026). 
See Section 4.4 for the definition of the end of the trial. 
Participants will be randomly assigned in a 1:1 ratio between test IMP and placebo IMP 
treatment groups: 
• monthly sc administration of test IMP 
• monthly sc administration of matching placebo IMP 
The dose of test IMP to be administered will be determined by the participant’s weight at 
randomization (visit 2): 
• participants weighing ≥45.0 kg will receive monthly sc administration of test IMP at 
225 mg. 
• participants weighing <45.0 kg will receive monthly sc administration of test IMP at 
120 mg. 
The enrollment target is approximately 278 randomized participants in total. The trial 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 IMP). See Section 13.5 for recruitment strategy. 
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 trial assessments will be performed at visit 5 (EOT visit), 
approximately 28 days after the third (last) dose of IMP. Overall, participants will participate in 
the current trial for up to 4 months (including a 28-day baseline period and a 12-week, double-
blind treatment period).  
Participants 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 trial assessments, all eligible participants will be offered enrollment 
in a long-term safety and tolerability trial (Trial TV48125-CNS-30084), consisting of 9 months 
(36 weeks) of open-label treatment and 5 months of follow-up commencing from the last IMP 
administration. In the long-term safety extension trial, participants rolling over from the current 
trial will be weighed at visit 2 and will receive monthly test IMP with dose adjusted every 3 
months per weight category (225 mg in participants ≥45.0 kg or 120 mg in participants 
<45.0 kg). Participants who do not complete this trial and participants who complete this trial but 
do not wish to continue treatment may enroll in Trial TV48125-CNS-30084 for the purpose of 
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attending a follow-up visit for safety and antidrug antibodies (ADA) assessments approximately 
5 months (150 days [5 half-lives]) after receiving the last dose of IMP. 
Trial procedures and assessments with their time points are shown in Table 1. The trial schematic 
diagram is presented in Figure 1. 
The end of trial is defined as the date the last participant attends the EOT/early withdrawal visit 
(visit 5). 
4.1.1. 
Planned Number of Participants and Countries  
A planned total of approximately 278 participants will be randomized. The number of evaluable 
participants is planned to be approximately 266 (133 evaluable participants completing the trial 
per treatment group). Details on definition of evaluable participants and sample size are given in 
Section 9. 
The trial is planned to be conducted in 6 to 10 countries in approximately 85 investigational 
centers.  
4.1.2. 
Data Monitoring Committee/Safety Review Committee  
There will be no Data Monitoring Committee (DMC) in this trial. 
4.2. 
Rationale for Trial Design  
A multicenter, randomized, double-blind, placebo-controlled, parallel-group design is 
appropriate, given the objectives of this trial. 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 trial 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 all participants 
with CM due to the frequency of headaches and high degree of disability, participants using no 
more than 2 migraine preventive medications for any condition at the time of trial 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). For the purpose of this protocol, these medications 
are listed in Section 13.8. Participants on concomitant migraine preventive medications listed in 
Section 13.8 must be on a stable dose for at least 2 months prior to screening (visit 1), without 
anticipated changes during the trial. A list of migraine preventive medications allowed for any 
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condition for the duration of the trial for approximately 35% of participants is presented in 
Section 13.8. The total number of participants receiving concomitant preventive medication 
during the trial will not exceed approximately 35% of the total number of participants 
randomized. Randomization will be stratified by participants with and without migraine 
preventive medications in Section 13.8. 
4.3. 
Access to Trial Intervention After End of Trial  
For participants who do not wish to roll-over in the long term safety trial (TV48125-CNS-30084; 
Section 4.1) there is no access to test IMP (and/or pre-filled syringe [PFS]) after the end of the 
trial.  
4.4. 
Start of Trial and End of Trial  
The trial start date is the date on which the clinical trial will be open for recruitment of 
participants. 
The end of trial is defined as the date the last participant attends the EOT/early withdrawal visit 
(visit 5). 
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5. 
TRIAL POPULATION  
5.1. 
Selection of Trial Population  
This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial 
comparing the efficacy, safety, and tolerability of sc administration of test IMP versus placebo 
IMP for preventive treatment of CM in pediatric participants 6 through 17 years of age, 
inclusive. Eligible participants will be randomized in a 1:1 ratio between test IMP and placebo 
IMP treatment groups. Participants weighing ≥45.0 kg at randomization (visit 2) will receive a 
225 mg administration of test IMP or matching placebo IMP. Participants weighing <45.0 kg at 
randomization (visit 2) will receive a 120 mg administration of test IMP or matching placebo 
IMP. Randomization will be stratified by country, sex, puberty status, and preventive medication 
use at baseline (Yes/No). 
5.2. 
Rationale for Trial Population  
See Section 4.2. 
Prospective waivers (exceptions) from trial inclusion and exclusion criteria to allow participants 
to be randomized/enrolled are not granted by Teva (Section 11.2).  
5.3. 
Inclusion Criteria  
Participants may be included in this trial only if they meet all of the following criteria: 
a. The participants is a male or female between the ages of 6 to 17 years (inclusive) on 
the day of randomization to test IMP/placebo IMP. 
b. The participant’s parent(s) or legal guardian(s) must give written informed consent, 
and the participant must give assent (in accordance with local regulations). 
Note: In some countries, participants aged 15 to 17 years (inclusive) may give written 
informed consent; however, the participant’s parent(s) or legal guardian(s) must be 
informed, per local regulations. 
c. [Revision 01]The participant 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 ≥15 headache days per month on average during the 3 months prior to screening 
(visit 1). 
d. The participant or parent/caregiver has maintained a prospectively collected headache 
diary during a 28-day baseline period in which headache days were recorded on 15 or 
more days, and 8 or more of these headache days had 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. 
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− headache is preceded by an aura, as described by ICHD-3 criteria. 
− headache was treated by a nonsteroidal anti-inflammatory drug, paracetamol, 
triptan, or ergot preparation. 
e. This criterion was deleted  
f. [Revision 01]Not using migraine preventive medications (listed in Section 13.8) or 
using no more than 2 migraine preventive medications (listed in Section 13.8) for 
migraine or other medical condition, 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 trial for approximately 
35% of participants is presented in Section 13.8 . 
Note: A person is considered to be not using migraine preventive medications (listed 
in Section 13.8) 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 Section 13.8 but used for migraine prevention is permitted 
during the trial; however, these participants will not be counted towards the 
approximately 35% participant 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 Section 13.1. 
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 
trial (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 
trial and for 6 months after the last administration of IMP. Further details are included 
in Section 13.1. 
i. The participant/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 participant is in good health, as determined by a medical and psychiatric history, 
medical examination, 12-lead electrocardiogram (ECG), serum chemistry, 
hematology, coagulation, urinalysis, and serology. 
k. The participant/caregiver must be willing and able to comply with trial requirements 
and return to the clinic as required for the duration of the trial. 
l. The participant weighs at least 17.0 kg on the day of randomization to test 
IMP/placebo IMP. 
m. The participant 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 participant has received all recommended age-appropriate vaccines according to 
local standard of care and schedule prior to screening.  
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5.4. 
Exclusion Criteria  
Participants will be excluded from participating in this trial if they meet any of the following 
criteria: 
a. The participant 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 participant 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 participant 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 participant 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 participant 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 COVID-19. 
f. The participant has a past or current history of cancer. 
g. The participant is pregnant or nursing.  
h. The participant 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 participant is concomitantly using lamotrigine. 
i. The participant has participated in another trial 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 trial of an 
IMP (or a medical device). 
j. The participant 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 trial 
(Trial TV48125-CNS-10141). 
l. In the judgment of the Investigator, the participant has an abnormal finding on the 
baseline 12-lead ECG considered clinically significant. 
m. In the judgment of the Investigator, the participant has a significantly abnormal 
finding during the 28-day baseline period, including hematology, blood chemistry, 
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coagulation tests, or urinalysis values/findings (abnormal tests may be repeated for 
confirmation). 
n. The participant 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 participant has serum creatinine more than 1.5× the ULN, clinically significant 
proteinuria (urine dipstick +4), an estimated glomerular filtration rate (eGFR) 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 participant has any history of alcohol or drug abuse. The definition of alcohol or 
drug abuse, including marijuana, is based on the Investigator's clinical judgement. 
q. In the judgment of the Investigator, the participant cannot fully participate in or 
successfully complete the trial for its full duration for any of the following reasons: 
− The participant is mentally or legally incapacitated, or unable to give 
assent/consent for any reason. 
− The participant is in custody due to an administrative or a legal decision or is in 
residential treatment. 
− The participant /caregiver is unable to be contacted in case of emergency. 
− The participant has any other condition, which, in the opinion of the Investigator, 
makes the patient inappropriate for inclusion in the trial. 
− The participant is a relative of a trial center or Sponsor employee who is directly 
involved in the trial. 
r. Vulnerable participants (eg, people kept in detention) whose vulnerability is based on 
a condition other than the age required for trial eligibility. 
s. The participant 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 trial, the participant may receive a live 
attenuated vaccine. 
t. The participant has a known hypersensitivity to the active substance or to any of the 
excipients of the IMP. 
u. The participant has a current or past medical history of hemiplegic migraine. 
5.5. 
Lifestyle Considerations  
Medications prohibited before and/or during the trial are described in Section 6.8 and the 
exclusion criteria (Section 5.4). Restrictions with regard to pregnancy and required laboratory 
values are provided in the inclusion and exclusion criteria (Section 5.3 and Section 5.4, 
respectively). Restrictions regarding contraception methods are detailed in the inclusion and 
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exclusion criteria (Section 5.3 and Section 5.4, respectively) and are also described in 
Section 13.1. 
Participants 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 trial. 
5.6. 
Screen Failures  
Screen failures are defined as participants who consent to participate in the clinical trial but are 
not subsequently randomized in the trial. A minimal set of screening failure information will be 
entered in the Case Report Form (CRF). Minimal information includes but is not limited to 
demography, screening failure details, eligibility criteria, and any serious adverse events. 
A participant who is screened but not enrolled (eg, because trial 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 participant’s medical background, a 
modification of trial 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 participant may be rescreened 1 time; this information should 
be recorded in the CRF. 
Participants may have individual parameters retested at the discretion of both the Investigator 
and the Sponsor. 
Participants 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 participant is rescreened, an informed consent form (ICF) will need to be re-signed, and a 
new screening number will be assigned.  
A participant who is randomized/enrolled but does not complete the treatment period will not be 
replaced.  
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6. 
TRIAL INTERVENTION AND CONCOMITANT THERAPY  
6.1. 
Description of Trial Intervention(s)  
6.1.1. 
Investigational Medicinal Products Used in the Trial  
Investigational medicinal product is defined as the test IMPs and matching placebo IMPs to the 
respective test IMPs. The IMPs used in this trial are described in Table 2. 
 
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Table 2: 
Investigational Medicinal Products Used in the Trial  
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 participants  with body 
weight ≥45.0 kg at randomization (visit 2) 
120 mg monthly dose in participants with body 
weight <45.0 kg at randomization (visit 2) 
Not applicable 
Route of administration 
Subcutaneous injection 
Subcutaneous injection  
Dosing instructions 
Participants 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 
 
Participants 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 
Participants with body weight ≥45.0 kg at 
randomization (visit 2):  
Placebo: single 1.5-mL injection at visits 2, 3, and 
4  
 
Participants with body weight <45.0 kg at 
randomization (visit 2):  
Placebo: single 0.8-mL injection at visits 2, 3, and 
4 
Intervention type 
Drug 
Placebo 
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 
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IMP name 
Test IMP 
Placebo IMP 
Manufacturer 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
IMP=investigational medicinal product; INN=international nonproprietary name; PFS=pre-filled syringe. 
 
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6.1.1.1. 
Test Investigational Medicinal Product  
The formulation of test IMP to be used for clinical investigations in the pediatric population will 
be identical to the sc formulation of test IMP that will be used in the clinical program for adults.  
Additional details may be found in the IB for test IMP.  
6.1.1.1.1. Starting Dose and Dose Levels  
Participants will be randomly assigned in a 1:1 ratio between test IMP and placebo IMP 
treatment groups: 
• monthly sc administration of test IMP 
• monthly sc administration of matching placebo IMP 
The dose of test IMP to be administered will be determined by the participant’s weight at 
randomization (visit 2): 
• participants weighing ≥45.0 kg at randomization (visit 2) will receive monthly sc 
administration of test IMP at 225 mg. 
• participants weighing <45.0 kg at randomization (visit 2) will receive monthly sc 
administration of test IMP at 120 mg. 
(Note: For this trial, 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 (participants weighing ≥45.0 kg at randomization [visit 2]) or a 0.8 mL 
volume (participants 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. Participants randomized to the placebo IMP group will receive volume-
matched doses of placebo IMP. 
6.1.1.2. 
Placebo Investigational Medicinal Product  
The placebo IMP will match the test IMP in appearance and volume. See Table 2 for a 
description of the placebo IMP. 
6.2. 
Rationale for Trial Intervention(s)  
6.2.1. 
Justification for Test Investigational Medicinal Product and/or Device and Dose  
Examination of the relationship between test IMP exposure and baseline body weight supports 
the consideration of a weight cutoff of 45.0 kg for dose selection. Participants weighing ≥45.0 kg 
will be administered the approved adult dose of 225 mg monthly, and participants weighing 
<45.0 kg will be administered 120 mg monthly based on the results of the modeling and 
simulation-based strategy described below. 
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Aside from the effects of weight on clearance and volume of distribution, other physiological 
differences between adults and children are not anticipated to have a significant influence on the 
pharmacokinetic profile of test IMP. Absorption of mAbs is believed to occur via convective 
transport through the lymphatic endothelium and by diffusion of antibody at the site of injection 
(Wang et al 2008). As such, differences in lymph flow between adults and pediatric participants 
may have an impact on the absorption of mAbs. Elimination of test IMP is expected to occur via 
proteolytic catabolism. Based on this mechanism, differences in endogenous immunoglobulin G 
(IgG) concentrations or neonatal Fc receptor expression may impact the pharmacokinetic profile 
of test IMP in children compared to adults. Although IgG1 concentrations reach adult levels by 
age 5, the concentrations of IgG2 (test IMP is recombinant humanized IgG2 mAb) reach adult 
levels more slowly (Edlund et al 2015). 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 participants 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 test IMP 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 participants with migraine weighing ≥45 kg, 
in addition to the evidence supporting the lack of expected difference in pharmacokinetics 
between adults and adolescent participants, the use of 225 mg monthly was proposed in pediatric 
participants weighing ≥45 kg. 
The final dose for participants <45.0 kg was determined by taking into account observed 
pharmacokinetic data from Trial TV48125-CNS-10141, a Phase 1 trial in pediatric participants 6 
to 11 years of age (inclusive). Data from this trial (TV48125-CNS-10141) were used to refine the 
current adult population pharmacokinetic model (which was based on adult data from 2 Phase 1 
trials [Trials LBR-101-011 and TV48125-PK-10078], 2 Phase 2b trials [Trials LBR-101-021 and 
LBR-101-022], and 3 Phase 3 trials [Trials 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 weight effect on clearance and central volume adequately 
described the test IMP concentration-time data observed in pediatric participants with migraine. 
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 test 
IMP 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 
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were calculated at steady state for the virtual pediatric patients and compared to exposure 
measured at steady state in the adult population receiving test IMP 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 participant 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 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.  
Additional simulations of dose selection for pediatric participants 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 trial 
(Trial 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 test IMP. 
Considering the wide safety margin for f test IMP with substantial evidence supporting the safety 
of the approved dose of 225 mg sc monthly in adults, the expected exposures in pediatric 
participants 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 trials and were found to be safe 
and well tolerated. Safety margin data from a nonclinical study in juvenile rats indicate that at 
the no observed adverse effect level dose of 450 mg/kg/week (see IB), 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. 
Given the wide safety margin of test IMP 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 participants aged 6 to 
17 years (inclusive) with weight values <45.0 kg based on targeting the achievement of a similar 
distribution of test IMP exposure levels (following multiple dosing) of 225 mg monthly in adult 
participants with EM and CM.  
The formulation of test IMP to be used for clinical investigations in the pediatric population will 
be identical to the sc formulation of test IMP that was used in the clinical program for adults. 
6.2.2. 
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 trial. 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 IMP rather than an active comparator is justified in this trial because of the 
limited availability of a suitable comparator. Topiramate is the only migraine preventive 
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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 
participants ages 6 through 11. 
6.3. 
Dosing and Administration  
See Section 6.1.1.1.1. 
Participants must remain at the site, for safety observation, for at least 30 minutes after injection 
or longer if deemed necessary by medical judgment.  
6.4. 
Treatment of Overdose  
See Section 8.3.7. 
6.5. 
Preparation, Handling, Labeling, Storage, and Accountability  
6.5.1. 
Storage Conditions and Handling  
The test IMP 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 test IMP remains suitable for use until the expiration date printed on the 
primary container and/or carton. Do not use test IMP if the liquid is cloudy, discolored, or 
contains visible flakes or particles. The test IMP 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. 
6.5.2. 
Labeling  
Supplies of IMPs will be labeled according to the current ICH guidelines on Good Clinical 
Practice (GCP), Good Manufacturing Practice and will include any locally required statements. 
If necessary, labels will be translated into the local language. 
6.5.3. 
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 trial 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 participants enrolled in the trial 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 
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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 trial 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. 
Further guidance and information are provided in the Trial Reference Manual, Pharmacy 
Manual, or other specified location. 
6.6. 
Participant Assignment, Randomization, and Blinding  
6.6.1. 
Participant Assignment and Randomization  
This is a double-blind trial. The Sponsor, Investigators, trial staff (except for staff involved in 
bioanalytical analyses), and participants 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 trial 
visits will be managed by interactive response technology (IRT) and kept (refrigerated at 2°C to 
8°C) on site.  
This is a randomized trial. Randomization will be stratified by country, sex, puberty status, and 
preventive medication use at baseline (Yes/No). Participants 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 
participant will undergo randomization in a 1:1 ratio within the stratum to which he or she 
belongs to receive test IMP or placebo IMP, as assigned by the IRT. The IRT will manage initial 
drug supply, maintenance of adequate IMP supplies on site, and trial randomization centrally. At 
the time of each trial visit, the IRT will be queried, and site personnel will retrieve and 
administer a 1.5 mL volume for participants weighing ≥45.0 kg at randomization (visit 2) or a 
0.8 mL volume for participants 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 trial 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. 
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6.6.2. 
Maintenance of Randomization  
Participant 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 trial), after receiving 
unblinding request from Teva statistician, the service provider will provide the unblinded IMP 
assignment according to the processes defined in the relevant SOP. 
6.6.3. 
Blinding and Unblinding  
Blinded pharmacokinetic data may be assessed during the trial. For participants 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 trial (of those participants 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 participants (ie, a dummy participant identifier will be 
linked to the concentration data of an individual participant). 
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 participant’s 
IMP assignment as deemed necessary, mainly in emergency situations. Individual randomization 
codes, indicating the IMP assignment for each randomized participant, will be available to the 
Investigator(s) or pharmacist(s) at the investigational center via the Randomization and Trial 
Supply Management system, 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 participant’s IMP 
assignment should not be revealed to the Sponsor. 
When a blind is broken, the participant will be withdrawn from the trial 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 trial files and in the participant’s source documentation. 
Assignment of IMP should not be recorded in any trial documents or source document. 
In blinded trials, for an adverse event defined as a suspected unexpected serious adverse reaction 
(SUSAR) (ie, reasonable possibility; see Section 8.4.4.2 ), Global Pharmacovigilance (Global 
PV) 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 trial, and analysis and reporting of the data. 
6.7. 
Trial Intervention Compliance  
The Investigator will be responsible for monitoring participant compliance. If the Investigator or 
the Sponsor determines that the participant is not in compliance with the trial protocol, the 
Investigator and the Sponsor should determine whether the participant should be withdrawn from 
the trial. The Independent Ethics Committee (IEC)/Institutional Review Board (IRB) should be 
notified. 
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6.8. 
Prior and Concomitant Therapy  
All prior therapy, medication, or procedure (ie, procedures for the treatment of migraine [eg, 
nerve blocks]) for the treatment of migraine a participant has had during their lifetime will be 
recorded on the CRF. In addition, all concomitant medications taken during the trial 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 or chronic use during the trial: opioids 
(including codeine), barbiturates (including Fiorinal®, Fioricet®, or any other combination 
containing butalbital), and lamotrigine. 
Approximately 35% of participants 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. For the purpose of this protocol, these 
medications are listed in Section 13.8. Additional details on migraine preventive medications are 
provided in Section 13.8. For chronic use of these medications for any indication, participants 
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 trial. For the remaining approximately 65% of participants, 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 trial 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. Participants 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. 
Participants 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. 
The chronic use of concomitant therapies not listed in Section 13.8 for any indication is allowed 
throughout the course of the trial. All participants 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 trial. PRN use of medications for adverse 
events or intercurrent acute situations are allowed.  
Participants 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 trial, the participant may receive a live 
attenuated vaccine. 
All concomitant medications taken during the trial, 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 participants will be questioned about concomitant 
medication use at each visit. 
Concomitant medication and treatment will be recorded until visit 5. 
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7. 
DISCONTINUATION OF TRIAL INTERVENTION AND 
PARTICIPANT WITHDRAWAL FROM TRIAL  
7.1. 
Discontinuation of Trial Intervention  
In the following circumstances for participant 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 participant must be withdrawn from the IMP if the participant experiences a severe 
hypersensitivity reaction or anaphylaxis. 
Additionally, IMP should be discontinued if the participant experiences an adverse event or other 
medical condition indicating to the Investigator that continued participation is not in the best 
interest of the participant. 
A participant who is randomized/enrolled but does not complete the treatment period will not be 
replaced (see Section 9.8). 
All protocol-specified procedures/assessments should be performed at the EOT/early withdrawal 
visit (see Table 1).  
7.2. 
Participant Withdrawal from the Trial  
Each participant is free to withdraw from the trial or discontinue from IMP at any time, without 
prejudice to their continued care. Participants must be withdrawn from the trial if any of the 
following events occur:  
• Participant withdraws consent or requests discontinuation from the IMP or 
withdrawal from the trial for any reason. 
• Participant develops an illness that would interfere with his/her continued 
participation. 
• Participant is noncompliant with the trial procedures and assessments or 
administration of IMPs in the opinion of the Investigator. 
• Participant takes prohibited concomitant medications chronically. 
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• A female participant has a confirmation of pregnancy during the trial from a positive 
pregnancy test.  
• The Sponsor requests withdrawal of the participant. 
• Participant experiences an adverse event or other medical condition indicating to the 
Investigator that continued participation is not in the best interest of the participant. 
• Any participant who demonstrates suicidal ideation and/or any suicidal bahavior at 
any point during the trial should be withdrawn from the trial and discontinued from 
trial treatment. 
Participants should be treated with standard of care after withdrawal from or termination of the 
trial as appropriate. 
Investigators should attempt to obtain information on participants in the case of withdrawal from 
the trial or discontinuation from IMP. Results of any evaluations and observations, together with 
a narrative describing the reason(s) for withdrawal from the trial or discontinuation from IMP, 
must be recorded in the source documents. The CRF must document the primary reason for 
withdrawal from the trial or discontinuation from IMP. 
See Section 7.3 for information regarding how the trial will define and address lost to follow-up 
participants to help limit the amount and impact of missing data. 
If the reason for withdrawal from the trial 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 participant 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 trial 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 Investigator must inform the Trial Leader as soon as possible of each participant who is 
being considered for withdrawal due to adverse events. Additional reports must be provided 
when requested. 
If a participant is withdrawn from the trial 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 participant. 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). Participants who withdraw from the trial or have an early termination will be 
invited to enter the long-term safety extension (within Trial 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 IMP in this trial. 
In the case of participants lost to follow-up, attempts to contact the participant must be made and 
documented in the participant’s medical records and transcribed to the CRF. 
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7.3. 
Lost to Follow-Up  
A participant 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 participant fails to return to the investigational center 
for a required trial visit: 
• The investigational center must attempt to contact the participant and reschedule the 
missed visit as soon as possible and counsel the participant on the importance of 
maintaining the assigned visit schedule and ascertain whether or not the participant 
wishes to and/or should continue in the trial. 
• In cases in which the participant is deemed lost to follow-up, the Investigator or 
designee must make every effort to regain contact with the participant in accordance 
with the investigational center standard procedures (where possible, 3 telephone calls 
and, if necessary, a certified letter to the participant’s last known mailing address or 
local equivalent methods). These contact attempts should be documented in the 
participant’s medical record and transcribed to the electronic case report forms. 
• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the trial with a primary reason of “lost to follow-up.” 
7.4. 
Trial Stopping Rules  
There are no formal rules for early termination of the trial. During the conduct of the trial, 
serious adverse events will be reviewed as they are reported from the investigational centers to 
identify safety concerns.  
The trial may be terminated by the Sponsor for any reason at any time. For example, the Sponsor 
should terminate the trial 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 IMP 
If the whole trial or arms of the trial are stopped, the participants that are terminated early will be 
followed according to criteria outlined in Section 7.2.  
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8. 
TRIAL ASSESSMENTS AND PROCEDURES  
8.1. 
Screening/Baseline Assessments and Procedures  
A signed and dated ICF will be obtained before screening procedures commence (see 
Section 10.3). Procedures performed at screening are listed in Table 1 and Section 13.9. 
Evaluations obtained as part of routine medical care and performed during the screening period 
may be used in place of the protocol-specific evaluations. Participants will acknowledge and 
agree to the possible use of this information for the trial by giving informed consent.  
Participants may have individual parameters retested at the discretion of both the Investigator 
and the Sponsor (also see Section 5.6). 
Participants who fulfil the inclusion criteria and meet none of the exclusion criteria at the 
screening visit may be enrolled in the trial.  
8.2. 
Efficacy Assessments and Procedures  
Data from any efficacy assessments performed after the specified time (see Table 1) will not be 
collected on the CRF; in the event, however, that such data are collected, these data will not be 
analyzed. 
8.2.1. 
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 participants and parents/caregivers will receive comprehensive training from site 
personnel on the use of the electronic headache diary device. Site personnel will also instruct 
participants and parents/caregivers on the requirement for timely and daily completion of the 
eDiary. Participants will complete an electronic headache diary. If the participant is unable to 
complete the diary themselves then a parent/caregiver will complete the diary for them. 
On each day, the participant or parent/caregiver will be asked to record diary data for the 
previous 24-hour period. Participants and parents/caregivers may be asked about their (child’s) 
performance at school and when doing household chores (ie, functional assessments). 
Participants 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 participants or parents/guardians will answer can be found in the electronic headache 
diary training manual.  
If a participant or parent/caregiver fails to complete the diary for the preceding day, the 
participant will be prompted to enter the missed day’s information the next time he/she accesses 
the eDiary, 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 participant 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 
eDiary.  
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If headache is reported, then headache severity will be subjectively rated by the participant 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). Participants 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. 
8.2.2. 
Pediatric Migraine Disability Assessment  
The Pediatric Migraine Disability Assessment (PedMIDAS) questionnaire is a 6-item instrument 
to assess migraine-related disability in pediatric participants, which can be self-administered by 
the participant or administered by a caregiver. It has been validated in patients aged 4 through 18 
years (Hershey et al 2001) and includes questions related to the impact of headache on school 
performance, disability at home (eg, inability to do chores or homework), and social/sport 
functioning.  
8.2.3. 
  
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.2.4. 
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 
trial will use the young child, child, and adolescent formats. The PedsQL version that will be 
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used for the participant for the duration of the trial will be based on the age of the participant at 
visit 2 and will not change during the course of the trial. 
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.  
8.3. 
Safety Assessments and Procedures  
In this trial, safety will be assessed by qualified trial personnel by evaluating reported adverse 
events, vital signs measurements, clinical laboratory test results, ECG findings, physical 
examination findings (including body weight and height measurements), suicidal ideation and 
behavior (as suggested by the Columbia-Suicide Severity Rating Scale [C-SSRS]), and use of 
concomitant medication.  
8.3.1. 
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 participants’ self-report or by physical examination 
according to the Tanner staging card provided. 
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 8.4.5.  
8.3.2. 
Vital Signs  
Vital signs (pulse, systolic and diastolic blood pressure (BP), 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 participant must be the same at each time point. 
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Before pulse and BP are measured, the participant 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 participant. 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 8.4.5.  
8.3.3. 
Electrocardiograms  
Twelve-lead ECGs will be conducted at any time during the visit, prior to IMP administration, as 
detailed in Table 1. The ECGs should be performed after the participant 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 
source documentation and transcribed onto the CRF, and monitored as described in 
Section 8.4.5.  
8.3.4. 
Clinical Laboratory Tests  
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 trial 
Laboratory Manual and the central laboratory's SOPs. 
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8.3.4.1. 
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 8.4.5. An adverse event may include a laboratory or diagnostic test abnormality (once 
confirmed by repeated testing) that results in the withdrawal of the participant from the trial, 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 
participant from entering the trial 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 in Section 13.2. Note, reflex tests (eg, red 
blood cell [RBC] shapes, RBC morphology, and other microscopic findings) may be triggered 
automatically.  
8.3.4.2. 
Other Laboratory Tests  
8.3.4.2.1. Human Chorionic Gonadotropin Tests  
Serum β-HCG tests will be performed for all female participants 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 participant who becomes pregnant during the trial will be withdrawn. 
Procedures for reporting the pregnancy are provided in Section 8.5.  
8.3.5. 
Suicidal Ideation and Behavior Risk Monitoring  
The C-SSRS, combined with the Investigator’s clinical evaluation, will be used to assess whether 
the participant 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 participant /caregiver at the time points described in Table 1. Any 
participant who demonstrates suicidal ideation and/or any suicidal behavior at any point during 
the trial should be withdrawn from the trial and discontinued from trial treatment. In addition, if 
a participant endorses suicidal ideation or behavior at any point during the trial (including during 
screening), the Investigator must explain to the participant /caregiver the need for follow-up with 
a mental health professional and make any necessary referrals.  
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8.3.6. 
Assessment of Local Tolerability and Pain  
Injection site assessment will be performed after administration of each dose of IMP, before the 
participant 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 participant’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 8.4.1.1 and 
Section 9.5.1.  
8.3.7. 
Medication Error and Special Situations Related to the Investigational 
Medicinal Products  
Any administration of IMP that is not in accordance with the trial protocol should be reported as 
a protocol deviation and documented in the participant’s source documents (see Section 11.2), 
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, 
participant, 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. 
4. Abuse: Persistent or sporadic, intentional excessive use of IMP which is accompanied by 
harmful physical or psychological effects. 
5. Occupational exposure: Exposure to an IMP, as a result of one’s professional or 
non-professional occupation. 
The Investigator should refer to Section 8.6 to evaluate whether the medication error or special 
situation may be due to a device deficiency. 
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8.4. 
Adverse Events and Serious Adverse Events  
8.4.1. 
Definitions of Adverse Events and Serious Adverse Events  
8.4.1.1. 
Adverse Events  
Adverse events are categorized according to ICH guidelines and adverse device effects are 
categorized and classified according to ISO standard 14155. The procedures for device 
deficiencies that are not associated with an adverse event, as well as those that are associated 
with an adverse event or that have the potential to cause a serious adverse event, are described in 
Section 8.6. 
An adverse event is any untoward medical occurrence in a participant administered a 
pharmaceutical product and which does not necessarily 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 trial, or 
significant worsening of the disease under study, or of any concurrent disease, whether or not 
considered related to fremanezumab. 
Accordingly, an adverse event can include any of the following:  
• a new condition or the worsening of a preexisting condition  
• intercurrent illnesses  
• physical injuries and the mechanism that caused the injury 
• events possibly related to concomitant medication 
• drug/drug or drug/device interactions 
• events occurring during diagnostic procedures or during any washout phase of this 
trial 
• laboratory or diagnostic test abnormalities (note: Abnormal laboratory or diagnostic 
test results at the screening visit that preclude a participant from entering the trial or 
receiving trial treatment are not considered adverse events 
Worsening of the disease under study that occurs during the trial that is not typical of the 
participant’s daily symptoms or leads to the participant’s discontinuation will be considered an 
adverse event. Stable chronic conditions (such as arthritis) that are present before trial entry and 
do not worsen during this trial will not be considered adverse events. 
Migraine exacerbations, including acute headache, requiring headache medications will be 
collected as part of the efficacy assessment in this trial. 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 participant or if they are severe enough to require hospitalization of the participant, in 
which case they are recorded as serious adverse events. 
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8.4.1.2. 
Serious Adverse Events  
A serious adverse event is an adverse event occurring at any dose that results in any of the 
following outcomes or actions: 
• results in death 
• is a life-threatening adverse event (ie, the participant 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 participant signed the ICF will not be 
considered serious adverse events, unless there was worsening of the preexisting 
condition during the participant’s participation in this trial. 
• 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 participant 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 liver injury that meets the criteria for Hy’s Law; or the 
development of drug dependency or drug abuse. Note: Any suspected transmission of 
an infectious agent via a medicinal product is considered an important medical event. 
An adverse event that does not meet any of the criteria for seriousness listed above will be 
regarded as a nonserious adverse event. 
See Section 12.2 for guidance regarding monitoring participants with elevated liver function 
tests. 
8.4.1.3. 
Adverse Device Effects and Serious Adverse Device Effects  
An adverse device effect is an adverse event related to the use of a medical device (standalone or 
in 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. 
A serious adverse device effect results in any of the consequences characteristic of a serious 
adverse event (Section 8.4.1.2) and is reported per Section 8.4.7. 
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8.4.2. 
Time Period and Frequency for Collecting Adverse Event and Serious Adverse 
Event Information  
For adverse event recording, the trial period is defined for each participant as the time period 
from signature of the ICF through completion of visit 5 or the early withdrawal visit (for 
participants who withdraw from the trial for any reason). Adverse events will be collected at 
each visit via adverse event inquiry.  
For recording of serious adverse events, the trial period is defined for each participant as that 
time period from signature of the ICF to visit 5 (EOT visit). Serious adverse events occurring in 
a participant after visit 5 (EOT visit) should be reported to the Sponsor if the Investigator 
becomes aware of them, following the procedures described in Section 8.4.7. 
Treatment-emergent adverse events are defined as adverse events that occurred after the first 
dose of IMP (and/or PFS) was administered through the end of the trial. 
8.4.3. 
Identifying Adverse Events and Serious Adverse Events  
At each contact with the participant, the Investigator or designee must question the participant 
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, if it is a serious adverse 
event, also on the serious adverse event form. 
8.4.4. 
Recording of Adverse Events and Serious Adverse Events  
All adverse events that occur during the defined trial period must be recorded both on the source 
documentation and the CRF, regardless of the severity of the event or judged relationship to the 
IMP (and/or PFS). The Investigator will record all relevant information regarding every adverse 
event/serious adverse event and will categorize each as guided in Figure 2. For serious adverse 
events and protocol-defined adverse events of special interest for expedited reporting to Global 
PV, 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 within 24 hours (Section 8.4.7). The Investigator does not need 
to actively monitor participants for new adverse events after the end of the trial. 
Serious adverse events and/or serious adverse device effects occurring in a participant after the 
end of trial should be reported to the Sponsor if the Investigator becomes aware of them, 
following the procedures described in Section 8.4.7.  
The onset and end dates, duration (in case of adverse event duration of less than 24 hours), action 
taken regarding IMP (and/or PFS), treatment administered, and outcome for each adverse event 
must be recorded on both the source documentation and the CRF.  
The relationship of each adverse event to IMP (and relationship to the device, if applicable), and 
the severity and seriousness of each adverse event, as judged by the Investigator, must be 
recorded. 
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The Investigator should make an initial determination whether the adverse event may be related 
to a device deficiency, using Figure 2, Table 4, and Table 5. 
Figure 2: 
Decision Tree for Adverse Events and Adverse Device Effects Classification  
AE
NO
YES
YES
YES
NO
AE
ADE
• 
Record on the source documentation and 
on the CRF
• 
Report the device deficiency according to 
Section 8.6
SAE
NO
SADE
• 
Notify Teva and IEC/IRB according to the 
process outlined in Section 8.4.7
• 
Report the device deficiency according to 
Section 8.6
Initial determination 
per Section 8.6: Could 
the SAE be related to 
the device?
Initial 
determination per 
Section 8.6: Could the 
AE be related to the 
device?
Does the AE meet the 
serious criteria? 
Is the device 
manufactured by Teva?
YES
NO
• 
Forward details of the AE related to the 
device to the manufacturer or wholesaler 
of the device
Is the device 
manufactured by Teva?
YES
• 
Forward details of the SAE related to the 
device, together with the CIOMS form, to 
the manufacturer or wholesaler of the 
device
NO
 
AE=adverse event; ADE=adverse device effect; CIOMS=Council for International Organizations of Medical 
Sciences; CRF=case report form; IEC=Independent Ethics Committee; IRB=Institutional Review Board; 
SADE=serious adverse device effect; SAE=serious adverse event. 
Further details are given in the Safety Monitoring Plan. 
8.4.4.1. 
Severity of an Adverse Event  
The severity of each adverse event must be recorded as one of the following: 
• Mild:  
No limitation of usual activities 
• Moderate:Some limitation of usual activities 
• Severe: 
Inability to carry out usual activities 
8.4.4.2. 
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 in Table 3: 
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Table 3: 
The Relationship of an Adverse Event to the Investigational Medicinal 
Product 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 
participant’s clinical state, environmental or toxic 
factors, or other modes of therapy administered to 
the participant. 
• 
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 participant’s clinical state, 
environmental or toxic factors, or other modes of 
therapy administered to the participant. 
• 
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; PFS=pre-filled syringe. 
8.4.4.3. 
Expectedness of Serious Adverse Events  
A serious adverse event that is not included in the Adverse Reaction section of the relevant 
Reference Safety Information (RSI) by its specificity, severity, outcome, or frequency is 
considered an unexpected adverse event. The RSI for this trial is the IB. 
The Sponsor’s Global PV will determine the expectedness for all serious adverse events. 
For the purpose of SUSAR reporting, the version of the IB effective at the time of occurrence of 
the SUSAR applies. 
An unanticipated serious adverse device effect for the integral medical device developed by the 
Sponsor is a serious adverse effect caused by, or associated with, the device that is not listed in 
Section 8.6.5, Table 4 and Table 5. 
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8.4.5. 
Follow-Up of Adverse Events and Serious Adverse Events  
The clinical course of each adverse event will be monitored at suitable intervals until resolved, 
stabilized, or returned to baseline; or until the participant is referred for continued care to a 
healthcare professional; or until a determination of a cause unrelated to the IMP (and/or PFS) or 
trial procedure is made.  
The Investigator may perform additional laboratory tests or investigations, histopathological 
examinations, or consult with other healthcare professionals to elucidate the nature and/or 
causality of the adverse event or serious adverse event as fully as possible. 
If a participant dies during participation in the trial or during a recognized follow-up period, the 
Investigator will provide postmortem findings including histopathology, if available, within the 
Serious Adverse Event Form. 
New or updated information will be recorded in the originally submitted documents. 
The Investigator will submit any updated data on serious adverse events to Global PV within 
24 hours of receipt of the information, following the process described in Section 8.4.7. 
8.4.6. 
Reporting of Serious Adverse Events  
To satisfy regulatory requirements, the Investigator must report all serious adverse events that 
occur during the trial, regardless of the judgment of relationship to administration of the IMP 
(and/or PFS), to the Sponsor except for serious adverse events listed in Section 8.4.9. The 
Investigator must report the event within 24 hours of learning 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 Serious Adverse Event Form should be sent to the Local Safety Officer (LSO) or designee 
(as applicable, for eg, a contract research organization [CRO]) in a country without a Sponsor 
LSO); the LSO will forward the report to the Sponsor’s Global PV. 
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 (and/or 
PFS), trial procedures, and to underlying disease. 
The Investigator should forward additional information (follow-up) about any serious adverse 
event unavailable at the initial reporting within 24 hours of when it becomes known, following 
the same process as for the initial report. 
The process for serious adverse device effect reporting to Global PV is the same as for serious 
adverse event reporting.  
The following information should be provided to record the event accurately and completely: 
• trial number 
• Investigator and investigational center identification 
• participant number 
• onset date and detailed description of adverse event 
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• 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 participant 
• date of first dose of IMP 
• date and amount of last administered dose of IMP 
• action taken 
• outcome, if known 
• severity 
• explanation of assessment of relatedness 
• concomitant medication (including doses, routes of administration, and regimens) and 
treatment of the event 
• pertinent laboratory or other diagnostic test data 
• medical history 
• results of dechallenge/rechallenge, if known 
• for an adverse event resulting in death 
− cause of death (whether or not the death was related to IMP) 
− autopsy findings (if available) 
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 8.5).  
8.4.7. 
Regulatory Reporting Requirements for Serious Adverse Events  
If a serious unexpected adverse event (ie, the event fulfills the criteria for a SUSAR) or serious 
adverse device effect is believed to be related to the IMP (and/or PFS), the Sponsor will take 
appropriate steps to notify all Investigators participating in sponsored clinical trials of 
fremanezumab and the appropriate competent authorities (and IRB/IEC, as applicable). 
For all countries, the Sponsor’s Global PV will distribute the Council for International 
Organizations of Medical Sciences (CIOMS) form/XML file to the LSO/CRO for submission to 
the competent authorities, IRBs/IECs, and Investigators, according to regulations. For trials in 
the EEA, submission of SUSARs is done centrally to European Medicines Agency (EMA) by the 
Global PV. The Investigator must ensure that the IRB/IEC is also informed of the event, in 
accordance with national and local regulations. 
Blinding will be maintained for all trial personnel. Therefore, in case of a SUSAR, only the 
LSO/CRO unblinded personnel will receive the unblinded report for regulatory submission; the 
others will receive a blinded report. 
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In addition to notifying the Investigators and competent authorities (and IRB/IEC, if 
appropriate), other measures may be required, including the following: 
• modifying the protocol and/or ICF 
• discontinuing or suspending the trial 
• modifying listings of expected toxicities to include adverse events newly identified as 
related to fremanezumab (and/or PFS).  
8.4.8. 
Adverse Events of Special Interest  
8.4.8.1. 
Protocol-Defined Adverse Events of Special Interest that Require Reporting to 
Sponsor’s Global PV  
For purposes of this protocol, the following are considered protocol-defined adverse events of 
special interest to be sent to the Sponsor’s Global PV 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 Section 12.1. In the event of suspected 
anaphylaxis, vital signs (including oxygen saturation and respiration rate) will be measured. 
The process for reporting a protocol-defined adverse event of special interest is the same as that 
for reporting a serious adverse event (Section 8.4.6), using the same Serious Adverse 
Event/Protocol-Defined Adverse Events of Special Interest Form. Protocol-defined adverse 
events of special interest to be reported to Global PV can be either serious or nonserious, 
according to the criteria outlined in Section 8.4.1. Protocol-defined adverse events of special 
interest that occur before IMP (and/or PFS) administration do not require reporting to Global PV.  
Adverse events of special interest for pediatric participants are not listed in the Pediatric 
Investigation Plan or Pediatric Study Plan. 
8.4.9. 
Disease-Related Events or Outcomes not Qualifying as Adverse Events or 
Serious Adverse Events  
Disease state is an efficacy variable for this trial and should be captured on the eCRF; 
accordingly, disease-related manifestations should not be recorded as adverse events unless 
assessed as more severe than the participant’s usual disease course. Disease manifestations that 
are more severe than the participant’s usual course of disease and meet the criteria for a serious 
adverse event should be reported as a serious adverse event. 
8.4.10. 
Protocol Deviations Because of an Adverse Event  
If a participant experiences an adverse event or medical emergency, deviations from the protocol 
may be allowed on a case-by-case basis. To ensure participant safety, after the event has 
stabilized or treatment has been administered (or both), the Investigator or other physician in 
attendance must contact the Clinical Leader as soon as possible to discuss the situation. The 
Investigator, in consultation with the Sponsor, will decide whether the participant should 
continue to participate in the trial. 
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8.5. 
Pregnancy and Postpartum Information  
Any female participant becoming pregnant during the trial will discontinue IMP (and/or PFS) 
and will be withdrawn from the trial. 
All pregnancies of women participating in the trial and female partners of men participating in 
the trial , if applicable that occur during the trial or within at least 5 half-lives (ie, 6 months) or 
180 days from last IMP dose, whichever is longer, are to be reported within 24 hours from 
Investigator awareness. The completed Pregnancy Form should be sent to the LSO/CRO (as 
applicable, for eg, a CRO in a country without a Sponsor LSO); the LSO will forward the report 
to the Sponsor’s Global PV. The process for reporting a pregnancy is the same as that for 
reporting a serious adverse event but using the Pregnancy Form (Section 8.4.7). 
The Investigator is not required to report participants who are found to be pregnant between 
screening and baseline, provided no protocol related procedures were applied.  
Because there is lack of data on human teratogenicity, genotoxicity, fetotoxicity, or 
spermatoxicity for this IMP, female partners of men participating in the trial who become 
pregnant will be asked to sign an ICF. All female participants and female partners of men 
participating in the trial 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 trial 
and any complication of pregnancy that the Investigator becomes aware of after withdrawal from 
the trial will be reported as an adverse event or serious adverse event, as appropriate. 
If the pregnancy in the women participating in the trial and/or the female partners of men 
participating in the trial does not continue to term, one of the following actions will be taken: 
• For a spontaneous abortion, report as a serious adverse event (both Pregnancy and 
Serious Adverse Event Forms should be completed). 
• For an elective abortion due to developmental anomalies, report as a serious adverse 
event (both Pregnancy and Serious Adverse Event Forms should be completed). 
• For an elective abortion not due to developmental anomalies, report on the Pregnancy 
Form; do not report as an adverse event. 
8.6. 
Clinical Product Complaints  
8.6.1. 
Definition of Clinical Product Complaints  
A clinical product complaint is defined as a problem or potential problem with the physical 
quality or characteristics of clinical IMP supplies and/or clinical device supplies used in a 
clinical research trial sponsored by Teva.  
A device deficiency is an inadequacy of a medical device with respect to its identity, quality, 
durability, reliability, safety, or performance. Device deficiencies include malfunctions, use 
errors, and inadequacy of the information supplied by the manufacturer.  
Examples of a clinical product complaint include, but are not limited to, the following:  
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• suspected contamination 
• questionable stability (eg, color change, flaking, crumbling) 
• 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 deficiency eg, any inadequacy of an investigational medical device or 
combination product with respect to its identity, quality, durability, reliability, 
usability, safety, or performance. This includes malfunctions, use errors, inadequate 
labeling (eg, unintelligible label, incorrect expiry date) 
Each investigational center will be responsible for detecting, documenting, and reporting a 
clinical product complaint by completing the Product Complaint Form provided by Teva and 
emailing it to clinical.productcomplaints@tevapharm.com as soon as possible after becoming 
aware of the issue. 
Reporting a complaint must not be delayed even if not all the required information can be 
immediately obtained. Known information must be immediately reported. The Sponsor will 
collaborate with the Investigator to obtain any outstanding information. 
Once the complaint has been investigated by the Sponsor, when required, an event closure letter 
may be sent to the investigational center where the complaint originated or to all investigational 
centers using the product. 
If the clinical product complaint is related to a device, comparator, co-medication, rescue 
medication, or any other product planned in the protocol not manufactured by Teva, the 
complaint will be forwarded to the manufacturer/wholesaler of that product. 
8.6.2. 
Handling the IMP/Devices at the Investigational Center  
The Investigator is responsible for retaining the product in question in a location separate from 
the Investigator’s clinical trial supplies. The Sponsor may request that the Investigator return the 
product for further evaluation and/or analysis. If this is necessary, the clinical trial 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 participant.  
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8.6.3. 
Product Complaint Associated with Adverse Events or Serious Adverse Events  
If there is an adverse event or serious adverse event due to product complaint, the protocol 
should be followed for recording and reporting of the adverse event or serious adverse event 
(Section 8.4.2 to Section 8.4.7). 
8.6.4. 
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 
• participant identifier (participant trial number) and corresponding visit numbers, if 
applicable 
• product name and strength for open-label trials 
• participant number, bottle, and kit numbers (if applicable) for double-blind or 
open-label trials 
• product available for return Yes/No 
• product was taken or used according to protocol Yes/No 
• description or nature of complaint 
• associated serious adverse event Yes/No 
• clinical supplies unblinded (for blinded trials) Yes/No 
• date and name of person receiving the complaint 
8.6.5. 
Device Deficiency that Could Have Led to Serious Adverse Event  
Device deficiencies that could have led to serious adverse events are defined as deficiencies that 
might have led to a serious adverse device effect if (see Figure 2): 
• 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 IRB/IEC by the Investigator and to the 
regulatory authorities by the Sponsor or manufacturer (for devices not manufactured by the 
Sponsor) according to the national and local regulations. 
The Investigator will record in the source documentation a description of the complaint, the 
initial determination whether the device deficiency could have led to a serious adverse event, and 
any actions taken to resolve the complaint and to preserve the safety of the participant.  
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The Investigator should use Table 4, and Table 5 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. 
Table 4: 
Anticipated Use-Related Deficiencies and Their Potential Hazards and 
Serious Harms  
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 
Participant death 
Store carton 
within the 
refrigerator 
Fail to store product correctly 
Participant exposed 
to toxic substance 
due to degraded 
drug 
Permanent 
impairment or life 
threatening injury 
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. 
Table 5: 
Anticipated Design-Related Deficiencies and Their Potential Hazards and 
Serious Harms  
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. 
Participant 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 
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Device component 
Failure mode 
Potential hazard situation 
Potential harm 
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. 
8.7. 
Pharmacokinetics  
Sampling for pharmacokinetics will be sparse. Thus, the test IMP pharmacokinetic samples will 
be analyzed using a population pharmacokinetic approach and will be reported separately from 
the clinical study report (CSR).  
Samples from participants who receive test IMP will be analyzed for fremanezumab using a 
validated method. Samples from participants who receive placebo IMP will not be analyzed.  
8.7.1. 
Pharmacokinetic Sampling  
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 IMP 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 the Laboratory Manual. 
Assessment of ECG should precede pharmacokinetic blood sampling (see Table 1).  
8.8. 
Pharmacodynamics  
Pharmacodynamic parameters are not evaluated in this trial. 
8.9. 
Genetics  
Genetic parameters are not evaluated in this trial. 
8.10. 
Biomarkers  
Biomarkers are not evaluated in this trial. 
8.11. 
Immunogenicity Assessments  
Samples from participants who receive test IMP will be analyzed for ADA using a validated 
method. Samples from participants who receive placebo IMP 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 the Laboratory Manual.  
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8.12. 
Medical Resource Utilization and Health Economics  
Health economics or medical resource utilization and health economics parameters are not 
evaluated in this trial. 
8.13. 
Total Blood Volume  
The total blood volume to be collected for each participant in this trial is approximately 48 mL, 
as summarized in Table 6. 
Table 6: 
Total Blood Volumes to be Collected from an Individual Trial Participant  
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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9. 
STATISTICAL CONSIDERATIONS  
This section describes the statistical analysis as foreseen at the time of planning the trial. 
Changes, additions, and further details about the analyses will be described in the Statistical 
Analysis Plan. After finalization of the Statistical Analysis Plan, any additional analyses or 
changes to analyses that may be required will be fully disclosed in the CSR. 
The analysis will be conducted on all participant data at the time the trial ends. 
9.1. 
Analysis Sets  
9.1.1. 
Safety Analysis Set  
The safety analysis set will include all randomized participants who receive at least 1 dose of 
IMP. 
In the safety analysis set, treatment will be assigned based on the treatment participants actually 
received, regardless of the treatment to which they were randomized.  
9.1.2. 
Intent-to-Treat Analysis Set  
The intent-to-treat (ITT) analysis set will include all randomized participants.  
In the ITT analysis set, treatment will be assigned based on the treatment to which participants 
were randomized, regardless of which treatment they actually received.  
9.1.3. 
Full Analysis Set  
The full analysis set (FAS) will include all participants in the ITT population who receive at least 
1 dose of IMP and have at least 10 days of diary entries postbaseline for efficacy assessments on 
the primary endpoint.  
9.1.4. 
Per-Protocol Analysis Set  
The per-protocol analysis set will consist of all participants in the FAS who have completed the 
trial 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 have at least 75% diary compliance after the start of treatment.  
9.1.5. 
Trial Population  
The ITT analysis set (Section 9.1.2) will be used for all trial population summaries unless 
otherwise specified. Summaries will be presented by treatment group and for all participants.  
9.1.5.1. 
Participant Disposition  
Data from participants screened; participants screened but not randomized and reason not 
randomized; participants who are randomized; participants randomized but not treated; 
participants in the ITT, safety, and other analysis sets;participants who complete the trial; and 
participants who withdraw from the trial will be summarized using descriptive statistics. Data 
from participants who withdraw from the trial will also be summarized by reason for withdrawal 
using descriptive statistics.  
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9.1.5.2. 
Demographic and Baseline Characteristics  
Participants 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, standard 
deviation [SD], median, minimum, and maximum) will be provided. For categorical variables, 
participant 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 participant 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). 
9.2. 
Analyses Supporting Primary Objective(s)  
For the purpose of this trial, a migraine day will be defined as a calendar day where the 
participant 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. 
9.2.1. 
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 IMP.  
9.2.1.1. 
Estimand for the Primary Endpoint  
The primary estimand for this trial 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 IMP and have 
at least 10 days of eDiary 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 IMP as if 
there were no intercurrent events. Data collected after treatment discontinuation or prohibited 
therapy will not be used for assessing the primary estimand.  
9.2.2. 
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 IMP 
• proportion of participants reaching at least 50% reduction in the monthly average 
number of migraine days during the 12-week period after the first dose of IMP 
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• 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 IMP 
• 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 
IMP 
• 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 IMP 
• proportion of participants developing ADAs throughout the trial. The impact of 
ADAs on safety and efficacy will be analyzed if the number of ADA-positive 
participants allows  
9.2.3. 
Exploratory/Other Endpoints  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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9.2.4. 
Planned Method of Analysis  
The FAS (see Section 9.1.3) will be used for all efficacy analyses. Summaries will be presented 
by treatment group.  
9.2.4.1. 
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 IMP, 
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 test IMP group and the placebo IMP group. A hierarchical procedure 
will be used to control Type 1 error rate, as described in Section 9.2.6. 
9.2.4.2. 
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 (Section 13.8), and receiving 
alternative preventive medications that belong to the same classes but are not listed in 
Section 13.8. The details will be described in the statistical analysis plan. 
9.2.5. 
Data Handling Conventions  
Efficacy variables from participants who do not have their diary completed for the entire trial 
period will be imputed. The detailed data imputation rules will be described in the statistical 
analysis plan. 
9.2.5.1. 
Handling of 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. 
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9.2.6. 
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 9.2.2. Final order and details will be confirmed in the statistical analysis plan, which will 
be finalized before database lock. 
9.3. 
Analysis Supporting Secondary Objective(s)  
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. 
9.4. 
Analysis of Exploratory Objective(s)  
 
 
9.5. 
Safety Analyses  
Safety analyses will be performed on the safety analysis set (Section 9.1.1). 
Safety assessments and time points are provided in Table 1. 
All adverse events will be coded using the Medical Dictionary for Regulatory Activities. Each 
participant 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, adverse events, and adverse device effects causing withdrawal from the trial. 
Summaries will be presented by treatment group and for all participants. Participant 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 participants with 
positive findings will be listed. 
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The use of concomitant medications will be summarized by therapeutic class using descriptive 
statistics. Concomitant medications will include all medications taken while the participant is 
treated with IMP. 
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, participant counts and percentages will be provided. Descriptive summaries of serious 
adverse events, participant 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 participant dies during the trial, a listing of deaths will be provided, and all relevant 
information will be discussed in the participant narrative included in the CSR. 
9.5.1. 
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 patricipant’s self-report of pain 
intensity, as described for the recording of headache pain in Section 8.2.1. 
• 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 participants who fail to complete the trial (day 85, final 
assessment) 
• the number (%) of participants who fail to complete the trial due to adverse events 
Local tolerability findings will be listed and summarized descriptively. 
9.6. 
Other Analyses  
9.6.1. 
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.  
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9.6.2. 
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.  
9.6.3. 
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.  
9.7. 
Interim Analyses  
There will be no formal interim analysis. 
9.8. 
Sample Size Determination  
The sample size planned is approximately 266 participants (133 evaluable participants 
completing the trial per treatment group). Assuming a treatment difference of 1.7 days (reduction 
in monthly average number of headache days of at least moderate severity) and a common SD of 
4.92, a sample size of 133 participants per treatment group gives at least 80% power for the trial 
to succeed at an alpha level of 0.05. Assuming a 4% discontinuation rate, approximately 
278 participants (139 participants per treatment group) will be randomized. Participants will be 
randomized to receive either monthly sc administration of test IMP or placebo IMP.  
9.9. 
Protocol Deviations  
Information related to protocol amendments and deviations are provided in Section 11.2. 
Deviations from the statistical plan, along with the reasons for the deviations, will be described 
in protocol amendments, the statistical analysis plan, the CSR, or any combination of these, as 
appropriate, and in accordance with applicable national, local, and regional requirements and 
regulations. 
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10. 
GENERAL CONSIDERATIONS: REGULATORY, ETHICAL, 
AND TRIAL OVERSIGHT  
10.1. 
Regulatory and Ethical Considerations  
Competent Authorities and Independent Ethics Committees/Institutional Review Boards 
Before this trial starts, the protocol will be submitted to the national competent authority and to 
the respective IRB/IEC for review. As required, the trial will not start at a given investigational 
center before the IRB/IEC and competent authority (as applicable) for the investigational center 
give written approval or a favorable opinion. 
Compliance Statement 
This trial will be conducted in full accordance with the ICH Harmonised Tripartite Guideline, 
Guideline for GCP E6, ISO 14155: Clinical investigation of medical devices for human subjects 
– Good Clinical Practice, and any applicable national and local laws and regulations (eg, 
Title 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, Regulation [EU] No. 536/2014 
[CTR] regulations and administrative provisions of the Member States relating to the 
implementation of GCP in the conduct of clinical trials on medicinal products for human use). 
Any episode of noncompliance will be documented. 
The Investigator is responsible for performing the clinical trial 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 trial in accordance with the protocol and applicable regulations will be documented in 
separate clinical trial agreements with the Sponsor and other forms as required by national 
competent authorities in the country where each investigational center is located.  
The clinical trial agreement shall outline the Investigator’s and the institution’s responsibilities 
with respect to the conduct of the clinical trial, including the Investigator’s reporting obligation 
to the Sponsor for suspected cases of serious breach from GCP and/or protocol. 
The Investigator is responsible for ensuring the privacy, health, and welfare of the participants 
during and after the clinical trial; and must ensure that trained personnel are immediately 
available in the event of a medical emergency. The Investigator and the involved clinical trial 
personnel must be familiar with the background and requirements of the trial; 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 trial at that/each investigational center and for contacts 
with trial management, with the IRB/IEC, and with competent authorities. 
See Section 10.3 for the ethics expectations of informed consent or assent, Section 10.4 for 
confidentiality regarding trial participants, Section 13.6 for requirements for registration of the 
clinical trial, and Section 13.7 for the publication policy. 
10.2. 
Committees  
There will be no DMC in this trial. 
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10.3. 
Informed Consent Process  
The Investigator, or a qualified person designated by the Investigator, should fully inform the 
participant of all pertinent aspects of the trial, including the written information approved by the 
IRB/IEC, per local regulations. All written and oral information about the trial will be provided 
in a language as nontechnical as practical to be understood by the participant. The participant 
should be given ample time and opportunity to inquire about details of the trial and to decide 
whether or not to participate in the trial. The above should be detailed in the source documents. 
Written informed consent will be obtained from each participant before any trial-specific 
procedures or assessments are done and after the aims, methods, anticipated benefits, and 
potential hazards are explained. The participant’s willingness to participate in the trial will be 
documented in the ICF, which will be signed and personally dated by the participant and by the 
person who conducted the informed consent discussion.  
The Investigator, or a qualified person designated by the Investigator, should fully inform the 
participant and each parent/legally acceptable representative of all pertinent aspects of the trial, 
including the written information approved by the IRB/IEC, per local regulations. All written 
and oral information about the trial will be provided in a language as nontechnical as practical to 
be understood by each parent/legally acceptable representative and the participant. The 
participant and each parent/legally acceptable representative should be given ample time and 
opportunity to inquire about details of the trial and to decide whether or not to participate in the 
trial. 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 participant (if the 
participant is able) before any trial-specific procedures or assessments are done and after the 
aims, methods, anticipated benefits, and potential hazards are explained; according to IRB/IEC 
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 participants (and each parent/legally acceptable 
representative). It will also be explained to the participants (and each parent/legally acceptable 
representative) that they are free to refuse participation in the trial and free to withdraw from the 
trial at any time without prejudice to future treatment. 
If, during the trial, a minor reaches the age of legal competence to give informed consent as 
defined in national law, his or her informed consent shall be obtained before that participant can 
continue to participate in the clinical investigation. 
10.4. 
Data Protection  
Data protection and confidentiality 
All personal data will be processed in accordance with applicable data protection law. 
Teva has implemented appropriate technical, physical, organizational, and administrative 
information, and privacy security measures to protect the confidentiality, integrity, and 
availability of data in its systems. Teva’s Information Security Team keeps the measures under 
continuous review to align with state-of-the-art standards, taking into account the nature and 
context of the processing. Teva systems and policies are aligned with industry-standard 
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information security and privacy frameworks such as ISO 27001 covering categories of security 
controls including: 
• Access Control 
• Awareness and Training 
• Backup and Recovery 
• Change Control 
• Encryption and Communication Controls 
• Identity and Authentication 
• Incident Response and Recovery 
• Logging, Monitoring, and Alerting 
• Media Protection 
• Operations Control 
• Personnel Security 
• Physical and Environmental  
• Program and Risk Management 
• System and Communications Protection 
• Third Party/Supplier Relationship Control 
Teva employs an Information Security Team and where needed, Teva also leverages independent 
data security experts. 
Teva employs a Cyber Defense Center to direct and coordinate all security incident activity.  
Teva has implemented Incident Response and Recovery policies and processes to identify and 
respond to security incidents and/or data breaches both internally as well as from other involved 
third parties. These policies cover the full Incident Response and Recovery lifecycle from initial 
response/notification through triage and mitigation activities to recovery and root-cause 
resolution. Teva also has a “Global Privacy Incident and Breach Reporting Policy” to address a 
privacy incident or breach (suspected or confirmed).  
Where personal data is stored, transmitted, or processed externally utilizing third parties, Teva 
employs appropriate contractual language, and other controls requiring the third party to employ 
appropriate information security controls and protections to guard the confidentiality, integrity, 
and availability of such data.  
Teva has completed Data Protection Impact Assessments in respect of the processing of personal 
data gathered in the course of clinical trials.  
Teva trains its staff as regarding the handling of personal data in accordance with applicable law. 
This includes training on how to recognize, respond to, and mitigate a personal data breach. 
Teva has implemented role-based access which means that personal data will only be available to 
those who need access. 
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The confidentiality of participant data is protected. For eg, participant data will be randomized 
and blinded in accordance with Section 6.6; and Teva staff are subject to a contractual obligation 
of confidentiality. 
The Investigator must ensure that the privacy of the participants, including their identity, and all 
personal medical information will be maintained at all times. In CRFs and other documents or 
image material submitted to the Sponsor, participants will be identified not by their names, but 
by an identification number. 
Personal medical information may be reviewed for the purpose of participant safety or for 
verifying data in the source and the CRF. This review may be conducted by the trial monitor, 
properly authorized persons on behalf of the Sponsor, Global Quality Assurance, or competent 
authorities. Personal medical information will always be treated as confidential. 
10.5. 
Early Investigational Center Closure or Trial Termination  
For clinical investigational centers located in the EU, a declaration of the end of the clinical trial 
will be made in accordance with the procedures outlined in Directive 2001/20/EC, Article 10(c) 
or Regulation (EU) No. 536/2014 (CTR), as applicable, for other countries, local regulations will 
be followed. 
The Sponsor or designee reserves the right to close the investigational center or terminate the 
trial at any time for any reason at the sole discretion of the Sponsor. In such cases, 
investigational centers will be closed upon trial completion. An investigational center is 
considered closed when all required documents and trial supplies have been collected and an 
investigational center closure visit has been performed. 
The Investigator may initiate investigational center closure at any time, provided there is 
reasonable cause and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of an investigational center by the Sponsor or Investigator may 
include but are not limited to: 
For trial termination: 
• Discontinuation of further trial intervention development. 
For investigational center termination: 
• Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the Sponsor’s procedures, or GCP guidelines. 
• Inadequate or no recruitment (evaluated after a reasonable amount of time) of 
participants by the Investigator. 
• Total number of participants included earlier than expected. 
If the trial is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IRBs/IECs, the regulatory authorities, and any CRO(s) used in the trial of the 
reason for termination or suspension, as specified by the applicable regulatory requirements. The 
Investigator shall promptly inform the participant and should assure appropriate participant 
therapy and/or follow-up. 
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11. 
GENERAL CONSIDERATIONS: RISK MANAGEMENT AND 
QUALITY ASSURANCE  
11.1. 
Quality Tolerance Limits  
Quality Tolerance Limits are not evaluated in this trial. 
11.2. 
Data Quality Assurance  
Refer to Section 8.6 for the definition of a clinical product complaint or device deficiency and 
Investigator responsibilities in the management of a clinical product complaint or device 
deficiency. Further details are given in a Pharmacy Manual. 
Data Management is responsible for the accuracy, quality, completeness, and internal 
consistency of the data from this trial. 
Oversight will be carried out as described in the Sponsor’s SOPs for clinical trials. Day to day 
data management tasks for this trial are delegated to a contract organization, and these functions 
may be carried out as described in the SOPs for clinical trials at that organization. These SOPs 
will be reviewed by the Sponsor before the start of data management activities. 
Data will be verified by the trial 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 Clinical Data Management System (CDMS) and 
any discrepancies will be queried. 
CRFs received will be processed and reviewed for completeness, consistency, and the presence 
of mandatory values. Applicable terms will be coded according to the coding conventions for 
this trial. Logical checks will be implemented to ensure data quality and accuracy. Any necessary 
changes will be made in the clinical database, and data review and validation procedures will be 
repeated as needed. Data from external sources will be compared with the information available 
in the CDMS. Discrepancies found will be queried. 
Data corrections in the CDMS will be made using the CDMS update function. The system 
requires a reason for each change and keeps a complete audit trail of the data values, dates and 
times of modifications, and authorized electronic approvals of the changes. 
At the conclusion of the trial, the CDMS and all other trial data will be locked to further 
additions or corrections. Locking the trial 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. 
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 IRB/IEC and national and local 
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competent authorities, as applicable, except when necessary to address immediate safety 
concerns to the participants 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 participants in the trial and/or (b) the scientific value of the trial will be 
considered an important protocol deviation. Important protocol deviations may include 
non-adherence on the part of the participant, the Investigator, or the Sponsor to protocol-specific 
inclusion and exclusion criteria, primary objective variable criteria, or GCP guidelines; 
noncompliance to IMP administration; use of prohibited medications. Important protocol 
deviations will be documented by investigational center personnel. All important protocol 
deviations will be reported to the responsible IRB/IEC, as required. 
When an important protocol deviation is reported, the Sponsor will determine whether to 
withdraw the participant from the trial or permit the participant to continue in the trial, with 
documented approval from the medical expert. The decision will be based on ensuring the safety 
of the participant and preserving the integrity of the trial.  
If a participant experiences an adverse event or medical emergency, departures from the protocol 
may be allowed on a case-by-case basis. After stabilization and/or treatment has been 
administered to ensure participant safety, the Investigator or other physician in attendance must 
contact the Clinical Leader as soon as possible to discuss the situation. The Investigator, in 
consultation with the Sponsor, will decide whether the participant should continue to participate 
in the trial. 
Changes in the inclusion and exclusion criteria of the protocol are not prospectively granted by 
the Sponsor. If investigational center personnel learn that a participant who did not meet protocol 
inclusion and exclusion criteria was entered in a trial, they must immediately inform the Sponsor 
of the important protocol deviation. If such participant has already completed the trial or has 
withdrawn early, no action will be taken but the deviation will be recorded.  
Information to Trial Personnel 
The Investigator is responsible for giving information about the trial to all personnel members 
involved in the trial or in any element of participant management, both before starting the trial 
and during the course of the trial (eg, when new personnel become involved). The Investigator 
must ensure that all trial personnel are qualified by education, experience, and training to 
perform their specific task. These trial 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 trial, as necessary. 
The trial monitor is responsible for explaining the protocol to all trial personnel, including the 
Investigator, and for ensuring they comply with the protocol. 
Trial Monitoring 
To ensure compliance with GCP guidelines, the trial monitor or representative is responsible for 
ensuring that participants have signed the ICF and the trial is conducted according to applicable 
SOPs, the protocol, and other written instructions and regulatory guidelines. Details of the 
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monitoring procedures are outlined in the trial’s monitoring plan which is maintained by the 
Sponsor. 
The trial monitor is the primary association between the Sponsor and the Investigator. The main 
responsibilities of the trial monitor(s) are to explain the protocol to all trial staff including the 
Investigator, visit the Investigator before, during, and after the trial 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 participants before they participate in the trial and when 
changes to the consent form are warranted, in accordance with IRB/IEC approvals. 
The trial monitor(s) will contact the Investigator and visit the investigational center according to 
the monitoring plan. The trial monitor will be permitted to review and verify the various records 
(CRFs and other pertinent source data records, including specific electronic source document 
relating to the trial) to verify adherence to the protocol and to ensure the completeness, 
consistency, and accuracy of the data being recorded.  
If electronic CRFs are used for the trial, the trial monitor will indicate verification by 
electronically applying source document verification flags to the CRF and will ensure that all 
required electronic signatures are being implemented accordingly. 
As part of the supervision of trial progress, other Sponsor personnel may, on request, accompany 
the trial monitor on visits to the investigational center. The Investigator and assisting personnel 
must agree to cooperate with the trial monitor to resolve any problems, errors, or possible 
misunderstandings concerning the findings detected during the course of these monitoring visits 
or provided in follow-up written communication. 
In case of an emergency situation (eg, the COVID-19 pandemic), where trial monitors may not 
be able to access the investigational centers for on-site visits, investigational centers will be 
monitored remotely, where allowed, and in accordance with global and/or local regulations.  
Audit and Inspection 
The Sponsor may audit the investigational center to evaluate trial conduct and compliance with 
protocols, SOPs, GCP guidelines, and applicable regulatory requirements. The Sponsor’s Global 
Clinical Quality Assurance, independent of Global Specialty Development, is responsible for 
determining the need for (and timing of) an investigational center audit. 
The Investigator must accept that competent authorities and Sponsor representatives may 
conduct inspections and audits to verify compliance with GCP guidelines. 
In case of an emergency situation (eg, the COVID-19 pandemic), where auditors may not be able 
to access the investigational centers for on-site visits, investigational centers will be audited 
remotely, where allowed, and in accordance with global and/or local regulations.  
11.3. 
Source Data  
Direct Access to Source Data and Documents 
All participant data must have supportive original source documentation in the medical records, 
or equivalent, before they are transcribed to the CRF. Data may not be recorded directly on the 
CRF and considered as source data unless the Sponsor provides written instructions specifying 
which data are permitted to be recorded directly to the CRF. 
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If data are processed from other institutions or by other means (eg, clinical laboratory, central 
image center, or eDiary data, electronic patient reported outcomes tablet) the results will be sent 
to the investigational center unless otherwise noted in the protocol. These data will be retained 
but not transcribed to the CRF, unless otherwise noted in the protocol.  
The medical experts, trial monitors, auditors, IRB/IEC, 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, video images, and recordings) for source data 
verification, provided that participant confidentiality is maintained in accordance with national 
and local requirements. 
The Investigator must maintain the original records (ie, source documents) of each participant’s 
data at all times. The Investigator must maintain a confidential participant identification list that 
allows the unambiguous identification of each participant. 
Data Collection 
Data will be collected using CRFs that are specifically designed for this trial. The data collected 
on the CRFs will be captured in a 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 
trial-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 participant who provided informed consent. 
Participant 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, eDiary data, electronic patient reported outcomes 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.  
For participants who enter a trial 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.  
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 trial 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 ICFs 
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• participant identification lists 
• CRFs for each participant on a per-visit basis 
• data from other sources (eg, central laboratory, bioanalytical laboratory, central image 
center, eDiary) 
• safety reports 
• financial disclosure reports/forms 
• reports of receipt, use, and disposition of the IMPs 
• copies of all correspondence with Sponsor, the IRB/IEC, and any competent authority 
The Investigator will retain all records related to the trial and any additional records required, as 
indicated by the protocol and according to applicable laws and regulations, until the CRO or 
Sponsor notifies the institution in writing that records may be destroyed. If, after 25 years from 
trial completion, or earlier in the case of the investigational center closing or going out of 
business, the Investigator reasonably determines that trial 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 trial 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 trial records.  
See Section 13.4 for financial and insurance information. 
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12. 
APPENDIX: ADVERSE EVENTS AND SERIOUS ADVERSE 
EVENTS – DEFINITIONS, SEVERITY, AND CAUSALITY  
12.1. 
Further Details and Clarifications on the Adverse Event Definition  
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 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: Sampson et al 2006.  
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12.2. 
Further Details and Clarifications on the Serious Adverse Event 
Definition  
12.2.1. 
Guidance on Safety Monitoring  
Guidance on Monitoring Participants with Elevated Liver Function Tests 
Liver enzymes (ALT, AST, gamma glutamyl transpeptidase [GGT], and ALP) as well as total 
bilirubin1 will be measured at each trial 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 participants whose baseline ALT or AST levels are ≥2× and ≤3× the ULN, who may 
be enrolled in the trial), a thorough medical history and physical examination with a focus on 
liver disease should be undertaken.2 In addition, the participant should be instructed to refrain 
from alcoholic beverages. 
In case of symptoms compatible with drug-induced liver injury during the trial, participants will 
be instructed to return to the trial 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 IMP discontinuation in cases of elevation of either ALT or AST 
≥3× ULN (Note: In cases of elevation of ALT or AST ≥8× the ULN, no confirmation is required 
prior to IMP discontinuation, but the assessments below should be performed). The following 
procedures should be followed: 
• The day in which the abnormal value is received from the laboratory will be 
considered as day 0.  
• The Investigator should repeat the test for confirmation purposes (this may be 
performed in a local laboratory along with complete blood 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 INR [separate tube; not to be sent in a confirmatory test]). The 
Investigator should also question the participant 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 CRF, 
accompanied by the reference range of the relevant measurements. 
• Should the abnormality (≥3× the ULN in case baseline was within the normal range 
or ≥2× the ULN in case the baseline value was above ULN but still <5× the ULN) 
persist further, the participant 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. 
• 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. 
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ALT or AST ≥8× the ULN 
In addition to the above procedures required for any elevation to levels >3× the ULN: 
• The IMP should be discontinued immediately, and the early withdrawal visit should 
be performed. 
• For follow-up guidance, please see below section “Follow-Up of Liver Enzymes 
After Stopping Rules Are Met.” 
Stopping Rules 
In the following circumstances, the IMP will be discontinued immediately: 
• any increase in ALT or AST to ≥3× the ULN, combined with INR >1.5× the ULN or 
total bilirubin >2× the ULN 
• any increase in ALT or AST to ≥3× the ULN, which is accompanied by symptoms 
clearly associated with impaired liver function (eg, vomiting, nausea, fever, rash, 
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 participant who meets the above criteria for discontinuation of the IMP should be 
invited to the site to return the IMP. Early withdrawal visit activities should be 
performed as soon as possible. 
• Liver enzymes should be monitored until normalization or stabilization of the 
abnormality, according to the discretion of the Investigator. 
• In any case, following the early withdrawal visit, the minimal follow-up period will 
be 30 days and will include measurement of liver enzymes at least once weekly (may 
be performed in local laboratory, with at least 1 test being sent to the central 
laboratory). 
• Every effort should be made to complete the additional tests/evaluations, as described 
above. 
• Every effort should be made to ensure that the participant continues to receive 
ongoing evaluation and treatment by their primary care physician after withdrawal 
from the trial.  
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13. 
APPENDIX: DEFINITIONS AND SUPPORTING OPERATIONAL 
DETAILS  
13.1. 
Contraception and Pregnancy Testing  
13.1.1. 
Definitions Related to Childbearing Potential  
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 
13.1.2. 
Contraception  
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 trial 
and the preferred and usual lifestyle of the participant. 
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. 
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Male contraception 
Male participants who are sexually active with female partners must always use a condom for the 
duration of the trial and for 6 months after the last administration of IMP.  
13.1.3. 
Pregnancy Testing  
Beta-human chorionic gonadotropin (β-HCG) tests in serum or urine will be performed for all 
woman of childbearing potential at the time points as specified in Table 1 and, if clinically 
indicated, thereafter: 
• Refer to Section 5.3 for pregnancy testing inclusion criteria. 
• Additional pregnancy tests (HCG in urine or serum) may be performed, as 
determined necessary by the Investigator or required by local regulation, to establish 
the absence of pregnancy at any time during the participant’s participation in the trial. 
13.2. 
Clinical Laboratory Tests  
Table 7: 
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. 
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13.3. 
Prior Protocol Amendments  
Administrative Letter 06 Dated 21 December 2021  
 
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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 
to 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 (standard deviation [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 less than 5.4, the sample 
size will not be changed; if the pooled 
SD is greater than 6, the sample size 
may will increase to approximately 
600 patients; and if the pooled SD is 
between 5.4 and 6, the sample size 
may will increase to approximately 
500 patients total. 
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% of patients have 
completed at least 3 months of treatment 
or have withdrawn from the study early. 
If the pooled SD is less than 5.4, the 
sample size will not be changed; if the 
pooled SD is greater than 6, the sample 
size will increase to approximately 
600 patients; and if the pooled SD is 
between 5.4 and 6, the sample size will 
increase to approximately 500 patients 
total. 
Added interim analysis 
language. 
The enrollment target is approximately 
418 patients in total with potential 
increase (up to approximately 
600 patients total) depending on the 
planned interim analysis of blinded 
sample size re-estimation (Section 
9.12). 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 
418 patients in total with potential 
increase (up to approximately 
600 patients total) depending on the 
planned interim analysis of blinded 
sample size re-estimation (Section 9.12). 
Removal of language 
regarding similar number of 
patients for each age group 
and the addition of interim 
analysis language.  
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 
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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 
-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 
towards the 30% patient limit threshold. 
Clarification 
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. 
Change reflecting 
allowance of combination 
contraception 
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Original text with changes shown 
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Reason/justification for 
change 
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=[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 the 
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 judgement. 
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. 
Addition of an exclusion 
criterion 
Table 2: Investigational Medicinal Products Used in the Study 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
Change updating 
manufacturer name for the 
test and placebo 
investigational medicinal 
product s 
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. 
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 
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 
Clarification 
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Reason/justification for 
change 
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. 
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. 
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, 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). 
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 
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, 
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 
Clarification of 
preventative migraine 
medications to reflect real-
world use 
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Reason/justification for 
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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. 
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. 
• 
Other: riboflavin, magnesium 
See Original text with changes shown 
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 efficacy 
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 efficacy 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 
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 
Change allowing 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 is 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 
Clarification regarding the 
COVID-19 vaccination. 
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published about the respective vaccines, 
Teva has no reason to believe there 
would be an interaction. However, the 
investigator should use his/her medical 
judgement 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 medicaion, the vaccine 
should be recorded in the source 
documentation and in the electronic data 
capture. 
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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 
, 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 48 months (from 
approximately Q1 2020 to Q4 2023). 
The total duration of the study is 
planned to be 48 months (from Q1 
2020 to Q4 2023). 
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 
2023. 
The study is expected to start in Q1 
2020 and last until Q4 2023. 
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. 
Table 1 has been modified as follows: 
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 
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 
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percentile, inclusive, on the day of 
randomizationat screening. 
included in the study, for 
greater enrolment.  
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 
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 
Clarification. 
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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. 
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. 
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. 
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 
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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) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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 
weight effect on clearance and central 
volume adequately described the 
fremanezumab concentration-time data 
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 
weight effect on clearance and central 
volume adequately described the 
fremanezumab concentration-time data 
Revised to provide additional 
context for the determination 
of the dose for patients 
weighing <45 kg. 
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observed in pediatric patients with 
migraine. 
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. 
 
 
 
 
 
 
 
 
 
 
 
 
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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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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 
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 
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 
Exclusion criterion was 
revised to specify that 
exclusion of a patient based on 
clinically significant 
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years, at the discretion of the 
investigator. 
years, at the discretion of the 
investigator. 
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. 
4.7.1.13.1 
General Study Design and 
Study Schematic Diagram 
3.1 General Study Design and Study 
Schematic Diagram 
Section 4.7.1.1 was moved 
within the protocol to be 
Section 3.1 as it was 
inadvertently placed in the 
incorrect section. 
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 
Clarification to avoid 
confusion by referencing a 
screening period. 
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screeningbaseline period), the patient 
may be rescreened one time; this 
information should be recorded in the 
CRF. 
period), 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 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 
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 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. 
Additional information on the 
selected weight cutoff for the 
pediatric population has been 
added for investigator 
awareness. 
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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 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 
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 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 
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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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. 
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. 
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. 
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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 headache days of at least 
moderate severity 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 headache days of at least moderate 
severity 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-report of pain intensity, as 
described for the recording of headache 
pain in Section 6.1.1. 
• 
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. 
Injection site pain assessments 
were revised to use the 11-
point NRS to harmonize with 
the other pain assessments in 
the study. 
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 
An interim analysis with blinded sample 
size re-estimation will be conducted by 
This sentence was revised to 
ensure it is clear that the 
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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%. 
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.  
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 ovulation; these 
should be initiated at least 1 month 
before the first dose of IMP 
- 
This bullet was deleted from 
highly effective birth control 
methods as combined estrogen 
and progestogen hormonal 
contraception has been 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 
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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. 
 
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 
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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 
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. 
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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. 
 
 
  
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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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. 
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 
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 
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 
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change 
since the last use of Onabotulinium 
toxin A or B prior to screening 
(visit 1). 
Onabotulinium toxin A or B prior to 
screening (visit 1). 
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. 
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. 
To indicate the appendix that 
provides the guidance 
regarding monitoring patients 
with elevated liver function 
tests. 
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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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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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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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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 are 
ongoing 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 
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 completed clinical pharmacology 
studies. 
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pediatric migraine patients 6 to 11 years of age, 
inclusive (Study TV48125-CNS-10141). 
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 
2023). 
The total duration of the study is planned to be 48 
months (from approximately Q1 2020 to Q4 2023). 
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 418 patients 
in total. 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 418 patients 
in total. 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 
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 
Clarified who will be completing the C-SSRS 
and what occurs if there is a positive finding. 
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the patient/caregiver at all other time points. Any 
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. 
with the patient/caregiver at all other time points. 
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 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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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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• 
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. 
6.1.4. 
Pediatric Quality of Life Inventory 
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 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). 
Clarification. 
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. 
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Reason/Justification for change 
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 
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 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 
STUDY PROCEDURES AND ASSESSMENTS BY VISIT 
• 
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 
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 
Clarification. 
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patients, these medications are not allowed for 
migraine or for any other indications. 
patients, these medications are not allowed for 
migraine or for any other indications. 
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, 
hematolog
y, 
coagulatio
n) 
10 
3 
30 
Pharmaco
kinetics 
2 
3 
6 
ADA 
4 
3 
12 
Virology 
(hepatitis, 
HIV, 
Lyme 
disease, 
and 
tuberculos
is) 
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, 
hematolog
y, 
coagulatio
n) 
10 
3 
30 
Pharmaco
kinetics 
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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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-
002053-33 
EudraCT number: 2019-002053-33 
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. 
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 
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Original text with changes shown 
New wording 
Reason/Justification for change 
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 and 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. 
<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>
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This change was made to add 
details for the Coordinating 
Investigator. 
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New wording 
Reason/Justification for change 
 
 
Tel: 
 
 
 
Tel: 
 
 
<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. 
<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) 
1
8 
1 1
8 
Total blood draws were adjusted 
to reflect the addition of virology 
testing.  
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Reason/Justification for change 
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) 
1
0 
3 3
0 
Blood draw volumes were 
adjusted to include β-HCG 
testing. 
Total 
 
 
44.5
5566 
Total 
 
 
6
6 
Total blood draws were updated 
to reflect the new total based on 
blood draw adjustments.  
13.4. 
Financial Disclosure  
A separate clinical trial agreement, including a trial budget, will be signed between each 
Principal Investigator/institution and the Sponsor (or the CRO designated by the Sponsor) before 
the IMP is delivered. 
The participants in this clinical trial are insured in accordance with applicable legal provisions. 
The policy coverage is subject to the full policy terms, conditions, extensions, and exclusions. 
Excluded from the insurance coverage are eg, damages to health, and worsening of previous 
existing disease that would have occurred or continued if the participant had not taken part in the 
clinical trial. 
The policy of Clinical Trials Insurance will be provided to the investigational centers by the 
Sponsor. 
For covered clinical trials (see 21CFR Part 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 trial and for 1 year after the trial has 
been completed. 
13.5. 
Recruitment Strategy  
Recruitment will be conducted by the sites. Where needed recruitment strategies may include site 
outreach and encouragement, and employment of recruitment vendors. More details can be found 
in the Project Recruitment Strategy Plan.  
13.6. 
Dissemination of Clinical Trial Data  
In compliance with national and local regulations and in accordance with Teva standard 
procedures, this clinical trial will be registered on clinical trial registries if applicable. 
13.7. 
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 trial 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. 
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Further details pertaining to publications and review periods are described in the clinical trial 
agreement with the Investigator/institution. 
The Sponsor will comply with the requirements for publication of trial 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 trials only in their entirety and not 
as individual investigational center data. In this case, a Coordinating Investigator will be 
designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International Committee of 
Medical Journal Editors authorship requirements: 
• substantial contributions to the conception or design of the work; or the acquisition, 
analysis, or interpretation of data for the work 
• drafting the work or revising it critically for important intellectual content 
• final approval of the version to be published 
• agreement to be accountable for all aspects of the work in ensuring that questions 
related to the accuracy or integrity of any part of the work are appropriately 
investigated and resolved 
The publications committee established by the Sponsor will oversee this process. Additional 
publications may follow. 
No patent applications based on the results of the trial 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. 
13.8. 
Preventive Migraine Medications for Any Condition Allowed for the 
Duration of the Trial  
The chronic use of 2 of the following concomitant medications is allowed in approximately 35% 
of participants, and should be entered in electronic case report form (eCRF) pages specific for 
migraine preventive medication. Participants using no more than 2 of the following migraine 
preventive medications for any condition at the time of trial enrollment will be allowed to remain 
on the medication. Participants 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 trial. For the remaining approximately 65% of participants, 
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 trial 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. Participants 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. Participants 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. 
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• 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 efficacy 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 et al 2015 and Lewis and Winner 2006.  
13.9. 
Trial 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 participant before any trial-related 
procedures are performed 
• inform participants of trial 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 ECG 
• vital signs measurements 
• review adverse events 
• review concomitant medications 
• clinical laboratory tests 
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• serum β-HCG and urine pregnancy tests (only female participants 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 C-SSRS 
2. Visit 2 (Day 1+3 days) 
Participant s 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 participant’s self-report or by 
physical examination 
• assign randomization number and enter into CRF 
• triplicate 12-lead ECG 
• vital signs measurements 
• review adverse events 
• review concomitant medications 
• urine β-HCG pregnancy test (only female participants 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 ADA prior to dosing 
• administer C-SSRS 
• administer PedMIDAS questionnaire 
• administer PedsQL 
• administer IMP 
• 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 
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• collect blood samples for plasma drug concentration and serum ADA prior to dosing 
- visit 3 only 
• urine β-HCG pregnancy test (only female participants 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 IMP 
• assess injection site 
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 participant’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 participants 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 
• 
 
5. Unscheduled Visits 
An unscheduled procedure or visit may be performed at any time during the trial at the 
participant’s request or as deemed necessary by the Investigator.  
Unscheduled procedures may include the following: 
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• concomitant medication review 
• vital signs measurements 
• inquire and record start/stop date of menstrual period 
• adverse event inquiry 
• trial compliance review 
Other procedures may be performed at the discretion of the Investigator, who may consult 
with the Sponsor. 
In the case that a participant is not able to go to the investigational center or the investigational 
center staff are not able to see participants at the investigational center, certain 
assessments/procedures, as detailed in Table 1, may be performed remotely. 
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14. 
APPENDIX: GLOSSARY OF TERMS  
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 
CBC 
complete blood count 
CDMS 
clinical data management system 
CFR 
Code of Federal Regulations (USA) 
CGRP 
calcitonin gene-related peptide 
CH 
cluster headache 
CIOMS 
Council for International Organizations of Medical Sciences 
CM 
chronic migraine 
COVID-19 
coronavirus disease 2019 
CRF 
case report form (refers to any media used to collect trial data [ie, paper or 
electronic]) 
CRO 
contract research organization 
CSR 
clinical study report 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DMC 
Data Monitoring Committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
eDiary 
electronic diary 
eGFR 
estimated glomerular filtration rate 
EM 
episodic migraine 
EMA 
European Medicines Agency 
EOT 
end-of-treatment 
EU 
European Union 
EudraCT 
European Clinical Trials 
FAS 
full analysis set 
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Abbreviation 
Term 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
gamma glutamyl transpeptidase 
Global PV 
Global 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 
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 
PedMIDAS 
Pediatric Migraine Disability Assessment 
PedsQL 
Pediatric Quality of Life Inventory 
PEF 
peak expiratory flow 
PFS 
pre-filled syringe 
 
 
PPTH 
persistent posttraumatic headache 
PRN 
as-needed (use) 
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Abbreviation 
Term 
Q 
quarter 
RBC 
red blood cell 
RSI 
Reference Safety Information 
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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15. 
REFERENCES  
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Armour KL, Clark MR, Hadley AG, Williamson LM. Recombinant human IgG molecules 
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Barnes NP. Migraine headache in children. BMJ Clin Evid 2015;1-33. 
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Buse DC, Loder EW, Gorman JA, Stewart WF, Reed ML, Fanning KM, et al. Sex differences in 
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Edlund H, Melin J, Parra-Guillen ZP, Kloft C. Pharmacokinetics and pharmacokinetic-
pharmacodynamic relationships of monoclonal antibodies in children. Clin Pharmacokinet 
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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 
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Finegold D. Pediatric endocrinology. In: Zitelli BJ, Davis HW, editors. Atlas of pediatric 
physical diagnosis. 2nd ed. Philadelphia (Pennsylvania): Lippincott Williams & Wilkins, 
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Headache Classification Committee of the International Headache Society (IHS). The 
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Hershey AD, Powers SW, Vockell AL, LeCates S, Kabbouche MA, Maynard MK. PedMIDAS: 
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