Conditions: Post-Traumatic Headache
Keywords: posttraumatic headache (PTH)
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 87
Healthy volunteers: no

Brief summary:
This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the safety and efficacy of fremanezumab in adult participants aged 18 to 70 years, inclusive, for the prevention of PTH. The study will include a double-blind (DB) treatment period (12 weeks) and an open-label (OL) treatment period (12 weeks).

Detailed description:

Arms:
arm 1: Participants will receive fremanezumab 675 milligrams (mg) administered as 3 subcutaneous (SC) injections (225 mg/1.5 milliliters \[mL\] each) at randomization (Week 0), Weeks 4, and 8 during the DB treatment period. Participants who complete the DB treatment period and continue into the OL treatment period will receive fremanezumab 675 mg administered as 3 SC injections (225 mg/1.5 mL each) at Weeks 12, 16, and 20 during the OL treatment period. arm 2: Participants will receive placebo matching to fremanezumab administered as 3 SC injections (1.5 mL each) at randomization (Week 0), Weeks 4, and 8 during the DB treatment period. Participants who complete the DB treatment period and continue into the OL treatment period will receive fremanezumab 675 mg administered as 3 SC injections (225 mg/1.5 mL each) at Weeks 12, 16, and 20 during the OL treatment period.

Interventions: intervention 1: Fremanezumab intervention 2: Placebo
Intervention descriptions: intervention 1: Fremanezumab will be administered per dose and schedule specified in the arm. intervention 2: Placebo matching to fremanezumab will be administered per schedule specified in the arm.

Protocol document:
Prot_000.pdf: 
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Placebo-Controlled Study–PTH
Clinical Study Protocol with Amendment 02
Study TV48125-CNS-20024
1
TITLE PAGE
Clinical Study Protocol
Study Number TV48125-CNS-20024
A Phase 2, Multicenter, Randomized, Proof-of-Concept, Double-Blind, Placebo-Controlled, 
Parallel-Group Study, Including an Open-Label Period, Evaluating the Efficacy and Safety 
of 1 Subcutaneous Dose Regimen of Fremanezumab for the Treatment of Posttraumatic 
Headache (PTH)
Short Study Title: 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study, Including an 
Open-Label Period, to Evaluate the Efficacy and Safety of Fremanezumab in the 
Treatment of Posttraumatic Headache (PTH)
Lay Language Title: 
A Study to Test if Fremanezumab Reduces Headache in Patients with Posttraumatic 
Headache
Efficacy and Safety Study (Phase 2)
IND number: 106533;
BLA number: Not Applicable; EudraCT number: Not Applicable
EMA Decision number of Pediatric Investigation Plan: Not Applicable
Article 45 or 46 of 1901/2006 does not apply
Protocol Approval Date: 27 June 2017
Protocol with Amendment 01 Approval Date: 25 March 2019
Protocol with Amendment 02 Approval Date: 30 March 2020
Sponsor
Teva Branded Pharmaceutical
Products R&D, Inc. 
145 Brandywine Parkway
West Chester, Pennsylvania 19380
United States of America
Information regarding clinical laboratories and other departments and institutions is 
found in Appendix A
This clinical study will be conducted in accordance with current Good Clinical Practice (GCP) as directed 
by the provisions of the International Council for Harmonisation (ICH); United States (US) Code of 
Federal Regulations (CFR), and European Union (EU) Directives (as applicable in the region of the 
study); national country legislation; and the sponsor’s Standard Operating Procedures (SOPs).


Placebo-Controlled Study–PTH
Clinical Study Protocol with Amendment 02
Study TV48125-CNS-20024
2
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.
© 2020 Teva Branded Pharmaceutical Products R&D, Inc. All rights reserved.


Placebo-Controlled Study–PTH
Clinical Study Protocol with Amendment 02
Study TV48125-CNS-20024
3
AMENDMENT HISTORY
The protocol for Study TV48125-CNS-20024 (original protocol dated 27 June 2017) has been 
amended and reissued as follows:
Amendment 02
30 March 2020
87 patients have been 
randomized/enrolled to date.
Letter of Clarification 09
30 October 2019
Letter of Clarification 08
24 September 2019
Letter of Clarification 07
01 August 2019
Letter of Clarification 06
18 April 2019
Amendment 01
25 March 2019
70 patients have been 
randomized/enrolled to date.
Letter of Clarification 05
01 October 2018
Letter of Clarification 04
06 February 2018
Letter of Clarification 03
11 December 2017
Letter of Clarification 02
16 November 2017
Letter of Clarification 01
10 November 2017
The Summary of Changes to the Protocol includes the corresponding reason/justification for 
each change and is provided in Section 16.


Placebo-Controlled Study–PTH
Clinical Study Protocol with Amendment 02
Study TV48125-CNS-20024
4
INVESTIGATOR AGREEMENT
Original Protocol Dated 27 June 2017
Clinical Study Protocol with Amendment 02
IND number: 106533; BLA number: Not Applicable; EudraCT number: Not Applicable; 
EMA Decision number of Pediatric Investigation Plan: Not Applicable; Article 45 or 46 of 
1901/2006 does not apply
A Phase 2, Multicenter, Randomized, Proof-of-Concept, Double-Blind, Placebo-Controlled, 
Parallel-Group Study, Including an Open-Label Period, Evaluating the Efficacy and Safety 
of 1 Subcutaneous Dose Regimen of Fremanezumab for the Treatment of Posttraumatic 
Headache (PTH)
Principal Investigator: 
Title:
Address of Investigational Center:
Tel:
I have read the protocol with Amendment 02 and agree that it contains all necessary details for carrying 
out this study. I am qualified by education, experience, and training to conduct this clinical research 
study. The signature below constitutes agreement with this protocol and attachments, and provides 
assurance that this study will be conducted according to all stipulations of the protocol, including all 
statements regarding confidentiality, and according to national or local legal and regulatory requirements 
and applicable regulations and guidelines.
I will make available the protocol and all information on the investigational medicinal product (IMP) that 
were furnished to me by the sponsor to all physicians and other study personnel reporting to me who 
participate in this study and will discuss this material with them to ensure that they are fully informed 
regarding the IMP and the conduct of the study. I agree to keep records on all patient information, 
investigational medicinal products (IMP) shipment and return forms, and all other information collected 
during the study, in accordance with national and local Good Clinical Practice (GCP) regulations as well 
as all other national and international laws and regulations.
Principal Investigator
 
Signature
Date


Placebo-Controlled Study–PTH
Clinical Study Protocol with Amendment 02
Study TV48125-CNS-20024
5
SPONSOR PROTOCOL APPROVAL


Placebo-Controlled Study–PTH
Clinical Study Protocol with Amendment 02
Study TV48125-CNS-20024
6
COORDINATING INVESTIGATOR AGREEMENT
Original Protocol Dated 27 June 2017
Clinical Study Protocol with Amendment 02
IND number: 106533; BLA number: Not Applicable; EudraCT number: Not Applicable
EMA Decision number of Pediatric Investigation Plan: Not Applicable
Article 45 or 46 of 1901/2006 does not apply
A Phase 2, Multicenter, Randomized, Proof-of-Concept, Double-Blind, Placebo-Controlled, 
Parallel-Group Study, Including an Open-Label Period, Evaluating the Efficacy and Safety
of 1 Subcutaneous Dose Regimen of Fremanezumab for the Treatment of Posttraumatic 
Headache (PTH)
I have read the protocol with Amendment 02 and agree that it contains all necessary details for 
carrying out this study. I am qualified by education, experience, and training to conduct this 
clinical research study. The signature below constitutes agreement with this protocol and 
attachments, and provides assurance that this study will be conducted according to all 
stipulations of the protocol, including all statements regarding confidentiality, and according to 
national or local legal and regulatory requirements and applicable regulations and guidelines.
I will make available the protocol and all information on the investigational medicinal product 
(IMP) that were furnished to me by the sponsor to all physicians and other study personnel 
reporting to me who participate in this study and will discuss this material with them to ensure 
that they are fully informed regarding the IMP and the conduct of the study. I agree to keep 
records on all patient information, investigational medicinal products (IMP) shipment and return 
forms, and all other information collected during the study, in accordance with national and local 
Good Clinical Practice (GCP) regulations as well as all other national and international laws and 
regulations.
Coordinating Investigator
Title:
Director
Address of Investigational Center:
Tel:
Coordinating Investigator
Signature 
Date


Placebo-Controlled Study–PTH
Clinical Study Protocol with Amendment 02
Study TV48125-CNS-20024
7
CLINICAL STUDY PROTOCOL SYNOPSIS
with Amendment 02
Study TV48125-CNS-20024
Title of Study: A Phase 2, Multicenter, Randomized, Proof-of-Concept, Double-Blind,
Placebo-Controlled, Parallel-Group Study, Including an Open-label Period, Evaluating the 
Efficacy and Safety of 1 Subcutaneous Dose Regimen of Fremanezumab for the Treatment of 
Posttraumatic Headache (PTH)
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc., 145 Brandywine Parkway, West 
Chester, Pennsylvania 19380, USA
Investigational New Drug (IND) Number: 106533
Biological License Application (BLA) Number: Not applicable
EudraCT Number: Not applicable
EMA Decision number of Pediatric Investigation Plan: Not applicable
Article 45 or 46 of 1901/2006 does not apply
Name of Test Investigational Medicinal Product (IMP): Fremanezumab (TEV-48125); a 
humanized anti-calcitonin gene-related peptide (CGRP) monoclonal antibody
EudraVigilance (EV) code for the IMP: Not applicable
Type of the Study: Efficacy and safety study (Phase 2)
Indication: Fremanezumab is planned as an indication for the treatment of posttraumatic 
headache (PTH).
Is this study conducted to investigate the New Use of an approved, marketed product? Yes
Number of Investigational Centers Planned: This study is planned to be conducted in 
approximately 32 investigational centers.
Countries Planned: The study is planned to be conducted in the United States.
Planned Study Period: The study is expected to be executed between the period of Q4 2017 and 
Q2 2020. 
Number of Patients Planned (total): The total number of patients planned was approximately 
172 (86 patients per treatment group). Study recruitment was discontinued at 87 patients due to 
challenges to enrollment and not for any safety concerns.
Study Population: The study population will be composed of male and female patients aged 18 
to 70 years, inclusive, with a history of PTH (as defined by International Classification of 
Headache Disorders 3rd revision [ICHD-3] (beta version) criteria).
This will include patients with headache attributed to mild, traumatic injury of the head and 
patients with headache attributed to whiplash. 


Placebo-Controlled Study–PTH
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Study TV48125-CNS-20024
8
Primary and Secondary Objectives and Endpoints 
The primary and secondary study objectives and endpoints are as follows:
Objectives
Endpoints
The primary objective of the 
study is to evaluate the efficacy 
of fremanezumab administered 
subcutaneously (sc) in adult 
patients with posttraumatic 
headache (PTH).
The primary efficacy endpoint is the mean change from 
baseline (baseline period) in the monthly average number of 
headache days of at least moderate severity during the 12-week 
period after the first dose of the IMP.
A secondary objective is to 
evaluate the efficacy of 
fremanezumab administered sc 
in adult patients with PTH.
The secondary efficacy endpoints are:

proportion of patients reaching at least 50% 
reduction from baseline (baseline period) in the 
monthly average number of headache days of at 
least moderate severity during the 12-week period 
of treatment with the IMP

proportion of patients reaching at least 50% 
reduction from baseline (baseline period) in the 
monthly average number of headache days of at 
least moderate severity during the first 4-week 
period after the first dose of the IMP

proportion of patients reaching at least 50% 
reduction from baseline (baseline period) in the 
monthly average number of headache days of at 
least moderate severity during the 5- to 8-week 
period after the first dose of the IMP

proportion of patients reaching at least 50% 
reduction from baseline (baseline period) in the 
monthly average number of headache days of at 
least moderate severity during the 9- to 12-week 
period after the first dose of the IMP

mean change from baseline (baseline period) in the 
number of headache days of at least moderate 
severity during the first 4-week period after the first 
dose of the IMP

mean change from baseline (baseline period) in the 
number of headache days of at least moderate 
severity during the 5- to 8-week period after the 
first dose of the IMP

mean change from baseline (baseline period) in the 
number of headache days of at least moderate 


Placebo-Controlled Study–PTH
Clinical Study Protocol with Amendment 02
Study TV48125-CNS-20024
9
Objectives
Endpoints
severity during the 9- to 12-week period after the 
first dose of the IMP

mean change from baseline (visit 2) in disability 
score, as measured by the 6-item Headache Impact 
Test (HIT-6) at week 12 after the first dose of the 
IMP

mean change from baseline (visit 2) in the 
assessment of patient satisfaction, as measured by 
the Patient Global Impression of Change scale, at 4, 
8, and 12 weeks after the first dose of the IMP
A secondary objective of the 
study is to evaluate the safety 
and tolerability of 
fremanezumab administered sc 
in adult patients with PTH 
compared with placebo and 
during the open-label period.
The safety and tolerability endpoints are:

occurrence of adverse events during the study

clinically significant changes in physical 
examinations, including body weight

clinical laboratory (serum chemistry, hematology 
and coagulation, and urinalysis) test results at each 
visit

vital signs (blood pressure, respiratory rate, body 
temperature, and pulse) measurements at each visit
Note: Oxygen saturation and respiratory rate will 
be measured in cases of suspected anaphylaxis and 
severe hypersensitivity.

12-lead electrocardiogram (ECG) findings at each 
visit

use of concomitant medication during the study

number (%) of patients who did not complete the 
study (day 168, end-of-study)

number (%) of patients who did not complete the 
study due to adverse events

local tolerability at the injection site (ie, erythema, 
induration, ecchymosis, and pain) at the following 
time points postdose: day 0, day 28, and day 56

hypersensitivity reaction assessment

Columbia Suicide Severity Rating Scale (C-SSRS)


Placebo-Controlled Study–PTH
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Study TV48125-CNS-20024
10
Objectives
Endpoints
The immunogenicity objective
is to evaluate the 
immunogenicity of 
fremanezumab and the impact 
of anti-drug antibodies (ADAs) 
on clinical outcomes in patients 
exposed to fremanezumab.
The immunogenicity endpoints are ADA incidence and 
characteristics (eg, titer, kinetics, and neutralizing activities). 
ADA=antidrug antibody; C-SSRS=Columbia Suicide Severity Rating Scale, ECG=electrocardiogram; 
HIT-6=6-item Headache Impact Test; IMP=investigational medicinal product; PTH= posttraumatic headache; 
sc=subcutaneous.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Placebo-Controlled Study–PTH
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Placebo-Controlled Study–PTH
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Study TV48125-CNS-20024
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General Study Design: This is a multicenter, randomized, proof-of-concept, double-blind, 
placebo-controlled, parallel-group study, including an open-label period, evaluating the efficacy 
and safety of 1 subcutaneous dose regimen of fremanezumab in adult patients with PTH. The 
study will consist of a screening visit, a baseline period, a double-blind treatment period lasting 
approximately 12 weeks, and an open-label period lasting approximately 12 weeks. 
The total duration of patient participation in the study is planned to be approximately 28 weeks, 
including a baseline period lasting approximately 4 weeks, a double-blind treatment period 
lasting 12 weeks, and an open-label period lasting 12 weeks.
Patients will complete a screening visit (visit 1) after providing informed consent, and eligible 
patients will enter a baseline period lasting approximately 4 weeks (28+3 days), during which 
they will enter their baseline PTH information into a daily electronic headache diary. Patients 
meeting eligibility requirements will be randomly assigned to 1 of 2 treatment groups with 
fremanezumab or placebo in a 1:1 ratio. Treatment assignment will take place with stratification 
based on the duration of the patient’s history of PTH (<12 months and ≥12 months duration).
Screening results will be reviewed for eligibility, additional baseline assessments will be 
administered, and the first treatment administration will occur at visit 2. Patients will return to 
the study center approximately every 4 weeks (visit 3 and visit 4) for a continuation of the 
blinded treatment administered sc; for safety and efficacy assessments; and for blood and urine 
sampling for pharmacokinetics, immunogenicity, and biomarker analysis. At visit 5, all patients 
will proceed directly to an open-label treatment phase, with fremanezumab administered sc. 
Patients will then return to the study center approximately every 4 weeks (visits 6 and 7) for 
continued open-label treatment and safety tolerability and efficacy assessments. Final study 
assessments will be performed on visit 8, at the end of treatment or early termination visit, 
approximately 24 weeks after first administration of the IMP.
A database lock from the double-blind period will occur following the completion of visit 5 by 
the last patient. Unblinding will occur after the database lock from the double-blind period.
Patients who complete all scheduled visits will have procedures and assessments performed at 
visit 8. Patients who withdraw from the study before completing either the double blind or the 
open label treatment phases will have visit 8 procedures and assessments performed at their final 
visit. For all patients in the study, the end-of -treatment visit (visit 8) is defined as the final visit 
of the study and the conclusion of all study activities for the patient; patients will not receive any 
further treatments with IMP and will be treated according to guidelines and treating physicians’ 
discretion.
However, a final database lock will occur following the end-of-treatment visit (visit 8) of the last 
patient for analysis of the study data.


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Study TV48125-CNS-20024
13
Brief Summary of Study Design for the Trial Registry(s):
This is a 12-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group 
study, including an open-label period, to evaluate the safety and efficacy of 1 subcutaneous dose 
regimen of fremanezumab in adult patients aged 18 to 70 years, inclusive, for the prevention of 
PTH. Patients who provide written informed consent and complete a screening visit will enter a 
baseline period lasting approximately 4 weeks (28+3 days), during which they will record their 
PTH symptoms into a daily electronic diary application, to establish a clinical baseline. Patients 
will return to the study center after completing the baseline period, and those who meet all 
eligibility requirements will be randomized to receive the test IMP or placebo IMP. Patients will 
then return to the study center monthly for continued treatment with 2 further doses of sc 
fremanezumab or placebo (a total of 12 weeks placebo-controlled treatment phase), followed by 
a 12-week open-label treatment phase in which all patients will receive 3 monthly doses of sc 
fremanezumab. A final visit will occur approximately 28 days after the last dose of IMP, which 
should occur at approximately 24 weeks after the first dose of IMP, to evaluate treatment 
efficacy, ADAs, fremanezumab concentrations and safety. 
Efficacy will be evaluated using PTH data entered daily into an electronic diary throughout the 
12-week placebo-controlled treatment period and administration of questionnaires to evaluate 
PTH-related disability, change in quality of life, health status, and satisfaction with treatment. 
The safety will be evaluated through adverse event and concomitant medication inquiries, ECGs, 
vital signs measurements, clinical laboratory tests, physical examinations, injection site reaction 
and pain assessments, assessments for anaphylaxis and severe hypersensitivity, and 
administration of the Patient Health Questionnaire (PHQ)-2/PHQ-9 and C-SSRS. In addition, 
blood will be collected for pharmacokinetics, immunogenicity, biomarker analyses, and urine 
will be collected for biomarker analysis. 
Method of Randomization and Blinding: Randomization will be performed using electronic 
interactive response technology (IRT). Blinded treatment will be administered subcutaneously at 
visit 2, visit 3, and visit 4 for a total of 3 doses. 
The sponsor, investigators, study staff (except for staff involved in bioanalytical analyses), and 
patients will be blinded to treatment assignment. A computer-generated master randomization 
list will be provided to drug packaging facilities. Packaging vendor(s) will package active and 
placebo IMP into single-visit kits according to Good Manufacturing Practice procedures. Kits 
will be identical in appearance and will contain prefilled syringes (active or placebo). Adequate 
kit supply for upcoming study visits will be managed by Medidata and kept refrigerated at 2°C to 
8°C on site.
Patients meeting eligibility criteria in the screening procedure will be randomized if they meet 
the additional clinical eligibility criteria as recorded in their baseline headache diaries: (1) 
patients must record 8 or more headache days of moderate to severe intensity (defined as a day 
when a patient reports at least 4 hours of headache [not necessarily consecutive] of at least 
moderate severity at any time during the headache; or when a patient has a headache and takes a 
prescription abortive medication with intent to alleviate the headache [regardless of duration or 
severity]) during the baseline period, and (2) electronic diary compliance must be at least 75% 
during the baseline period for randomization eligibility and at least 75% during the double-blind 
treatment period, during which the patient cannot miss more than 7 days of recording nor more 
than 4 days in a row. Randomization will be performed using electronic IRT. Patients will be 


Placebo-Controlled Study–PTH
Clinical Study Protocol with Amendment 02
Study TV48125-CNS-20024
14
randomly assigned with stratification based on the PTH onset (<12 months and ≥12 months since 
the brain injury) in a 1:1 ratio to receive fremanezumab or placebo, as assigned by the IRT. The 
IRT will centrally manage initial IMP supply, maintenance of adequate IMP supplies at the 
investigational centers, and study randomization. 
Investigational Medicinal Products: Dose, Pharmaceutical Form, Route of Administration, 
and Administration Rate 
Investigational medicinal products are defined as the test IMP and placebo IMP. The IMPs used 
in this study are described in the table below:
IMP name
Fremanezumab
Placebo IMP
Company-assigned 
number
Fremanezumab (formerly TEV-48125, 
LBR-101, PF-04427429, or RN307)
Not applicable
Product 
configuration
Prefilled syringes
Prefilled syringes
Unit dose 
strength(s)/Dosage 
level(s)
For sc administration: 
2.25 mL prefilled syringes (1.5 mL 
deliverable volume each) at a nominal 
concentration of 150 mg/mL 
fremanezumab
For sc administration:
2.25 mL prefilled syringes (1.5 mL deliverable 
volume each) with the same vehicle and 
excipients as those for the active injections
Route of 
administration
sc injection
Fremanezumab will be administered by 
qualified study personnel who will retrieve 
the appropriately numbered kit containing 
the prefilled syringes.
sc injection
Placebo will be administered by qualified 
study personnel who will retrieve the 
appropriately numbered kit containing the 
prefilled syringes.
Dosing instructions
Arm A: The contents of three prefilled 
syringes, each containing fremanezumab 
(225 mg/1.5 mL) injections sc at visit 2, 
visit 3, and visit 4
Arm B: The contents of three prefilled 
syringes, each containing 1.5 mL placebo 
injections sc at visit 2, visit 3, and visit 4
Packaging
Fremanezumab will be contained in 
uniquely numbered kits and stored 
refrigerated at 2°C to 8°C at the 
investigational center.
Placebo will be contained in uniquely 
numbered kits and stored refrigerated at 2°C 
to 8°C at the investigational center.
Manufacturer
Teva Branded Pharmaceutical Products 
R&D, Inc.
145 Brandywine Parkway
West Chester, PA 19380
Teva Branded Pharmaceutical Products R&D, 
Inc.
145 Brandywine Parkway
West Chester, PA 19380
IMP=investigational medicinal product; sc=subcutaneous
Patients will be randomized into one of the following treatment groups:
1. Arm A: Fremanezumab 675-mg sc treatment group 
Patients randomized to fremanezumab will receive 675 mg of fremanezumab administered as 
3 sc injections (225 mg/1.5 mL each) at visit 2 (randomization), visit 3 (week 4), and visit 4 
(week 8).
2. Arm B: Placebo treatment group


Placebo-Controlled Study–PTH
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Patients randomized to placebo will receive placebo administered as 3 sc injections (1.5 mL 
each) at visit 2 (randomization), visit 3 (week 4), and visit 4 (week 8).
Test IMP: Fremanezumab
Placebo IMP: The placebo will consist of the same vehicle and excipients as those for 
fremanezumab.
Study Duration: The overall duration of the study will be approximately 2 years from Q4 2017 
until approximately Q2 2020.
Open-Label Period: Patients will receive 675 mg of fremanezumab administered as 3 sc 
injections (225 mg/1.5 mL each) at visit 5 (week 12), visit 6 (week 16), and visit 7 (week 20).
Duration of Patient Participation and Maximal Exposure to IMP: The total duration of 
patient participation in the study is planned to be approximately 28 weeks, including a baseline 
period lasting approximately 4 weeks, a double-blind treatment period lasting 12 weeks, and an 
open-label period lasting 12 weeks. 
Patients are expected to complete the entire duration of the study. 
End of Study: End-of-study (EOS) is defined as the last safety visit (visit 8).
Plans for Treatment or Care After the Patient Has Ended Participation in the Study: No 
treatment is planned by the sponsor after the EOS (visit 8). Patients will thereafter be treated 
with standard of care as judged to be appropriate by the patient’s caregiver.
Inclusion Criteria: Patients may be included in the study only if they meet all of the following 
criteria: 
a.
The patient is capable of giving signed informed consent as described in Appendix C
of the protocol, which includes compliance with the requirements and restrictions 
listed in the informed consent form and in this protocol.
b. The patient is a man or woman 18 to 70 years of age, inclusive.
c.
The patient has a body weight 45 kg.
d. Traumatic injury to the head has occurred, defined as a structural or functional injury 
resulting from the action of external forces. These include striking the head with or 
the head striking an object, penetration of the head by a foreign body, forces 
generated from blasts or explosions; or whiplash has occurred, defined as sudden and 
inadequately restrained acceleration/deceleration movements of the head with 
flexion/extension of the neck. Whiplash may occur after either high or low impact 
forces. 
e.
The patient has a diagnosis of PTH as per the ICHD-3 (beta version) criteria:

Headache is reported to have developed within 7 days after one of the following:
○
mild traumatic injury to the head 
○
regaining of consciousness following the injury to the head 
○
discontinuation of medication(s) that impair ability to sense or report 
headache following the injury to the head 


Placebo-Controlled Study–PTH
Clinical Study Protocol with Amendment 02
Study TV48125-CNS-20024
16
In addition, the following criteria should be met: 

Headache persists for >1 month after injury to the head
f.
During the baseline period, the patient has at least 8 headache days of at least 
moderate severity, defined as a day when a patient reports at least 4 hours of 
headache (not necessarily consecutive) and at its worst at any point has at least 
moderate severity; or when a patient has a headache and takes a prescription abortive
medication with intent to alleviate the headache (regardless of duration or severity).
g. The patient demonstrated compliance with the electronic diary during the baseline 
period by entry of headache data at a minimum of 75% compliance. 
h. The patient is not using preventive medications for headache (presented in 
Appendix F of the protocol) (ie, at least 5 half-lives have passed since last use) or is 
using them in a dose and regimen that have been stable for at least 2 months prior to 
beginning the baseline period. 
i.
Women may be included only if they have a negative serum beta-human chorionic 
gonadotropin test at screening and a negative urine pregnancy test at baseline, are 
sterile, or postmenopausal. 
j.
Women of childbearing potential (WOCBP) whose male partners are potentially 
fertile (ie, no vasectomy) must use highly effective birth control methods for the 
duration of the study (ie, starting at screening) and for 30 weeks after the last IMP
administration. 
k. Men must be sterile or, if they are potentially fertile or reproductively competent (ie, 
not surgically or congenitally sterile) and their female partners are of childbearing 
potential, must use, together with their female partners, a condom for the duration of 
the study and for 30 weeks after the last IMP administration. Definitions of WOCBP, 
sterile and postmenopausal women, male contraception, and highly effective birth 
control methods, including examples, are given in Appendix D of the protocol.
Exclusion Criteria: Patients will be excluded from participating in this study if they meet any of 
the following criteria:
a.
The patient has a previous history of brain imaging showing evidence of intracerebral 
hemorrhage, subdural or epidural hematomas, or subarachnoid hemorrhage as a 
consequence of the traumatic head injury. Brain images with structurally insignificant 
changes, as discussed and approved by the sponsor, will be reviewed by the sponsor 
on a case-by-case basis.
b. The patient has PTH attributed to craniotomy.
c.
The patient has whiplash and subsequent headache but no history of head injury or 
concussion. 
d. The patient has an existing headache history prior to the head trauma, unless the 
patient reports a significant worsening of at least 50% in the frequency and/or 
severity of the headaches and, in the opinion of the investigator, the patient fulfills 
criteria for PTH.


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e.
The patient is using analgesic medications containing opioids (including codeine) or a 
barbiturate on average more than 15 days per month.
f.
The patient has participated in another study of an IMP (or a medical device) within 
the previous 30 days (or 90 days for biologics) or 5.5 half-lives, whichever is longer, 
of the IMP or is currently participating in another study of an IMP (or a medical 
device) prior to screening.
g. The patient has had exposure to a mAb targeting the CGRP pathway (erenumab, 
eptinezumab, galcanezumab, and fremanezumab) during the 6 months prior to the day 
of the screening visit.
h. The patient is currently being treated with onabotulinumtoxinA (eg, Botox, Dysport, 
Xeomin) application in the head or neck or has received any such injection during the 
3 months prior to the screening visit. 
i.
The patient has been implanted with any electronic devices for headache prevention 
during the 3 months prior to the screening visit or is currently using any implanted or 
externally applied stimulator or device.
j.
The patient has been treated with a nerve block for head and/or neck pain during the 
3 months prior to the screening visit.
k. The patient has a known hypersensitivity to any components of the IMPs stated in this 
protocol.
l.
The patient has a history or presence of other medical illness that, in the opinion of 
the investigator indicates a medical problem that would preclude study participation.
m. The patient is a pregnant or lactating woman or plans to become pregnant during the 
study.
n. The patient has clinically significant hematological, cardiac, renal, endocrine, 
pulmonary, gastrointestinal, genitourinary, neurologic, hepatic, or ocular disease or 
has any clinically significant uncontrolled medical condition (treated or untreated) at 
the discretion of the investigator.
o. The patient has any psychiatric condition or evidence of significant active or unstable 
psychiatric disease that, in the opinion of the investigator, could jeopardize or would 
compromise the patient’s ability to participate in this study.
p. The patient has major depression as assessed by the 2-item Patient Health 
Questionnaire (PHQ-2)/9-item Patient Health Questionnaire (PHQ-9) at screening. 
Any patient with a score ≥15 should be considered to have major depression and 
should be referred for appropriate treatment. Patients with lower scores (5 to 14) may 
also have major depression, and they should be carefully evaluated by the investigator 
for the presence of additional symptoms. 
q. The patient has a history of alcohol abuse or recreational drug abuse or at the 
discretion of the investigator is suspected of abusing alcohol or recreational drugs.
r.
The patient has any lifetime history of suicidal behaviors (suicide attempts, 
interrupted attempts, aborted attempts, suicidal ideation, or preparations for suicide). 


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s.
The patient fulfills any of the following criteria:

mentally or legally incapacitated or unable to give consent for any reason

in custody due to an administrative or a legal decision, under tutelage, or being 
admitted to a sanitarium or social institution

in current litigation for any civil or criminal offense

in current, ongoing or future litigation for the life of the study, relating to 
headaches, trauma or injury to the brain

unable to be contacted in case of emergency
t.
The patient has any other condition, which, in the opinion of the investigator, makes 
the patient inappropriate for inclusion in the study
 
 
 
 
Analysis of Primary Endpoint: The primary efficacy endpoint for this study will be derived 
from PTH data (ie, presence of headache [yes/no] and peak severity [mild/moderate/severe]) 
collected daily using an electronic headache diary application. 
Analysis of Secondary Endpoints: Secondary efficacy endpoints will be derived from PTH data 
(ie, presence of headache [yes/no] and peak severity [mild/moderate/severe]) collected daily 
using an electronic headache diary application. In addition, disability score will be derived from 
the HIT-6 assessment at time points detailed in Table 1 of the protocol.
Primary Efficacy Analysis: The primary efficacy endpoint, the mean change from baseline 
(baseline period) in the monthly average number of headache days of at least moderate severity 
during the 12-week period after the first dose of IMP, will be analyzed using an analysis of 
covariance (ANCOVA) method. The model will include treatment as fixed effect and the 
baseline number of headache days of at least moderate severity and the PTH onset (<12 months 
and ≥12 months) as covariates. A 95% confidence interval will be constructed for the least 
squares mean difference between the fremanezumab group and the placebo group, and the 
p-value will be presented. 
The primary estimand for this study is defined by the following attributes:


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
The target population includes male and female patients aged 18 to 70 years, 
inclusive, with a history of PTH (as defined by the ICHD-3 [beta version] criteria).

The primary outcome measure is the mean change from baseline (baseline period) in 
the monthly average number of headache days of at least moderate severity during the 
12-week period after the first dose of IMP.

The full analysis set (FAS) will be used for efficacy analyses. FAS is a subset of the 
ITT analysis set and includes only patients who receive at least 1 dose of IMP and 
have at least 1 postbaseline efficacy assessment on the primary endpoint. In the FAS, 
treatment will be assigned based on the treatment to which patients were randomized, 
regardless of which treatment they actually received.

Treatment effect will be measured via ANCOVA method, including treatment as 
fixed effect and the baseline number of headache days of at least moderate severity 
and the PTH onset (<12 months and ≥12 months) as covariates.
For patients assigned to active treatment who discontinue the study due to lack of efficacy, death, 
or adverse event, the proportion of headache days in the remainder of the analysis window will 
be imputed as the mean monthly average of headache days in the same analysis window for 
patients assigned to placebo. All other missing data for patients in either treatment group will be 
handled as follows:

For patients who have ≥10 days of e-diary data in an analysis window, the monthly 
average number of headache days will be calculated based on data available in that 
analysis window and prorated to 28 days.

For patients who have <10 days of e-diary data in an analysis window, the monthly 
average number of headache days will be imputed as the mean monthly average of 
headache days in the same analysis window for patients assigned to the same 
treatment group and having ≥10 days of e-diary data. Sensitivity analyses will be 
conducted as defined in the statistical analysis plan.
Sensitivity Analysis: Sensitivity analysis will be conducted to explore the impact of missing 
data in the primary efficacy analysis. In particular, endpoints analyzed using an ANCOVA 
method will be analyzed using a mixed model for repeated measures method. The details will be 
described in the statistical analysis plan.
Secondary Efficacy Analysis: The continuous secondary efficacy endpoints will be analyzed 
using an analysis of variance method or a mixed-model for repeated measures. For the 
proportion of responders defined as 50% or more reduction from baseline in the monthly average 
headache days, the Cochran-Mantel-Haenszel test will be used stratified by PTH onset 
(<12 months and ≥12 months). For the key secondary endpoints, a 95% confidence interval will 
be constructed to compare the treatment effect between the fremanezumab group and the placebo 
group, and the p-value will be presented.
 
Multiple Comparisons and Multiplicity: Testing of statistical significance at a 2-sided alpha of 
0.05 will be performed for the primary endpoint. If the primary endpoint meets statistical 
significance, then each of the key secondary endpoints will be tested for significance in a 


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pre-specified order at a 2-sided alpha of 0.05. If and when any p>0.05, no further comparisons 
will be interpreted inferentially. Details will be presented in the statistical analysis plan. 
Safety Analyses: All adverse events will be coded using the Medical Dictionary for Regulatory 
Activities. Each patient will be counted only once in each preferred term or system organ class 
category for the analyses of safety. Summaries will be presented for all adverse events (overall 
and by severity), adverse events determined by the investigator to be related to test IMP 
(ie, reasonable possibility; see Section 7.1.4 of the protocol) (defined as related or with missing 
relationship) (overall and by severity), serious adverse events, and adverse events causing 
withdrawal from the study. Summaries will be presented by treatment group and for all patients. 
Patient listings of serious adverse events and adverse events leading to withdrawal will be 
presented.
Changes in laboratory, ECG, and vital signs measurements data will be summarized 
descriptively. All values will be compared with predefined criteria to identify potentially 
clinically significant values or changes, and such values will be listed.
The use of concomitant medications will be summarized by therapeutic class using descriptive 
statistics. Concomitant medications will include all medications taken while the patient is treated 
with test IMP.
Safety data will be summarized descriptively overall and by treatment group. For continuous 
variables, descriptive statistics (n, mean, SD, median, minimum, and maximum) will be provided 
for actual values and changes from baseline to each time point. For categorical variables, patient 
counts and percentages will be provided. Descriptive summaries of serious adverse events, 
patient withdrawals due to adverse events, and potentially clinically significant abnormal values 
(clinical laboratory or vital signs) based on predefined criteria will be provided as well.
If any patient dies during the study, a listing of deaths will be provided and all relevant 
information will be discussed in the patient narrative included in the case study report.
Tolerability Analysis: Injection site reaction assessment will be listed and summarized 
descriptively.
Pharmacokinetic Analysis: Pharmacokinetic plasma concentration results for fremanezumab 
will be tabulated descriptively at each planned sampling time point. At the open-label period, 
pharmacokinetic plasma concentration results (fremanezumab) will be tabulated descriptively at 
each planned sampling time point by treatment group.
In addition, the most appropriate population pharmacokinetic model may be developed, and 
covariates that may affect it will be tested for inclusion in the model. If performed, this analysis 
will be reported separately.
Pharmacokinetic/Pharmacodynamic Analysis: The pharmacokinetics/pharmacodynamics 
relationship may be estimated by compartmental techniques. The pharmacokinetic parameters 
will be based on fremanezumab measurements. The pharmacodynamic endpoints will be the 
efficacy/safety response(s). 
The pharmacokinetic/pharmacodynamic relationship may be estimated using the most 
appropriate model after comparing different candidate models for their quality of fit. Covariates 
that may affect the pharmacokinetic/pharmacodynamic relationship will be tested for inclusion in 
the model. If performed, this analysis will be reported separately.


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Immunogenicity Analysis: A summary of immunogenicity results will be provided, and the 
incidence of immunogenicity will be calculated. The impact of immunogenicity on the 
pharmacokinetic profile, fremanezumab efficacy, and clinical safety will be evaluated. This 
analysis will be reported separately.
Planned Interim Analysis: There will be no formal interim analysis.


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TABLE OF CONTENTS
TITLE PAGE...................................................................................................................................1
AMENDMENT HISTORY .............................................................................................................3
INVESTIGATOR AGREEMENT...................................................................................................4
SPONSOR PROTOCOL APPROVAL ...........................................................................................5
COORDINATING INVESTIGATOR AGREEMENT...................................................................6
CLINICAL STUDY PROTOCOL SYNOPSIS...............................................................................7
LIST OF ABBREVIATIONS........................................................................................................30
1.
INTRODUCTION AND BACKGROUND INFORMATION ..................................32
1.1.
Introduction.................................................................................................................32
1.2.
Findings from Nonclinical and Clinical Studies.........................................................33
1.2.1.
Nonclinical Studies.....................................................................................................33
1.2.2.
Clinical Studies...........................................................................................................34
1.2.2.1.
Clinical Pharmacology Studies...................................................................................35
1.2.2.2.
Clinical Safety and Efficacy Studies ..........................................................................35
1.3.
Known and Potential Benefits and Risks to Patients..................................................36
1.3.1.
Known and Potential Benefits and Risks of the Test Investigational 
Medicinal Product(s) ..................................................................................................36
1.3.2.
Overall Benefit and Risk Assessment for This Study ................................................37
2.
STUDY OBJECTIVES AND ENDPOINTS..............................................................38
2.1.
Primary and Secondary Study Objectives and Endpoints ..........................................38
2.1.1.
Justification of Primary Endpoint...............................................................................41
2.2.
3.
STUDY DESIGN .......................................................................................................44
3.1.
General Study Design and Study Schematic Diagram ...............................................44
3.2.
Planned Number of Patients and Countries................................................................45
3.3.
Justification for Study Design and Selection of Population.......................................45
3.4.
Stopping Rules for the Study......................................................................................46
3.5.
Schedule of Study Procedures and Assessments........................................................46
4.
SELECTION AND WITHDRAWAL OF PATIENTS..............................................51
4.1.
Patient Inclusion Criteria ............................................................................................51
4.2.
Patient Exclusion Criteria...........................................................................................52
4.3.
Withdrawal Criteria and Procedures for the Patient...................................................54


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4.4.
Replacement of Patients .............................................................................................55
4.5.
Rescreening.................................................................................................................55
4.6.
Screening Failure........................................................................................................55
5.
TREATMENTS..........................................................................................................57
5.1.
Investigational Medicinal Products Used in the Study...............................................57
5.1.1.
Test Investigational Medicinal Product......................................................................57
5.1.1.1.
Starting Dose and Dose Levels...................................................................................57
5.1.2.
Placebo Investigational Medicinal Product ................................................................58
5.2.
Preparation, Handling, Labeling, Storage, and Accountability for IMPs...................58
5.2.1.
Preparation of Investigational Medicinal Product ......................................................58
5.2.2.
Storage and Security...................................................................................................58
5.2.3.
Labeling......................................................................................................................58
5.2.4.
Accountability.............................................................................................................58
5.3.
Justification for Investigational Medicinal Products..................................................59
5.3.1.
Justification for Dose of Test Investigational Medicinal Product ..............................59
5.3.2.
Justification for Use of Placebo Investigational Medicinal Product ..........................60
5.4.
Treatment After the End of the Study.........................................................................60
5.5.
Restrictions .................................................................................................................60
5.5.1.
Activity .......................................................................................................................60
5.5.2.
Blood Donation...........................................................................................................60
5.5.3.
Pregnancy ...................................................................................................................60
5.6.
Prior and Concomitant Medication or Therapy..........................................................60
5.7.
Procedures for Monitoring Patient Compliance .........................................................61
5.8.
Randomization and Blinding......................................................................................61
5.9.
Maintenance of Randomization and Blinding............................................................62
5.9.1.
Maintenance of Randomization..................................................................................62
5.9.2.
Blinding and Unblinding ............................................................................................62
5.9.3.
Data Monitoring Committee.......................................................................................63
5.10.
Total Blood Volume ...................................................................................................63
6.
ASSESSMENT OF EFFICACY ................................................................................64
6.1.
Electronic Diary Application......................................................................................64
6.2.
Six-Item Headache Impact Test..................................................................................64
6.3.
Twelve-Item Short-Form Health Survey....................................................................64


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6.4.
Patient Global Impression of Change Scale ...............................................................65
6.5.
Special Protocol Headache Questionnaire..................................................................65
7.
ASSESSMENT OF SAFETY.....................................................................................66
7.1.
Adverse Events ...........................................................................................................66
7.1.1.
Definition of an Adverse Event..................................................................................66
7.1.2.
Recording and Reporting of Adverse Events .............................................................67
7.1.3.
Severity of an Adverse Event .....................................................................................67
7.1.4.
Relationship of an Adverse Event to the Test Investigational Medicinal 
Product........................................................................................................................68
7.1.5.
Serious Adverse Events..............................................................................................68
7.1.5.1.
Definition of a Serious Adverse Event .......................................................................68
7.1.5.2.
Expectedness...............................................................................................................69
7.1.5.3.
Reporting a Serious Adverse Event............................................................................70
7.1.6.
Protocol-Defined Adverse Events Not for Expedited Reporting ...............................71
7.1.7.
Protocol-Defined Adverse Events of Special Interest ................................................72
7.1.8.
Protocol Deviations Because of an Adverse Event ....................................................72
7.2.
Pregnancy ...................................................................................................................72
7.3.
Medication Error and Special Situations Related to the Investigational 
Medicinal Products.....................................................................................................73
7.4.
Clinical Laboratory Tests ...........................................................................................74
7.4.1.
Serum Chemistry, Hematology, and Urinalysis .........................................................74
7.4.2.
Other Clinical Laboratory Tests .................................................................................74
7.4.2.1.
Human Chorionic Gonadotropin Tests.......................................................................74
7.4.2.2.
Follicle-Stimulating Hormone Tests...........................................................................74
7.4.2.3.
Saliva Collection.........................................................................................................74
7.5.
Physical Examinations................................................................................................74
7.6.
Vital Signs ..................................................................................................................75
7.7.
Electrocardiography....................................................................................................75
7.8.
Immunogenicity..........................................................................................................76
7.9.
Assessment of Local Tolerability and Pain ................................................................76
7.10.
Sport Concussion Assessment Tool 3rd Edition ........................................................77
7.11.
Two-Item Patient Health Questionnaire/Nine-Item Patient Health 
Questionnaire..............................................................................................................77


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7.12.
Assessment of Suicidality...........................................................................................77
7.13.
Concomitant Therapy or Medication..........................................................................78
8.
ASSESSMENT OF PHARMACOKINETICS, BIOMARKERS, AND 
IMMUNOGENICITY ................................................................................................79
8.1.
Pharmacokinetic Assessment......................................................................................79
8.2.
Pharmacodynamics Assessment.................................................................................79
8.3.
Immunogenicity Testing.............................................................................................79
9.
STATISTICS ..............................................................................................................81
9.1.
Sample Size and Power Considerations .....................................................................81
9.2.
Analysis Sets...............................................................................................................81
9.2.1.
Intent-to-Treat Analysis Set........................................................................................81
9.2.2.
Full Analysis Set.........................................................................................................81
9.2.3.
Safety Analysis Set.....................................................................................................81
9.2.4.
Per-Protocol Analysis Set...........................................................................................81
9.3.
Data Handling Conventions........................................................................................82
9.4.
Study Population.........................................................................................................82
9.4.1.
Patient Disposition......................................................................................................82
9.4.2.
Demographic and Baseline Characteristics ................................................................82
9.5.
Efficacy Analysis........................................................................................................82
9.5.1.
Primary Endpoint........................................................................................................83
9.5.2.
Secondary Endpoints ..................................................................................................83
9.5.3.
Immunogenicity Endpoints.........................................................................................83
......................................................................................84
9.5.5.
Planned Method of Analysis.......................................................................................85
9.5.5.1.
Primary Efficacy Analysis..........................................................................................86
9.5.5.2.
Sensitivity Analysis ....................................................................................................86
9.5.5.3.
Secondary Efficacy Analysis......................................................................................87
...................................................................................87
9.6.
Multiple Comparisons and Multiplicity......................................................................87
9.7.
Safety Analysis ...........................................................................................................87
9.8.
Tolerability Analysis ..................................................................................................88
9.9.
Pharmacokinetic Analysis ..........................................................................................88


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9.10.
Pharmacokinetic/Pharmacodynamic Analysis............................................................88
9.11.
Biomarker Analysis ....................................................................................................88
9.12.
Pharmacogenomic Analysis........................................................................................88
9.13.
Immunogenicity Analysis...........................................................................................88
9.14.
Planned Interim Analysis............................................................................................89
9.15.
Reporting Deviations from the Statistical Plan ..........................................................89
10.
QUALITY CONTROL AND QUALITY ASSURANCE .........................................90
11.
COMPLIANCE STATEMENT..................................................................................91
12.
DATA MANAGEMENT AND RECORD KEEPING ..............................................92
13.
FINANCING AND INSURANCE.............................................................................93
14.
PUBLICATION POLICY ..........................................................................................94
15.
REFERENCES ...........................................................................................................95
16.
SUMMARY OF CHANGES TO PROTOCOL .........................................................97
16.1.
Amendment 02 Dated 30 March 2020........................................................................97
16.2.
Letter of Clarification 09 Dated 30 October 2019....................................................111
16.3.
Letter of Clarification 08 Dated 24 September 2019................................................111
16.4.
Letter of Clarification 07 Dated 01 August 2019 .....................................................111
16.5.
Letter of Clarification 06 Dated 18 April 2019 ........................................................111
16.6.
Amendment 01 Dated 25 March 2019......................................................................111
16.7.
Letter of Clarification 05 Dated 01 October 2018....................................................124
16.8.
Letter of Clarification 04 Dated 06 February 2018 ..................................................124
16.9.
Letter of Clarification 03 Dated 11 December 2017 ................................................124
16.10.
Letter of Clarification 02 Dated 16 November 2017................................................124
16.11.
Letter of Clarification 01 Dated 10 November 2017................................................124
APPENDIX A.
CLINICAL LABORATORIES AND OTHER DEPARTMENTS AND 
INSTITUTIONS.......................................................................................................125
APPENDIX B.
QUALITY CONTROL AND QUALITY ASSURANCE ..............................128
APPENDIX C.
ETHICS ...........................................................................................................130
APPENDIX D.
BIRTH CONTROL METHODS AND PREGNANCY TESTING ................131
APPENDIX E.
LOST TO FOLLOW-UP .................................................................................133
APPENDIX F.
LIST OF PROHIBITED MEDICATIONS AND PROCEDURES AND 
ALLOWED MEDICATIONS WITH SPECIAL CONDITIONS............................134
APPENDIX G.
TOTAL BLOOD VOLUME ...........................................................................135


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APPENDIX H.
DETAILED DESCRIPTION OF ASSESSMENTS AND 
PROCEDURES ........................................................................................................136
APPENDIX I.
GUIDANCE ON SAFETY MONITORING ....................................................144
APPENDIX J.
CLINICAL CRITERIA FOR DIAGNOSING ANAPHYLAXIS....................147
APPENDIX K.
CLINICAL LABORATORY TESTS .............................................................148
APPENDIX L.
PHARMACOKINETICS SAMPLES..............................................................149
APPENDIX M.
IMMUNOGENICITY SAMPLES .................................................................150
..............................................151
APPENDIX O.
PRODUCT COMPLAINTS............................................................................152
APPENDIX P.
DATA MANAGEMENT AND RECORD KEEPING....................................154
APPENDIX Q.
PUBLICATION POLICY...............................................................................157


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LIST OF TABLES
Table 1:
Study Procedures and Assessments............................................................................47
Table 2:
Investigational Medicinal Products Used in the Study...............................................57
Table 3:
The Relationship of an Adverse Event to the Test IMP .............................................68
Table 4:
Severity of Pain Scale for Injection Site Assessments ...............................................76


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LIST OF FIGURES
Figure 1:
Overall Study Schematic Diagram .............................................................................45


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LIST OF ABBREVIATIONS
Abbreviation
Term
ADA
anti-drug antibody
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
ANOVA
analysis of variance
AST
aspartate aminotransferase
AUC
area under the plasma concentration-time curve
β-HCG
beta-human chorionic gonadotropin
BLA
biological license application
CDMS
clinical data management system
CFR
Code of Federal Regulations (USA)
CGRP
calcitonin gene-related peptide
CL/F
apparent total body clearance
Cmax
maximum observed plasma drug concentration
CRF
case report form (refers to any media used to collect study data [ie, paper or electronic])
CRO
contract research organization
CSR
clinical study report
C-SSRS
Columbia Suicide Severity Rating Scale
CYP
cytochrome
ECG
electrocardiogram
EOS
end of study
EOT
end of treatment
ET
early termination
FAS
full analysis set
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GCS
Glasgow Coma Scale
GGT
gamma-glutamyl transpeptidase
GLP
Good Laboratory Practice
GPSP
Global Patient Safety and Pharmacovigilance
HIT-6
6-item Headache Impact Test
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


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Abbreviation
Term
IgG2
immunoglobulin G2
IHS
International Headache Society
IMP
investigational medicinal product
IND
investigational new drug
IL
interleukin
IRB
Institutional Review Board
IRT
interactive response technology
ITT
intent-to-treat
iv
intravenous
LSO
local safety officer
PGIC
Patient Global Impression of Change
PHQ-2
2-item Patient Health Questionnaire
PHQ-9
9-item Patient Health Questionnaire
PK
pharmacokinetic(s)
PP
per-protocol
PTH
posttraumatic headache
RSI
reference safety information
sc
subcutaneous
SCAT-3
Sport Concussion Assessment Tool 3rd edition
SD
standard deviation
SF-12
12-item Short-Form Health Survey
SOP
standard operating procedure
SUSAR
suspected unexpected serious adverse reaction
t½
terminal elimination half-life
tmax
median time of maximum observed concentration
ULN
upper limit of normal
Vss
volume of distribution at steady state
Vz/F 
apparent volume of distribution during the terminal phase
WHO
World Health Organization
WOCBP
women of childbearing potential


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1.
INTRODUCTION AND BACKGROUND INFORMATION
1.1.
Introduction
When a headache occurs for the first time in close temporal relation to trauma or injury to the 
head, it is coded as a secondary headache attributed to the trauma or injury. Headache attributed 
to trauma or injuries, or posttraumatic headache (PTH), accounts for approximately 4% of all 
symptomatic headaches (D’Onofrio 2014) and is among the most common secondary headache 
disorders. A large number of patients with headaches are at risk to have PTH, thus, PTH should 
be considered an important public health issue.
There are no specific headache features known to distinguish the subtypes of PTH from other 
headache types. They can resemble a range of primary headache conditions such as migraine (ie, 
moderate to severe intensity, pulsating, associated nausea or vomiting, light or sound sensitivity, 
and worsened with activity) or tension-type headache (ie, mild to moderate intensity, 
non-pulsating, light or sound sensitivity, but no nausea or vomiting), or one of a number of more 
uncommon headache syndromes (Finkel et al 2017). Rather, the diagnosis of PTH is largely 
dependent on the close temporal relationship between the trauma or injury and headache onset. 
PTH requires that the headache must be reported to have developed within 7 days of trauma or 
injury, or within 7 days of having regained consciousness, and/or ability to report pain when 
these have been lost following trauma or injury (IHS 2013).
The PTH may occur as an isolated symptom following trauma or injury or as one of a 
constellation of symptoms, commonly including dizziness, fatigue, reduced ability to 
concentrate, psychomotor slowing, mild memory problems, insomnia, anxiety, personality 
changes, and irritability. When several of these symptoms follow head injury, the patient may be 
considered to have a post-concussion syndrome. Posttraumatic sleep disturbances, mood 
disturbances, and psychosocial stressors can plausibly influence the development and 
perpetuation of headache.
The pathogenesis of PTH is most commonly in the absence of overt brain injury. Numerous 
factors that may contribute to its development include, but are not limited to, axonal injury, 
alterations in cerebral metabolism and cerebral hemodynamics, underlying genetic 
predisposition, psychopathology, and a patient’s expectation of developing a headache after head 
injury (IHS 2013). It is recommended that treatment for secondary headache types, such as PTH, 
be consistent with the treatment of the primary headache type it most resembles (Lucas 2015). 
Fremanezumab (formerly TEV-48125, LBR-101, PF-04427429, and RN307) is a fully 
humanized IgG 2a/kappa monoclonal antibody, which is being developed for administration by 
the subcutaneous (sc) route for the preventive treatment of migraine. Fremanezumab is a potent, 
selective calcitonin gene-related peptide (CGRP) binder that blocks both CGRP isoforms (α- and 
β-CGRP) from binding to the CGRP receptor. Fremanezumab has been shown to be safe and 
efficacious in patients with migraine demonstrating onset of efficacy as early as 1 week after 
treatment and maintenance of effect throughout the 12-week treatment period (Bigal et al 2015a, 
Bigal et al 2015b).
The purpose of the study is to evaluate the efficacy and safety of fremanezumab administered 
subcutaneously for the prevention of PTH in adult patients.


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1.2.
Findings from Nonclinical and Clinical Studies
Brief summaries of nonclinical pharmacology, pharmacokinetics, and toxicology studies and 
clinical studies are provided in the following sections. More detailed information is provided in 
the Investigator’s Brochure (IB).
1.2.1.
Nonclinical Studies
Fremanezumab was evaluated in nonclinical pharmacology, pharmacokinetics, and toxicology 
studies. Pivotal studies were conducted under Good Laboratory Practice (GLP) via the 
intravenous (iv) and subcutaneous (sc) routes of administration with once-weekly dosing for up 
to 6 months.
In in vitro studies, fremanezumab demonstrated no potential for Fcγ receptor binding, cytokine 
release, or hemolysis up to tested concentrations of 25.5 mg/mL. The concentrations tested in 
these in vitro assays are relevant to the predicted range of concentrations for administration in 
human subjects. Fremanezumab prevents in vitro cyclic adenosine monophosphate production 
induced by CGRP while not binding to similar peptides such as amylin, calcitonin, or 
adrenomedullin. In vivo pharmacology studies of fremanezumab in animal models indicate that 
fremanezumab prevented an increase in blood flow in rat paw skin and the middle meningeal 
artery after electrical stimulation and produced a dose-dependent inhibition of the 
capsaicin-induced skin flare response in cynomolgus monkey.
Safety pharmacology studies to evaluate potential cardiovascular effect were performed. The 
data suggest no treatment-related findings after single and repeated administration up to 
6 months via once-weekly administration at high dose levels (up to 300 mg/kg/week).
Fremanezumab was tested in a series of nonclinical in vivo studies in Sprague Dawley rats and 
cynomolgus monkeys. Fremanezumab was administered to rats and monkeys by the iv or sc 
route for up to 3 months in duration and by sc route in the 6-month chronic toxicity study in 
monkeys, and no toxicological concerns were identified following chronic dosing to 
experimental animals at dose levels up to 300 mg/kg/week. 
It is relevant to note that due to the higher exposure observed in recent Study 
TV48125-PK-10078 (Japanese bridging study), a re-evaluation of the safety margins was 
performed. An internal investigation indicates that the original assay underestimated 
fremanezumab measured plasma concentrations. Comparison of the exposure parameters of 
maximum observed plasma drug concentration (Cmax) and area under the plasma 
concentration-time curve from time 0 to infinity (AUC0-∞) from Study LBR-101-011 (including 
iv dosing), which were analyzed by the original bioassay, with the exposure parameters from 
Study TV48125-PK-10078, which were analyzed using the newer validated assay for the 225-mg 
and 900-mg sc dose levels, indicates an apparent exposure difference between 2.9- and 3.5-fold 
in Study TV48125-PK-10078 relative to Study LBR-101-011. Thus, the most conservative value 
of 3.5 was used to recalculate the safety margins, meaning that LBR-101-011 exposure was 
assumed to be 3.5-fold higher than originally reported, and as such, safety margins decreased by 
3.5-fold.
For the 6-month chronic toxicity study in monkeys, the calculated safety margins based on 
exposure (area under the plasma concentration-time curve [AUC]) at 300 mg/kg/week dose, 
which was determined as the no-observable-adverse-effect level, is at least 54-fold higher 


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compared to the expected human exposure at a dosing regimen of 900 mg iv loading dose 
followed by the 225 mg sc monthly dose and at least 20 fold higher relative to Cmax.
Nevertheless, it is important to note that the change in safety margins has no impact on the safety 
of fremanezumab based on the overall toxicological data profile and adequate safety margins.
In a GLP embryo-fetal developmental toxicity study in rabbits, sc injection of fremanezumab to 
pregnant rabbits was well tolerated and did not induce any obvious maternal toxicity at any dose 
level. No apparent evidence of embryo-fetal toxicity was noted in any dose group. In addition, a 
GLP combined fertility and embryo-fetal developmental toxicity study in rats was conducted, 
and no treatment-related effects on gonadal function, mating behavior, reproductive 
performance, and embryo-fetal survival and development were observed in any dose group.
The pharmacokinetics of fremanezumab in animals (rats and monkeys) is typical of a humanized 
immunoglobulin G2 (IgG2) molecule, with low mean plasma clearance, low volume of 
distribution at steady state (Vss), and a long terminal elimination half-life (t½). Exposure, as 
defined by Cmax and AUC, increased linearly across doses following single and repeated 
once-weekly dosing. No gender differences in exposure were observed in rats or monkeys. 
Following sc administration, mean systemic exposure values (calculated using AUC from time 0 
to 168 hours postdose) were 65% to 67% and 81% to 92% of the equivalent iv doses for rats and 
monkey, respectively, demonstrating reasonably high sc bioavailability.
To conclude, the overall nonclinical safety data presented support the safe repeated (monthly) 
administration of fremanezumab in human subjects for the duration of the Phase 2 
proof-of-concept (3 months) study.
1.2.2.
Clinical Studies
The clinical program to date is composed of 6 completed Phase 1 clinical studies in healthy 
subjects (Studies B0141001, B0141002, B0141006, B0141007, LBR-101-008, and 
LBR-101-011) and 2 completed Phase 2b clinical studies in patients with migraine 
(Studies LBR-101-021 and LBR-101-022). In total, 484 subjects/patients (118 healthy subjects 
and 366 patients with migraine) have received at least 1 dose of fremanezumab via iv or sc 
routes of administration in these completed studies. In addition, there are 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1.2.2.1.
Clinical Pharmacology Studies
A total of 118 healthy subjects received fremanezumab across 6 completed Phase 1 studies in 
doses ranging from 0.2 through 2000 mg. Studies included 2 single-ascending-dose 
pharmacokinetic and pharmacodynamic studies in healthy men (Studies B0141001 and 
B0141002); a 2-cohort, placebo-controlled crossover study to examine the acute effects of 
administration of fremanezumab on capsaicin flare response in healthy men (Study B0141006); a 
parallel-group, repeat-dose study of fremanezumab in healthy subjects (Study B0141007); a 
single-dose study evaluating the safety, tolerability, and pharmacokinetics of doses up to 2000 
mg administered iv in healthy women (Study LBR-101-008 [formerly referred to as Study 
B0141008]); and a study assessing the safety, tolerability, absolute bioavailability, and 
pharmacokinetics of single iv or sc doses of fremanezumab in healthy subjects (Study 
LBR-101-011).These Phase 1 studies were analyzed using the original bioanalytical method that 
has since been determined to underestimate measured plasma concentrations compared to the 
current validated assay. In those analyses, fremanezumab pharmacokinetics appeared linear over 
the dose range from 100 to 2000 mg with Cmax and AUC generally increasing in proportion to 
the dose.
A recently completed pharmacokinetic, safety, and tolerability study in healthy Japanese and 
Caucasian subjects (TV48125-PK-10078) dosed fremanezumab as a single sc dose of 225, 675 
or 900 mg. Plasma concentration-time profile was measured using the current validated 
bioanalytical method and the pharmacokinetic results are described below. 
The pharmacokinetics (non-compartmental analysis) of fremanezumab demonstrated an increase 
in Cmax and AUCs values slightly greater than dose proportionality over sc dose range of 225 to 
900 mg. Median time to maximum observed concentration (tmax) values generally occurred 5 to 
7 days post sc doses. Mean values for apparent volume of distribution (Vz/F) after a single sc 
dose ranged from 5.7 to 6.4 L at 225 mg to 900 mg sc doses. The mean apparent total body 
clearance (CL/F) ranged from 0.0777 to 0.0895 mL/min at this dose range. The mean t½ ranged 
from 32.2 to 36.2 days. Fremanezumab exposure parameters and overall pharmacokinetic profile 
was similar for healthy Japanese and Caucasian subjects. Comparison of exposure parameters 
(Cmax and AUC0-∞) from Study LBR-101-011 and TV48125-PK-10078 at the 225 and 900 mg sc 
dose levels indicates a 2.9 to 3.5 fold higher exposure in Study TV48125-PK-10078 relative to 
LBR-101-011 study. The main reason for the difference in exposure appears to be the 
bioanalytical method used in the plasma sample analysis.
1.2.2.2.
Clinical Safety and Efficacy Studies
The safety, tolerability, and efficacy of fremanezumab have been evaluated in 2 completed Phase 
2b studies, Studies LBR-101-021 and LBR-101-022, in patients with migraine (Bigal et al 2015a, 
Bigal et al 2015b). The results of both studies showed fremanezumab to be superior to placebo 
for primary and secondary endpoints (benefit at 3 months of therapy).
Fremanezumab was well tolerated with favorable safety profile across the 6 completed Phase 1 
and 2 completed Phase 2b studies. In addition, no new safety findings were observed in the
 and no serious adverse events considered 


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related to the investigational medicinal product (IMP) have been reported for the 
 
as of 23 April 2016). 
The treatment-emergent adverse events reported in the Phase 1 and Phase 2b studies were 
predominantly mild to moderate in severity. A specific “pattern of adverse events” that could be 
associated with a dose or a dose range of fremanezumab has not been identified, nor has a 
maximally tolerated dose been identified. Overall, the nature and occurrence of the reported 
treatment-related adverse events across the clinical program have not raised any specific safety 
concerns.
No clinically relevant changes in clinical laboratory values, vital signs measurements, or 
electrocardiogram (ECG) findings have been observed in any of the studies to date.
1.3.
Known and Potential Benefits and Risks to Patients
Information regarding the risks and benefits of fremanezumab in patients is summarized in the 
following sections. Additional information regarding benefits and risks to patients may be found 
in the IB.
1.3.1.
Known and Potential Benefits and Risks of the Test Investigational Medicinal 
Product(s)
Results from Phase 2b clinical studies have demonstrated statistically significant reductions in 
mean headache hours after 1, 2, and 3 months of sc fremanezumab treatment in patients with 
chronic migraine and statistically significant reductions in monthly migraine days after 1, 2, and 
3 months of fremanezumab treatment in patients with episodic migraine. Results for several 
secondary 
 endpoints also showed fremanezumab to be superior to placebo. 
Fremanezumab has generally been well tolerated over the ranges of doses evaluated (single iv 
infusions at 0.02 to 2000 mg in healthy subjects, multiple iv infusions at 30 to 300 mg in healthy 
subjects, and multiple sc doses at 225 to 900 mg in healthy subjects and migraine patients). The 
most common treatment-emergent adverse events across all patients/subjects studied were mild 
to moderate transient general administration site disorders/reactions. Other commonly reported 
treatment-emergent adverse events were headache, back pain, and upper respiratory tract 
infection.
Reports of mild to moderate transient administration site disorders/reactions, including injection 
site bruising, injection site swelling, injection site pain, injection site pruritus, injection site 
dermatitis, injection site rash, injection site edema, injection site discomfort, injection site 
hemorrhage, injection site irritation, injection site mass, and injection site hematoma, have 
occurred with sc administration. In addition, reports of mild and transient infusion site pain and 
swelling following iv administration have occurred. Among these events, the following have 
been identified as adverse drug reactions (identified risks): injection site erythema, 
administration site pain, injection site pain, injection site pruritus, and injection site dermatitis. 
None of these identified risks are considered important risks.
Infusion-related reaction and drug hypersensitivity were also identified as adverse drug reactions. 
To date, 1 subject who received fremanezumab iv had a non-serious infusion-related reaction and 
1 patient who received fremanezumab via the sc route had a non-serious event of drug 
hypersensitivity. Both events resolved following IMP discontinuation and treatment with 


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diphenhydramine and methylprednisolone. Neither of these identified risks is considered 
important risks.
Potential risks for fremanezumab include perivascular inflammation; development of anti-drug 
antibodies (ADAs); liver enzyme elevations; and cardiovascular consequences of CGRP 
inhibition, including effects on blood pressure, heart rate, or other cardiovascular parameters.
1.3.2.
Overall Benefit and Risk Assessment for This Study
In summary, the benefit and risk assessment for fremanezumab is favorable following review of 
the outlined data.


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2.
STUDY OBJECTIVES AND ENDPOINTS
2.1.
Primary and Secondary Study Objectives and Endpoints
The primary and secondary study objectives and endpoints are:
Objectives
Endpoints
The primary objective of the 
study is to evaluate the efficacy 
of fremanezumab administered 
subcutaneously (sc) in adult 
patients with posttraumatic 
headache (PTH).
The primary efficacy endpoint is the mean change from 
baseline (baseline period) in the monthly average number of 
headache days of at least moderate severity during the 12-week 
period after the first dose of the IMP.


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Objectives
Endpoints
A secondary objective is to 
evaluate the efficacy of 
fremanezumab administered sc 
in adult patients with PTH.
The secondary efficacy endpoints are:

proportion of patients reaching at least 50% 
reduction from baseline (baseline period) in the 
monthly average number of headache days of at 
least moderate severity during the 12-week period 
of treatment with the IMP

proportion of patients reaching at least 50% 
reduction from baseline (baseline period) in the 
monthly average number of headache days of at 
least moderate severity during the first 4-week 
period after the first dose of the IMP

proportion of patients reaching at least 50% 
reduction from baseline (baseline period) in the 
monthly average number of headache days of at 
least moderate severity during the 5- to 8-week 
period after the first dose of the IMP

proportion of patients reaching at least 50% 
reduction from baseline (baseline period) in the 
monthly average number of headache days of at 
least moderate severity during the 9- to 12-week 
period after the first dose of the IMP

mean change from baseline (baseline period) in the 
number of headache days of at least moderate 
severity during the first 4-week period after the first 
dose of the IMP

mean change from baseline (baseline period) in the 
number of headache days of at least moderate 
severity during the 5- to 8-week period after the 
first dose of the IMP

mean change from baseline (baseline period) in the 
number of headache days of at least moderate 
severity during the 9- to 12-week period after the 
first dose of the IMP

mean change from baseline (visit 2) in disability 
score, as measured by the 6-item Headache Impact 
Test (HIT-6) at week 12 after the first dose of the 
IMP

mean change from baseline (visit 2) in the 
assessment of patient satisfaction, as measured by 
the Patient Global Impression of Change scale, at 4, 
8, and 12 weeks after the first dose of the IMP


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Objectives
Endpoints
A secondary objective of the 
study is to evaluate the safety 
and tolerability of 
fremanezumab administered sc 
in adult patients with PTH 
compared with placebo and 
during the open-label period.
The safety and tolerability endpoints are:

occurrence of adverse events during the study

clinically significant changes in physical 
examinations, including body weight

clinical laboratory (serum chemistry, hematology 
and coagulation, and urinalysis) test results at each 
visit

vital signs (blood pressure, respiratory rate, body 
temperature, and pulse) measurements at each visit
Note: Oxygen saturation and respiratory rate will 
be measured in cases of suspected anaphylaxis and 
severe hypersensitivity.

12-lead electrocardiogram (ECG) findings at each 
visit

use of concomitant medication during the study

number (%) of patients who did not complete the 
study (day 168,end-of-study [EOS])

number (%) of patients who did not complete the 
study due to adverse events

local tolerability at the injection site (ie, erythema, 
induration, ecchymosis, and pain) at the following 
time points postdose: day 0, day 28, and day 56

hypersensitivity reaction assessment

Columbia Suicide Severity Rating Scale (C-SSRS)
The immunogenicity objective
is to evaluate the 
immunogenicity of 
fremanezumab and the impact 
of antidrug antibodies (ADAs) 
on clinical outcomes in patients 
exposed to fremanezumab.
The immunogenicity endpoints are ADA incidence and 
characteristics (eg, titer, kinetics, and neutralizing activities). 
ADA=antidrug antibody; C-SSRS=Columbia Suicide Severity Rating Scale; ECG=electrocardiogram; 
HIT-6=6-item Headache Impact Test; IMP=investigational medicinal product; PTH= posttraumatic headache; 
sc=subcutaneous.


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2.1.1.
Justification of Primary Endpoint
For this study of patients with PTH, the primary efficacy endpoint is the mean change from 
baseline (baseline period) in the monthly average number of headache days of at least moderate 
severity during the 12-week period after the first dose of the IMP. A headache day is defined as a 
day when a patient reports a headache of at least moderate severity. This measure allows the use 
of a relatively simple headache diary.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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3.
STUDY DESIGN
3.1.
General Study Design and Study Schematic Diagram
This is a multicenter, randomized, proof-of-concept, double-blind, placebo-controlled, 
parallel-group study, including an open-label period, evaluating the efficacy and safety of 
1 subcutaneous dose regimen of fremanezumab in adult patients with PTH. The study will 
consist of a screening visit, a baseline period, a double-blind treatment period lasting 
approximately 12 weeks, and an open-label period lasting approximately 12 weeks. 
The total duration of patient participation in the study is planned to be approximately 28 weeks.
Patients will complete a screening visit (visit 1) after providing informed consent, and eligible 
patients will enter a baseline period lasting approximately 4 weeks (28+3 days), during which 
time they will enter their baseline PTH information into a daily electronic headache diary. 
Patients meeting eligibility requirements will be randomly assigned to 1 of 2 treatment groups 
with fremanezumab or placebo in a 1:1 ratio. Treatment assignment will take place with 
stratification based on the duration of the patient’s history of PTH (<12 months and ≥12 months 
duration).
Screening results will be reviewed for eligibility, additional baseline assessments will be 
administered, and the first treatment administration will occur at visit 2. Patients will return to 
the study center approximately every 4 weeks (visit 3 and visit 4) for a continuation of the 
blinded treatment administered sc; for safety and efficacy assessments; and for blood and urine 
sampling for pharmacokinetics, immunogenicity, and biomarker analysis. At visit 5, all patients 
will proceed directly to an open-label treatment phase, with fremanezumab administered sc. 
Patients will then return to the study center approximately every 4 weeks (visits 6 and 7) for 
continued open-label treatment and safety tolerability and efficacy assessments. Final study 
assessments will be performed on visit 8, at the end of treatment or early termination visit, 
approximately 24 weeks after first administration of the IMP.
A database lock from the double-blind period will occur following the completion of visit 5 by 
the last patient. Unblinding will occur after the database lock from the double-blind period.
Patients who complete all scheduled visits will have procedures and assessments performed at 
visit 8. Patients who withdraw from the study before completing either the double blind or the 
open label treatment phases will have visit 8 procedures and assessments performed at their final 
visit. For all patients in the study, the end-of-treatment visit (visit 8) is defined as the final visit 
of the study and the conclusion of all study activities for the patient; patients will not receive any 
further treatments with IMP and will be treated according to guidelines and treating physicians’ 
discretion.
The EOS is defined as the last safety visit. However, a final database lock will occur following 
the end-of-treatment visit (visit 8) of the last patient for analysis of the study data.
The total duration of the study will be approximately 2 years from Q4 of 2017 until 
approximately Q2 of 2020.
The study schematic diagram is presented in Figure 1.


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Figure 1:
Overall Study Schematic Diagram
PBO=placebo; SC=subcutaneous; V=visit.
3.2.
Planned Number of Patients and Countries
The total number of patients planned was 172 (86 patients per treatment group). Study 
recruitment was discontinued at 87 patients due to challenges to enrollment and not for any 
safety concerns.
The study is planned to be conducted in the United States in approximately 32 study centers. The 
study is expected to be executed between the period of Q4 2017 and Q2 2020.
3.3.
Justification for Study Design and Selection of Population
There are no evidence-based treatment guidelines for PTH management; however, expert 
opinion has suggested treating PTH using primary headache disorder treatment recommendations 
according to its type (Lucas 2015). The features of PTH most often resemble those of migraine, 
therefore, it is reasonable that the study design follows the recommendations of the International 
Headache Society (IHS) guidelines for controlled trials of drugs in migraine (Lipton et al 1995), 
which specify parallel-group, placebo-controlled studies (IHS 2013). 
The study population will be composed of male and female patients, aged 18 to 70 years, 
inclusive, with a history of PTH (as defined by International Classification of Headache 
Disorders 3rd revision [ICHD-3] (beta version) criteria) (IHS 2013). This will include patients 
with headache attributed to mild, traumatic injury of the head or headache attributed to whiplash.
PTH is a headache with >1 month duration attributed to mild head injury: Glasgow Coma Scale 
(GCS) score of 13 to 15, loss of consciousness less than 30 minutes, duration of posttraumatic 
amnesia of <24 hours, and 2 or more other symptoms suggestive of mild traumatic brain injury 
(ie, nausea, vomiting, visual disturbances, dizziness and/or vertigo, and impaired memory and/or 
concentration). 


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Persistent headache attributed to whiplash (with or without neck pain) is a headache that has 
developed within 7 days after the whiplash and with >1 month duration.
Traumatic injury to the head is defined as a structural or functional injury resulting from the 
action of external forces on the head. These include striking the head with or the head striking an 
object, penetration of the head by a foreign body, forces generated from blasts or explosions.
The duration of posttraumatic amnesia is defined as the time between head injury and recovery 
of memory of current events and those occurring in the last 24 hours.
Whiplash is defined as sudden and inadequately restrained acceleration/deceleration movements 
of the head with flexion/extension of the neck. Whiplash may occur after either high or low 
impact forces.
PTH is a common secondary headache disorder that negatively affects a patient’s quality of life, 
in which a significant unmet medical need for treatment exists.
3.4.
Stopping Rules for the Study
During the conduct of the study, serious adverse events will be reviewed (Section 7.1.5) as they 
are reported from the investigational centers to identify safety concerns.
The study may be terminated by the sponsor for any reason at any time. For example, the 
sponsor should terminate the study if any of the following conditions occur:

New toxicological or pharmacological findings or safety issues invalidate the earlier 
positive benefit-risk assessment.

Development of the IMP is discontinued.
A patient may discontinue participation in the study at any time for any reason (eg, lack of 
efficacy, withdrawal of consent, or adverse event). The investigator and/or sponsor can withdraw 
a patient from the study at any time for any reason (eg, protocol deviation as defined in 
Section 10, noncompliance, or adverse event). In addition, patients with positive C-SSRS 
findings or abnormal hepatic laboratory values may meet criteria for discontinuation as 
summarized in Appendix I.
3.5.
Schedule of Study Procedures and Assessments
Study procedures and assessments with their time points are presented in Table 1. Detailed 
descriptions of each method of procedures and assessments are provided in Section 6 (efficacy 
assessments), Section 7 (safety assessments), and Section 8 (pharmacokinetics and other 
assessments). Study procedures and assessments by visit are listed in Appendix H.


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Table 1:
Study Procedures and Assessments
Study period
Pretreatment 
(including 
screening visit 
and baseline 
period)
Double-blind treatment period 
(visit/day or week)
Open-label period (visit/day or week)
Visit number
V1a
V2
V3
V4
V5
V6
V7
V8b
Day and allowed time 
windows
Day -28 to -1 
(+3 days) 
Day 0±3 days
Day 28±3
days
Day 56±
3 days
Day 84±3
days
Day 112
±3 days
Day 140±3 days
Day 168±3 days
Procedures and assessments
Screening
Randomization
Week 0
Dose 1
Week 4
Dose 2
Week 8
Dose 3
Week 12
Dose 4
Week 16
Dose 5
Week 20
Dose 6
Week 24
EOT/EOS/ET
Informed consent
X
Inclusion and exclusion 
criteria
X
X
Assign 
randomization/treatment 
number
X
Medical and psychiatric 
history
X
Prior medication and 
treatment historyc
X
Record demographic 
characteristics
X
Adverse events inquiryd,e,f
X
X
X
X
X
X
X
X
Concomitant medication 
inquiryf
X
X
X
X
X
X
X
X
Clinical laboratory tests 
(serum chemistry, hematology 
and coagulation, and 
urinalysis)g
X
X
X
X
X
X
X
X
Full physical examinationh
X
X
X


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Study period
Pretreatment 
(including 
screening visit 
and baseline 
period)
Double-blind treatment period 
(visit/day or week)
Open-label period (visit/day or week)
Visit number
V1a
V2
V3
V4
V5
V6
V7
V8b
Day and allowed time 
windows
Day -28 to -1 
(+3 days) 
Day 0±3 days
Day 28±3
days
Day 56±
3 days
Day 84±3
days
Day 112
±3 days
Day 140±3 days
Day 168±3 days
Procedures and assessments
Screening
Randomization
Week 0
Dose 1
Week 4
Dose 2
Week 8
Dose 3
Week 12
Dose 4
Week 16
Dose 5
Week 20
Dose 6
Week 24
EOT/EOS/ET
Electrocardiographyi
X
X
X
X
X
X
X
X
Vital signs measurementj, f
X
X
X
X
X
X
X
X
Serum β-HCG test for women 
of childbearing potentialk
X
X
X
Urine pregnancy testk
X
X
X
X
FSHl
X
Inform patients of study 
restrictions and compliance 
requirements
X
Review study compliancef
X
X
X
X
Complete electronic headache 
diarym
X
X
X
X
X
Review electronic headache 
diaryf
X
X
X
X
Blood samples for plasma 
concentration of IMPn
X
X
X
X
X
X
X
Blood samples for serum
ADA concentrationo
X
X
X
X


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Study period
Pretreatment 
(including 
screening visit 
and baseline 
period)
Double-blind treatment period 
(visit/day or week)
Open-label period (visit/day or week)
Visit number
V1a
V2
V3
V4
V5
V6
V7
V8b
Day and allowed time 
windows
Day -28 to -1 
(+3 days) 
Day 0±3 days
Day 28±3
days
Day 56±
3 days
Day 84±3
days
Day 112
±3 days
Day 140±3 days
Day 168±3 days
Procedures and assessments
Screening
Randomization
Week 0
Dose 1
Week 4
Dose 2
Week 8
Dose 3
Week 12
Dose 4
Week 16
Dose 5
Week 20
Dose 6
Week 24
EOT/EOS/ET
Blood collection for 
biomarker analysisp
X
X
X
X
X
X
Urine collection for biomarker 
analysis
X
X
X
X
Saliva sample for biomarker 
analysis
X
X
X
X
X
X
X
HIT-6 questionnaire
X
X
X
X
X
PHQ-2/PHQ-9q
X
X
SF-12 questionnaire
X
X
X
X
X
SCAT-3 questionnaire
X
X
X
PGIC questionnaire
X
X
X
X
X
X
X
C-SSRSr, f
X
X
X
X
X
X
X
X
Administration of IMPs
X
X
X
X
X
X
Injection site assessmentst
X
X
X
X
X
X
Hypersensitivity/anaphylaxisu
X
X
X
X
X
X
Special Protocol Headache 
questionnairev
X
X
a Patients will complete a screening visit and a baseline period lasting 28 days (+3 days). An unscheduled visit may be performed at any time during the study at the 
patient’s request and as deemed necessary by the investigator. The date and reason for the unscheduled visit will be recorded on the CRF, as well as any other data 
obtained from procedures and assessments.


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b EOS is defined as the last safety visit (V8).
c The collection of prior medications is limited to those medications administered within 3 months before screening (V1).
d Adverse events will be recorded from the time informed consent is obtained through the EOS participation. Adverse Events Inquiry should take place both predose and 
postdose for visits 2 through 7.
e Patients will be assessed for anaphylaxis and severe hypersensitivity reaction during and after administration of the IMP.
f Procedures for unscheduled visits.
g Currently menstruating information (yes, no, or not applicable) will be collected prior to blood and urine collection for laboratory tests for all females.
h Height will be measured only at the screening visit.
i Electrocardiograms (12-lead) will be performed in triplicate with approximately 1 to 5 minutes between recordings before blood draws and administration of 
questionnaires.
j Oxygen saturation and respiratory rate will be measured in cases of suspected anaphylaxis and severe hypersensitivity.
k Serum β-HCG and urine pregnancy tests are required for women of childbearing potential only.
l The FSH test is required for postmenopausal women only.
m Patients will enter headache days of any severity (mild, moderate, or severe), their duration, and prescription medication use into the electronic diary application daily 
throughout the pretreatment period and double-blind treatment periods. Eligible patients will upload the application to their own device or use the provisioned device 
and will be trained in its use and compliance requirements on the day of screening (visit 1). Patients will be asked to return the provisioned electronic diary device on 
visit 5 and the electronic tablet on visit 8 to the investigational center.
n Blood samples for pharmacokinetic analysis (4 mL) will be collected prior to dosing at visit 2 (baseline). At each visit thereafter, a single blood sample for 
pharmacokinetic analysis will be collected prior to dosing, where applicable.
o Blood samples for serum ADA assessment (5 mL) will be collected prior to dosing at each applicable visit and will also be collected upon observation of any 
anaphylaxis or severe hypersensitivity reaction. 
p Blood for further biomarker analyses will be collected after blood collection for pharmacokinetic and immunogenicity analyses as follows: 6 mL for serum, 6 mL for 
plasma, and 6.5 mL for PAXgene® RNA.
q Patients will first complete the PHQ-2. If the PHQ-2 is positive (ie, a score of ≥3), they will complete the PHQ-9. 
r The C-SSRS Baseline/Screening version will be completed at visit 1, and the Since Last Visit version will be completed at all other subsequent visits, including 
unscheduled visits.
s Patients randomized to fremanezumab will receive 675 mg of fremanezumab administered as 3 sc injections (225 mg/1.5 mL) at visit 2 (randomization), visit 3 (week 
4), visit 4 (week 8), visit 5 (week 12), visit 6 (week 16), and visit 7 (week 20). Patients randomized to placebo will receive placebo administered as 3 sc injections 
(1.5 mL each) at visit 2 (randomization), visit 3 (week 4), and visit 4 (week 8).
t Patients will be assessed for injection site erythema, injection site induration, injection site ecchymosis, and injection site pain immediately (+10 minutes) and 1 hour 
(±15 minutes) after completion of each IMP administration. If a patient has severe injection site induration, injection site erythema, injection site ecchymosis, or 
injection site pain at 1 hour after completion of IMP administration, the patient will be reassessed 3 hours (±15 minutes) after IMP administration and hourly thereafter 
until the reaction is of moderate or less severity.
u Patients will be assessed for severe hypersensitivity/anaphylaxis reaction during and after administration of the IMP. Oxygen saturation and respiratory rate will be 
measured in cases of suspected anaphylaxis and severe hypersensitivity.
v Patients will complete the Special Protocol Headache questionnaire for visits 5 and 8 following all other procedures at visits 5 and 8. Patients will be instructed to return 
the electronic diary device on visit 5 and the electronic tablet on visit 8 to the investigational center after collection of the Special Protocol Headache Questionnaire.
ADA=anti-drug antibodies; β-HCG=beta-human chorionic gonadotropin; CRF=case report form; C-SSRS=Columbia Suicide Severity Rating Scale; EOS=end of study; 
EOT=end of treatment; ET=early termination; FSH=follicle-stimulating hormone; HIT-6=6-item Headache Impact Test; IMP=investigational medicinal product; 
PGIC=Patient Global Impression of Change; PHQ-2=2-item Patient Health Questionnaire; PHQ-9=9-item Patient Health Questionnaire; RNA=ribonucleic acid; 
sc=subcutaneous; SCAT-3=Sport Concussion Assessment Tool 3rd edition; SF-12=12-item Short-Form Health Survey; V=visit.


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4.
SELECTION AND WITHDRAWAL OF PATIENTS
Prospective waivers (exceptions) from study inclusion and exclusion criteria to allow patients to 
be randomized/enrolled are not granted by Teva (Appendix C).
Changes to inclusion or exclusion criteria are indicated below and detailed in Section 16.
4.1.
Patient Inclusion Criteria
Patients may be randomized/enrolled in this study only if they meet all of the following criteria:
a.
The patient is capable of giving signed informed consent as described in Appendix C,
which includes compliance with the requirements and restrictions listed in the 
informed consent form (ICF) and in this protocol.
b. The patient is a man or woman 18 to 70 years of age, inclusive.
c.
The patient has a body weight 45 kg.
d. Traumatic injury to the head has occurred, defined as a structural or functional injury 
resulting from the action of external forces. These include striking the head with or 
the head striking and object, penetration of the head by a foreign body, forces 
generated from blasts or explosions; or whiplash has occurred, defined as sudden and 
inadequately restrained acceleration/deceleration movements of the head with 
flexion/extension of the neck. Whiplash may occur after either high or low impact 
forces. 
e.
The patient has a diagnosis of PTH as per the ICHD-3 (beta version) criteria:

Headache is reported to have developed within 7 days after one of the following:
○
mild traumatic injury to the head 
○
regaining of consciousness following the injury to the head 
○
discontinuation of medication(s) that impair ability to sense or report 
headache following the injury to the head 
In addition, the following criteria should be met: 

Headache persists for >1 month after injury to the head
f.
During the baseline period, the patient has at least 8 headache days of at least 
moderate severity, defined as a day when a patient reports at least 4 hours of 
headache (not necessarily consecutive) and at its worst at any point has at least 
moderate severity; or when a patient has a headache and takes a prescription abortive
medication with intent to alleviate the headache (regardless of duration or severity).
g. The patient demonstrated compliance with the electronic diary during the baseline 
period by entry of headache data at a minimum of 75% compliance. 
h. The patient is not using preventive medications for headache (presented 
in Appendix F) (ie, at least 5 half-lives have passed since last use) or is using them in 


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a dose and regimen that have been stable for at least 2 months prior to beginning the 
baseline period.
i.
Women may be included only if they have a negative serum beta-human chorionic 
gonadotropin (β-HCG) test at screening and a negative urine pregnancy test at 
baseline, are sterile, or postmenopausal. Definitions of sterile and postmenopausal are 
given in Appendix D.
j.
Women of childbearing potential (WOCBP) whose male partners are potentially 
fertile (ie, no vasectomy) must use highly effective birth control methods for the 
duration of the study (ie, starting at screening) and for 30 weeks after the last IMP 
administration. Further details are included in Appendix D.
k. Men must be sterile or, if they are potentially fertile or reproductively competent (ie, 
not surgically or congenitally sterile) and their female partners are of childbearing 
potential, must use, together with their female partners, a condom for the duration of 
the study and for 30 weeks after the last IMP administration. Further details are 
included in Appendix D.
l.
Definitions of WOCBP, sterile and postmenopausal women, male contraception, 
and highly effective birth control methods, including examples, are given 
in Appendix D.
4.2.
Patient Exclusion Criteria
Patients will be excluded from participating in this study if they meet any of the following 
criteria:
a.
The patient has a previous history of brain imaging showing evidence of intracerebral 
hemorrhage, subdural or epidural hematomas, or subarachnoid hemorrhage as a 
consequence of the traumatic head injury. Brain images with structurally insignificant 
changes, as discussed and approved by the sponsor, will be reviewed by the sponsor 
on a case-by-case basis. 
b. The patient has PTH attributed to craniotomy.
c.
The patient has whiplash and subsequent headache but no history of head injury or 
concussion. 
d. The patient has an existing headache history prior to the head trauma, unless the 
patient reports a significant worsening of at least 50% in the frequency and/or 
severity of the headaches and in the opinion of the investigator, the patient fulfills 
criteria for PTH.
e.
The patient is using analgesic medications containing opioids (including codeine) or a 
barbiturate on average more than 15 days per month.
f.
The patient has participated in another study of an IMP (or a medical device) within 
the previous 30 days (or 90 days for biologics) or 5.5 half-lives, whichever is longer, 
of the IMP or is currently participating in another study of an IMP (or a medical 
device) prior to screening.


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g. The patient has had exposure to a mAb targeting the CGRP pathway (erenumab, 
eptinezumab, galcanezumab, and fremanezumab) during the 6 months prior to the day 
of the screening visit.
h. The patient is currently being treated with onabotulinumtoxinA (eg, Botox, Dysport, 
Xeomin) application in the head or neck or has received any such injection during the
3 months prior to the screening visit. 
i.
The patient has been implanted with any electronic devices for headache prevention 
during the 3 months prior to the screening visit or is currently using any implanted or 
externally applied stimulator or device.
j.
The patient has been treated with a nerve block for head and/or neck pain during the 
3 months prior to the screening visit.
k. The patient has a known hypersensitivity to any components of the IMPs stated in this 
protocol.
l.
The patient has a history or presence of other medical illness that, in the opinion of 
the investigator indicates a medical problem that would preclude study participation.
m. The patient is a pregnant or lactating woman or plans to become pregnant during the 
study.
n. The patient has clinically significant hematological, cardiac, renal, endocrine, 
pulmonary, gastrointestinal, genitourinary, neurologic, hepatic, or ocular disease or 
has any clinically significant uncontrolled medical condition (treated or untreated) at 
the discretion of the investigator.
o. The patient has any psychiatric condition or evidence of significant active or unstable 
psychiatric disease that, in the opinion of the investigator, could jeopardize or would 
compromise the patient’s ability to participate in this study.
p. The patient has major depression as assessed by the 2-item Patient Health 
Questionnaire (PHQ-2)/9-item Patient Health Questionnaire (PHQ-9) at screening. 
Any patient with a score ≥15 should be considered to have major depression and 
should be referred for appropriate treatment. Patients with lower scores (5 to 14) may 
also have major depression, and they should be carefully evaluated by the investigator 
for the presence of additional symptoms. 
q. The patient has a history of alcohol abuse or recreational drug abuse or at the 
discretion of the investigator is suspected of abusing alcohol or recreational drugs.
r.
The patient has any lifetime history of suicidal behaviors (suicide attempts, 
interrupted attempts, aborted attempts, suicidal ideation, or preparations for suicide).
s.
The patient fulfills any of the following criteria:

mentally or legally incapacitated or unable to give consent for any reason

in custody due to an administrative or a legal decision, under tutelage, or being 
admitted to a sanitarium or social institution

in current litigation for any civil or criminal offense


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
in current, ongoing or future litigation for the life of the study, relating to 
headaches, trauma or injury to the brain

unable to be contacted in case of emergency
t.
The patient has any other condition, which, in the opinion of the investigator, makes 
the patient inappropriate for inclusion in the study
4.3.
Withdrawal Criteria and Procedures for the Patient
Each patient is free to withdraw from the study or discontinue from IMP at any time, without 
prejudice to their continued care. Patients must be withdrawn from the study if any of the 
following events occur:
1. Patient withdraws consent or requests discontinuation from the study for any reason.
2. Patient develops an illness that would interfere with his/her continued participation.
3. Patient is noncompliant with the study procedures and assessments or administration of 
IMPs in the opinion of the investigator.
4. Patient takes prohibited concomitant medications as defined in this protocol.
5. A female patient has a confirmation of pregnancy during the study from a positive 
pregnancy test.
6. The sponsor requests withdrawal of the patient.
7. Patient experiences an adverse event or other medical condition, which indicates to the 
investigator that continued participation is not in the best interest of the patient.
8. Patient scores a 5 on the C-SSRS assessment.
Due to over-enrollment, meaning that the total number of patients that may be recruited for the 
study or when the site enrollment limit has been reached, the sponsor may decide to cancel 
patient participation in the study, either because they volunteered to withdraw or because they 
are one of the last patients to have been screened. Therefore, they will not be permitted to be 
randomized. The patient will be reimbursed for reasonable transportation, parking and meal 
costs, if necessary. In case of cancellation, the patient should discuss with their physician options 
for appropriate treatment.
Patients should be treated with standard of care after withdrawal from or termination of the study 
as appropriate.
Investigators should attempt to obtain information on patients in the case of withdrawal from the 
study or discontinuation from IMP. Results of any evaluations and observations, together with a 
narrative describing the reason(s) for withdrawal from the study or discontinuation from IMP, 
must be recorded in the source documents. The case report form (CRF) must document the 
primary reason for withdrawal from the study or discontinuation from the IMP.
See Appendix E for information regarding how the study will define and address lost to 
follow-up patients to help limit the amount and impact of missing data.
If the reason for withdrawal from the study or discontinuation from IMP is an adverse event 
and/or clinically significant abnormal laboratory test result, monitoring will be continued as 


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applicable (eg, until the event has resolved or stabilized, until the patient is referred to the care of 
a healthcare professional, or until a determination of a cause unrelated to the IMP or study 
procedure is made). The specific event or test result (including repeated test results, as 
applicable) must be recorded both on the source documentation and in the CRF; both the adverse 
events page and the relevant page of the CRF will be completed at that time.
If a patient is withdrawn from the study for multiple reasons that also include adverse events, the 
termination page of the CRF should indicate that the withdrawal was related to an adverse event. 
An exception to this requirement will be the occurrence of an adverse event that, in the opinion 
of the investigator, is not severe enough to warrant discontinuation but that requires the use of a 
prohibited medication, thereby requiring discontinuation of the patient. In such a case, the reason 
for discontinuation would be “need to take a prohibited medication,” not the adverse event.
Should a patient decide to withdraw after administration of the IMP or should the investigator 
decide to withdraw the patient, all efforts will be made to complete and report all observations up 
to the time of withdrawal. A complete final evaluation at the time of the patient’s withdrawal 
should be made and an explanation given as to the reason for withdrawal. If a patient withdraws 
consent, every attempt should be made to determine the reason. The reason for and date of 
withdrawal from the study must be recorded on the source documentation and transcribed to the 
CRF. 
All assessments should be performed at the early withdrawal visit according to the protocol 
(Appendix H).
A patient should only be designated as lost to follow-up if the investigational center is unable to 
establish contact with the patient after 3 documented attempts by 2 different methods (eg, phone, 
text message, email, or certified letter). In the case of patients lost to follow-up, attempts to 
contact the patient must be recorded on the source documentation.
4.4.
Replacement of Patients
A patient who is randomized/enrolled but does not complete the treatment period will not be 
replaced.
4.5.
Rescreening
Patients who historically screen-failed or have currently failed screening as a result of the 
following previous criteria will be rescreened if both conditions apply:

headache persists for >1 month after injury to the head

e-diary compliance level of at least 75% 
A patient who is screened and does not meet study inclusion and exclusion criteria will not be 
considered for screening again unless approved by the sponsor on a case-by-case basis. 
Patients enrolled after rescreening will be given a new patient identification number.
4.6.
Screening Failure
Screening failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomized/enrolled in the study. Minimal information includes, but is not 


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limited to, demography, screening failure details, eligibility criteria, and any serious adverse 
events.


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5.
TREATMENTS
5.1.
Investigational Medicinal Products Used in the Study
Investigational medicinal product is defined as the test IMP and placebo IMP. Details of the test 
and placebo IMPs are presented in Table 2.
Table 2:
Investigational Medicinal Products Used in the Study
IMP name
Fremanezumab
Placebo IMP
Company-assigned 
number
Fremanezumab (formerly TEV-48125, 
LBR-101, PF-04427429, or RN307)
Not applicable
Product configuration
Prefilled syringes
Prefilled syringes
Unit dose 
strength(s)/Dosage 
level(s)
For sc administration: 
2.25 mL prefilled syringes (1.5 mL deliverable 
volume each) at a nominal concentration of 
150 mg/mL fremanezumab
For sc administration: 2.25 mL 
prefilled syringes (1.5 mL 
deliverable volume each) with the 
same vehicle and excipients as those 
for the active injections
Route of administration
sc injection
fremanezumab will be administered by qualified 
study personnel who will retrieve the 
appropriately numbered kit containing the 
prefilled syringes.
sc injection
Placebo will be administered by 
qualified study personnel who will 
retrieve the appropriately numbered 
kit containing the prefilled syringes.
Dosing instructions
Arm A: The contents of three prefilled 
syringes, each containing fremanezumab 
(225 mg/1.5 mL) injections sc at visit 2, visit 3 
and visit 4
Arm B: The contents of three 
prefilled syringes, each containing 
1.5 mL placebo injections sc at visit 
2, visit 3 and visit 4
Packaging
Fremanezumab will be contained in uniquely 
numbered kits and stored refrigerated at 2°C to 
8°C at the investigational center.
Placebo will be contained in 
uniquely numbered kits and stored 
refrigerated at 2°C to 8°C at the 
investigational center.
Manufacturer
Teva Branded Pharmaceutical Products R&D, 
Inc.
145 Brandywine Parkway
West Chester, PA 19380
Teva Branded Pharmaceutical 
Products R&D, Inc.
145 Brandywine Parkway
West Chester, PA 19380
IMP=investigational medicinal product; sc=subcutaneous.
5.1.1.
Test Investigational Medicinal Product
Fremanezumab is a humanized IgG2a/kappa monoclonal antibody derived from a murine 
precursor. Fremanezumab for PTH is being developed for sc administration. 
Additional details may be found in Table 2 and the IB for fremanezumab.
5.1.1.1.
Starting Dose and Dose Levels
Patients randomized to fremanezumab will receive 675 mg of fremanezumab administered as 
3 sc injections (225 mg/1.5 mL each) at visit 2 (randomization), visit 3 (week 4), and visit 4 
(week 8). Patients will then enter the open-label period of the study, where they will receive 


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675 mg of fremanezumab administered as 3 sc injections (225 mg/1.5 mL each) at visit 5 
(week 12), visit 6 (week 16), and visit 7 (week 20).  
5.1.2.
Placebo Investigational Medicinal Product
The placebo will consist of the same vehicle and excipients as those for fremanezumab. See 
Table 2 for additional details. Patients randomized to placebo will receive placebo administered 
as 3 sc injections (1.5 mL each) at visit 2 (randomization), visit 3 (week 4), and visit 4 (week 8).
5.2.
Preparation, Handling, Labeling, Storage, and Accountability for 
IMPs
5.2.1.
Preparation of Investigational Medicinal Product
Fremanezumab or placebo will be provided in prefilled syringes contained in uniquely numbered 
kits and stored as described below. At the time of each study visit, the interactive response 
technology (IRT) will be queried and investigational center personnel will retrieve the 
appropriately numbered kit(s). Kit numbers will be automatically entered into the database 
through IRT. 
Preparation instructions for sc injections: IMP should be allowed to equilibrate at room 
temperature for 45 to 60 minutes before sc administration. A 1.5-mL volume from each 2.25-mL 
syringe in each visit kit must be injected sc for dosing to be considered complete. Refer to the 
pharmacy manual for additional details regarding recommended sc injection sites.
5.2.2.
Storage and Security
The investigator or designee must confirm that appropriate temperature conditions have been 
maintained for all IMPs received and that any discrepancies are reported and resolved before use 
of the IMPs.
The IMPs (fremanezumab and placebo IMP) must be stored refrigerated at 2°C to 8°C, protected 
from light. The investigational center must have a process for monitoring IMP storage 
temperature.
Diversion is considered to have occurred when the legal supply chain of prescription analgesic 
medicinal products is broken, and medicinal products are transferred from a licit to an illicit 
channel of distribution or use.
5.2.3.
Labeling
Supplies of IMPs will be labeled in accordance with the current International Council for 
Harmonisation (ICH) guidelines on Good Clinical Practice (GCP) and Good Manufacturing 
Practice and will include any locally required statements. If necessary, labels will be translated 
into the local language.
5.2.4.
Accountability
Each IMP shipment will include a packing slip listing the contents of the shipment, return 
instructions, and any applicable forms.


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The investigator is responsible for ensuring that deliveries of IMPs and other study materials 
from the sponsor are correctly received, recorded, handled, and stored safely and properly in 
accordance with the Code of Federal Regulations (CFR) or national and local regulations and 
used in accordance with this protocol.
Only patients enrolled in the study may receive IMPs, and only qualified staff at the 
investigational center may supply or administer IMPs. All IMPs must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labeled storage conditions or appropriate instructions with access limited to the investigator and 
authorized staff at the investigational center.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for IMP accountability, reconciliation, and record maintenance (ie, receipt, 
reconciliation, and final disposition records).
A record of IMP accountability (ie, IMP and other study materials received, used, retained, 
returned, or destroyed) must be prepared and signed by the principal investigator or designee, 
with an account given for any discrepancies. Prefilled syringes should never be used partially. 
Empty syringes should be destroyed at the investigational center after reconciliation is 
performed. If the investigational center does not have the capability to destroy the empty 
syringes, they should be sent back to the sponsor. Unused prefilled syringes of IMP will be 
returned to the sponsor or designee.
Additional information pertaining to the preparation, handling, labeling, storage, and 
accountability for the IMP used in this study can be found in the Pharmacy manual.
5.3.
Justification for Investigational Medicinal Products
5.3.1.
Justification for Dose of Test Investigational Medicinal Product
The fremanezumab dose and dosing regimen to be evaluated in this double-blind study was 
selected on the basis of animal pharmacodynamic and pharmacokinetic data, 
7 pharmacokinetic/safety studies in healthy volunteers, 5 safety/efficacy studies in patients with 
migraine, 2 safety/efficacy studies in patients with cluster headache and population 
pharmacokinetic and pharmacokinetic/pharmacodynamic modeling and simulations.
The dose of 675 mg sc monthly for 3 months may provide evidence of the efficacy of 
fremanezumab in patients with PTH (ie, proof-of-concept). The dose regimen used in this study 
will allow the exploration of the time of onset of action and assist in defining dose regimen(s) for 
Phase 3 studies in the PTH population. Model and simulations suggest that Cmax is the most 
significant pharmacokinetic parameter in the efficacy of fremanezumab (in migraine). The 
planned dose regimen in this Phase 2 study will provide practicality and feasible maximal 
exposure while applying sc doses.
In addition, fremanezumab 675 mg sc monthly for 3 months was also administered in a phase 2 
study with episodic migraine patients. The results of this study showed the dose to be effective, 
safe, and well tolerated by these patients. Moreover, fremanezumab was well tolerated and 
generally safe with single iv doses up to 2000 mg in healthy volunteers.


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5.3.2.
Justification for Use of Placebo Investigational Medicinal Product
A placebo-controlled design is appropriate given the purpose and objectives of this clinical 
study. Inclusion of a placebo-control group is consistent with the IHS guidelines for controlled 
trials of drugs in PTH (IHS 2013). 
5.4.
Treatment After the End of the Study
Patients will return to the investigational center approximately 24 weeks following 
administration of the first dose of IMP for safety evaluation. No treatment is planned by the 
sponsor after completion of the study. Patients should be treated with standard of care after 
withdrawal from or termination of the study, as appropriate.
5.5.
Restrictions
Patients will be required to comply with the following restrictions:
5.5.1.
Activity
Patients must remain at the investigational center for safety observation at least 60 minutes after 
administration of IMP or according to medical judgment.
5.5.2.
Blood Donation
Patients may not donate blood while taking the IMP and for 5 half-lives (7.5 months) after the 
last dose of IMP.
5.5.3.
Pregnancy
Restrictions in regard to pregnancy and required associated laboratory values (ie, serum and 
urine β-HCG tests) are provided in the inclusion and exclusion criteria (Section 4.1 and 
Section 4.2, respectively). Restrictions in regards to contraception methods are given 
in Appendix D.
5.6.
Prior and Concomitant Medication or Therapy
Any prior or concomitant medication, treatment, or procedure a patient has had within 3 months 
before screening (visit 1) and up to the EOS, including follow-up, will be recorded on the CRF. 
Trade name and international nonproprietary name (if available), indication, dose, and start and 
end dates of the administered medication must be recorded. The sponsor will encode all 
medication and treatment according to the World Health Organization (WHO) drug dictionary.
For daily-prescribed medications and preventative treatments, patients must be on a stable dose 
and regimen for at least 2 weeks prior to screening and maintained throughout the study until the 
completion of visit 8. 
The following medications will be prohibited during this study:

analgesic medications containing opioids (including codeine) if used for more than 
15 days per month

a barbiturate if used for more than 15 days per month


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
CGRP antibody or any antibody to the CGRP receptor

OnabotulinumtoxinA (eg, Botox, Dysport, Xeomin)

devices for headache prophylaxis

nerve block for head and/or neck
All patients will be questioned about concomitant medications at each study visit. Prohibited 
medications are provided in Appendix F.
5.7.
Procedures for Monitoring Patient Compliance
The investigator will be responsible for monitoring patient compliance. A check of compliance 
with IMP intake will be performed during each visit after the IMP has been administered; and 
IMP accountability records will be completed. 
If the investigator or the sponsor determines that the patient is not in compliance with the study 
protocol, the investigator and the sponsor should determine whether the patient should be 
withdrawn from the study.
Exposure to IMP will be assessed as required.
5.8.
Randomization and Blinding
This is a randomized, double-blind, placebo-controlled study. The sponsor, investigators, study 
staff (except for staff involved in bioanalytical analyses), and patients will be blinded to 
treatment assignment during the study. A computer-generated master randomization list will be 
provided to drug packaging facilities. Packaging vendor(s) will package active IMP and placebo 
IMP into single-visit kits according to Good Manufacturing Practice procedures. Kits will be 
identical in appearance and will contain prefilled syringes with test IMP or placebo IMP. 
Adequate kit supply for upcoming study visits will be managed by interactive response 
technology (IRT) and stored refrigerated (2°C to 8°C) on site.
Following the screening period, patients will be randomized if they have 8 or more headache 
days (defined as a day when a patient reports at least 4 hours of headache [not necessarily 
consecutive] and at its worst at any point has at least moderate severity; or when a patient has a 
headache and takes a prescription abortive medication with intent to alleviate the headache 
[regardless of duration or severity]) during the baseline period. Electronic diary completion must 
be at least 75% during the baseline period for randomization eligibility and at least 75% during 
the double-blind treatment period, during which the patient cannot miss more than 7 days of 
recording nor more than 4 days in a row. Randomization will be performed using electronic IRT. 
Patients will be randomly assigned with stratification based on the PTH onset (<12 months and 
≥12 months since the brain injury) in a 1:1 ratio to receive fremanezumab or placebo, as assigned 
by the IRT. The IRT will manage initial IMP supply, maintenance of adequate IMP supplies at 
the investigational centers, and study randomization centrally. 


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5.9.
Maintenance of Randomization and Blinding
5.9.1.
Maintenance of Randomization
The randomization code will be generated by the IRT third-party vendor according to 
specifications from the Biostatistics Department. A Teva statistician will be responsible for 
reviewing the dummy randomization codes, and the final randomization code will be maintained 
by the third-party vendor in a secure location.
After all patients have completed visit 5 and an unblinding request from the Teva statistician has 
been received, the third-party vendor will provide the unblinded IMP assignments according to 
the processes defined in the relevant Standard Operating Procedure.
5.9.2.
Blinding and Unblinding
Blinded pharmacokinetic data may be assessed during the study. Personnel responsible for 
sample bioanalysis (pharmacokinetics and immunogenicity) will be provided with the 
randomization code to facilitate the analysis. However, the personnel responsible for bioanalysis 
and pharmacokinetic data analysis will not have access to clinical safety and efficacy data and 
will provide concentration data to other personnel in a manner that will not identify individual 
patients (ie, a dummy patient identifier will be linked to the concentration data of an individual 
patient).
For information about personnel who may be aware of IMP assignments, see Section 5.8.These 
individuals will not be involved in the conduct of any study procedures or assessment of any 
adverse events.
In case of a serious adverse event, pregnancy, or in cases when knowledge of the IMP 
assignment is needed to make treatment decisions, the investigator may unblind the patient’s 
IMP assignment before the open-enrollment period as deemed necessary, mainly in emergency 
situations, through specialized access in the IRT system. If possible, the sponsor should be 
notified of the event before breaking of the code. If this is not possible, the sponsor should be 
notified immediately afterwards, and the patient’s randomization code should not be given. In 
emergency cases, breaking of the randomization code can be performed by the investigational 
center without prior approval by the sponsor.
When a blind is broken, the patient will be withdrawn from the study and the event will be 
recorded on the CRF. The circumstances leading to the breaking of the code should be fully 
documented in the investigator’s study files and in the patient’s source documentation. 
Assignment of IMP should not be recorded in any study documents or source document.
In blinded studies, for an adverse event defined as a suspected unexpected serious adverse 
reaction (SUSAR) (ie, reasonable possibility; see Section 7.1.4), Global Patient Safety and 
Pharmacovigilance (GPSP) may independently request that the blind code be broken (on a 
case-by-case basis) to comply with regulatory requirements. The report will be provided in an 
unblinded manner for regulatory submission. If this occurs, blinding will be maintained for the 
investigator and for other personnel involved in the conduct of the study and in the analysis and 
reporting of the data.
IMP assignments will be unblinded after all patients have completed visit 5. 


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5.9.3.
Data Monitoring Committee
There will be no Data Monitoring Committee for this study.
5.10.
Total Blood Volume
The total blood volume to be collected for each patient in this study is approximately 210 mL. 
Details are provided in Appendix G.


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6.
ASSESSMENT OF EFFICACY
Data from any efficacy assessments performed after the specified time will not be collected on 
the CRF. However, in the event that such data are collected, these data will not be analyzed.
6.1.
Electronic Diary Application
Efficacy endpoints related to PTH will be derived from data collected daily using an electronic 
diary application uploaded by the patient onto their own device. Should a patient not have a 
compatible device, the investigational center may supply a provisioned device. Eligible patients 
will receive comprehensive training at screening from the investigational center personnel on the 
use of the electronic diary application, including the requirement for timely and daily completion 
of the electronic diary.
On each day throughout the baseline and double-blind treatment periods, the patient will be 
asked to record in the electronic diary data regarding the headache. Patients will be asked a series 
of questions about the headache, for example, whether or not a headache was present (yes or no), 
the peak severity of the headache (mild, moderate, or severe), and the duration of the headache 
(did the patient have at least 4 hours [not necessarily consecutive] of headache).
If a patient fails to complete the diary for the preceding day within the allowed timeframe (up to 
48 hours), the patient will not be permitted to enter the missed day’s information into the 
electronic diary, and it will be recorded as a missed day. A check of compliance for the use of 
the device per protocol will be done during each visit. If the investigator or the sponsor 
determines that the patient is not in 75% compliance during the baseline period and 75% 
compliance during the active treatment period, the investigator and the sponsor should determine 
whether the patient should be withdrawn from the study. 
6.2.
Six-Item Headache Impact Test
HIT-6 is a tool used to measure the impact headaches have on a patient’s normal daily life and 
ability to function (Kosinski et al 2003). The HIT-6 consists of 6 items, including pain, social 
functioning, role functioning, vitality, cognitive functioning, and psychological distress. Each 
item is answered on a 5-point Likert scale (6 = never, 8 = rarely, 10 = sometimes, 11 = very 
often, or 13 = always), which are summed to produce a total score that ranges from 36 to 78, 
with larger scores reflecting greater impact of headache on the daily life of the patient. 
Patients will complete the HIT-6 questionnaire at the time points detailed in Table 1.
6.3.
Twelve-Item Short-Form Health Survey
The SF-12 (version 2) is a generic health survey containing 12 questions to measure functional 
health and well-being rated in 8 health domains, including physical function, role limitations due 
to physical problems, bodily pain, general health perceptions, vitality, social functioning, role 
limitations due to emotional problems, and mental health, with 1 or 2 questions per domain. The 
SF-12 was developed from the 36-item Short-Form Health Survey (Ware et al 1996). Scores 
range from 0 to 100, with higher scores indicating better health status. 
Patients will complete the SF-12 questionnaire at the time points detailed in Table 1.


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6.4.
Patient Global Impression of Change Scale
The PGIC scale is a validated generic tool for the assessment of overall change in the severity of 
illness following treatment. Patients will rate how they feel during assigned time points 
compared with how they felt before receiving IMP on a 7-point scale, where 1 is “no change (or 
condition has worsened),” 4 is “somewhat better, but the change has not made any real 
difference,” and 7 is “a great deal better, and a considerable improvement that has made all the 
difference.”
Patients will record responses to the PGIC scale at the time points detailed in Table 1.
6.5.
Special Protocol Headache Questionnaire
The Special Protocol Headache questionnaire was developed by Teva to assess patient headaches 
following treatment with IMP. Patients who complete the baseline period and 24-week treatment 
period will record responses to the Special Protocol Headache Questionnaire for visit 8 as the 
last procedure at the end-of-treatment visit (visit). Patients will be asked to record responses 
regarding their perception of the frequency and severity of headache during the prior 12 weeks of 
treatment with IMP, as well as the number of days of school, work, or social activities that were 
affected by headache during the treatment period. Patients will be instructed to return the 
electronic diary device on visit 5 and the electronic tablet on visit 8 to the investigational center 
after collection of the Special Protocol Headache Questionnaire.
The time points for the Special Protocol Headache questionnaire are detailed in Table 1. 


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7.
ASSESSMENT OF SAFETY
In this study, safety will be assessed by qualified study personnel by evaluating reported adverse 
events, clinical laboratory test results, vital signs measurements, ECG findings, physical 
examination findings (including body weight measurements), injection site assessments, 
PHQ-2/PHQ-9 and C-SSRS scores, and use of concomitant medication.
7.1.
Adverse Events
7.1.1.
Definition of an Adverse Event
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have to have a causal relationship with 
this treatment.
An adverse event can, therefore, be any unfavorable and unintended physical sign, symptom, or 
laboratory parameter that develops or worsens in severity during the course of this study, or 
significant worsening of the disease under study, or of any concurrent disease, whether or not 
considered related to the test IMP, fremanezumab. A new condition or the worsening of a 
pre-existing condition will be considered an adverse event. Stable chronic conditions (such as 
arthritis) that are present before study entry and do not worsen during this study will not be 
considered adverse events.
Accordingly, an adverse event can include any of the following:

intercurrent illnesses

physical injuries

events possibly related to concomitant medication

significant worsening (change in nature, severity, or frequency) of the disease under 
study or other pre-existing conditions

drug interactions

events occurring during diagnostic procedures or during any washout phase of this
study

laboratory or diagnostic test abnormalities that result in the withdrawal of the patient 
from the study, are associated with clinical signs and symptoms or a serious adverse 
event, require medical treatment or further diagnostic work-up, or are considered by 
the investigator to be clinically significant
(Note: Abnormal laboratory or diagnostic test results at the screening visit that 
preclude a patient from entering the study or receiving study treatment are not 
considered adverse events.)
Medical occurrences that begin before the first dose of IMP but after obtaining informed consent 
will be recorded on the Medical History/Current Medical Conditions section of the CRF.


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7.1.2.
Recording and Reporting of Adverse Events
For recording of adverse events, the study period is defined for each patient as the time period 
from signature of the ICF to the end of the final study period. The final period of recording of 
adverse events is defined as 24 weeks after the first dose of IMP (visit 8). The period for 
reporting treatment-emergent adverse events is defined as the period after the first dose of IMP is 
administered and until the end of the final study period (visit 8). 
All adverse events that occur during the defined study period must be recorded both on the 
source documentation and the CRF, regardless of the severity of the event or judged relationship 
to the test IMP. For serious adverse events and protocol-defined adverse events of special 
interest, the serious adverse event form must be completed and the serious adverse event or the 
adverse event of special interest must be reported immediately (Section 7.1.5.3.1). The 
investigator does not need to actively monitor patients for adverse events once the study has 
ended. Serious adverse events and adverse events of special interest occurring after the defined 
study period should be reported to the sponsor if the investigator becomes aware of them, 
following the procedures described in Section 7.1.5.3.1.
At each contact with the patient, the investigator or designee must question the patient about 
adverse events by asking an open-ended question such as “Have you had any unusual symptoms 
or medical problems since the last visit? If yes, please describe.” All reported or observed signs 
and symptoms will be recorded individually, except when considered manifestations of a 
medical condition or disease state. A precise diagnosis will be recorded whenever possible. 
When such a diagnosis is made, all related signs, symptoms, and any test findings will be 
recorded collectively as a single diagnosis on the CRF and, if it is a serious adverse event, on the 
serious adverse event form.
The clinical course of each adverse event will be monitored at suitable intervals until resolved, 
stabilized, or returned to baseline; or until the patient is referred for continued care to a 
healthcare professional; or until a determination of a cause unrelated to the test IMP or study 
procedure is made.
The onset and end dates, duration (in case of adverse event duration of less than 24 hours), action 
taken regarding IMP, treatment administered, and outcome for each adverse event must be 
recorded both on the source documentation and the CRF.
The severity, seriousness, and relationship of each adverse event to the test IMP and study 
procedures, as judged by the investigator, must be recorded as described below.
Further details are given in the Safety Monitoring Plan.
7.1.3.
Severity of an Adverse Event
The severity of each adverse event must be recorded as one of the following:
Mild:
No limitation of usual activities
Moderate: Some limitation of usual activities
Severe:
Inability to carry out usual activities
For severity grading of local tolerability (ie, injection site erythema, injection site induration, 
injection site ecchymosis, and injection site pain), please refer to Section 7.9.


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7.1.4.
Relationship of an Adverse Event to the Test Investigational Medicinal Product
The relationship of an adverse event to the test IMP is characterized as follows:
Table 3:
The Relationship of an Adverse Event to the Test IMP
Term
Definition
Clarification
No reasonable 
possibility
(not related)
This category applies to adverse 
events that, after careful 
consideration, are clearly due to 
extraneous causes (disease, 
environment, etc) or to adverse 
events that, after careful medical 
consideration at the time they are 
evaluated, are judged to be unrelated 
to the investigational medicinal 
product (IMP).
The relationship of an adverse event may be considered 
“no reasonable possibility” if it is clearly due to 
extraneous causes or if at least 2 of the following apply:

It does not follow a reasonable temporal sequence 
from the administration of the IMP.

It could readily have been produced by the patient’s 
clinical state, environmental or toxic factors, or other 
modes of therapy administered to the patient.

It does not follow a known pattern of response to the 
IMP.

It does not reappear or worsen when the IMP is 
re-administered.
Reasonable 
possibility
(related)
This category applies to adverse 
events for which, after careful 
medical consideration at the time 
they are evaluated, a connection with 
the administration of IMP cannot be 
ruled out with certainty.
The relationship of an adverse event may be considered 
“reasonable possibility” if at least 2 of the following 
apply:

It follows a reasonable temporal sequence from 
administration of the IMP.

It cannot be reasonably explained by the known 
characteristics of the patient’s clinical state, 
environmental or toxic factors, or other modes of 
therapy administered to the patient.

It disappears or decreases on cessation or reduction in 
dose. There are important exceptions when an 
adverse event does not disappear after 
discontinuation of the IMP, yet an IMP relationship 
clearly exists.

It follows a known pattern of response to the IMP.
7.1.5.
Serious Adverse Events
For recording of serious adverse events, the study period is defined for each patient as the time 
period from signature of the ICF to the end of the study period. Serious adverse events occurring 
in a patient after the end of the study period should be reported to the sponsor if the investigator 
becomes aware of them, following the procedures described in Section 7.1.5.3.1.
7.1.5.1.
Definition of a Serious Adverse Event
A serious adverse event is an adverse event occurring at any dose that results in any of the 
following outcomes or actions:

results in death

is life-threatening adverse event (ie, the patient was at risk of death at the time of the 
event); it does not refer to an event which hypothetically might have caused death if it 
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
requires inpatient hospitalization or prolongation of existing hospitalization, which 
means that hospital inpatient admission or prolongation of hospital stay were required 
for treatment of an adverse event, or that they occurred as a consequence of the event
Hospitalizations scheduled before the patient signed the ICF will not be considered 
serious adverse events, unless there was worsening of the preexisting condition 
during the patient’s participation in this study.

results in persistent or significant disability/incapacity (refers to a substantial 
disruption of one’s ability to conduct normal life functions)

is a congenital anomaly/birth defect

an important medical event that may not result in death, be life-threatening, or require 
hospitalization but may jeopardize the patient and may require medical intervention 
to prevent one of the outcomes listed in this definition
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalization, or the development of drug dependency or drug abuse. Note: Any 
suspected transmission of an infectious agent via a medicinal product is considered an 
important medical event.
All occurrences of possible drug-induced liver injury that meet Hy’s law criteria, defined as all 
of the below, must be reported by the investigator to the sponsor as a serious adverse event:

alanine aminotransferase (ALT) or aspartate aminotransferase (AST) increase of 
>3× the upper limit of normal (ULN)

total bilirubin increase of >2× ULN

absence of initial findings of cholestasis (ie, no substantial increase of alkaline 
phosphatase)

no other explanation for the observed abnormalities
An adverse event that does not meet any of the criteria for seriousness listed above will be 
regarded as a nonserious adverse event.
7.1.5.2.
Expectedness
A serious adverse event that is not included in the Adverse Reaction section of the relevant 
reference safety information (RSI) by its specificity, severity, outcome, or frequency is 
considered an unexpected adverse event. The RSI for this study is the IB.
The sponsor’s GPSP will determine the expectedness for all serious adverse events.
For the purpose of SUSAR reporting, the version of the IB at the time of occurrence of the 
SUSAR applies.


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7.1.5.3.
Reporting a Serious Adverse Event
7.1.5.3.1. Investigator Responsibility
To satisfy regulatory requirements, all serious adverse events that occur during the study, 
regardless of judged relationship to administration of the test IMP, must be reported to the 
sponsor by the investigator. The event must be reported within 24 hours of when the investigator 
learns about it. Completing the serious adverse event form and reporting the event must not be 
delayed, even if not all the information is available. The investigator does not need to actively 
monitor patients for adverse events once this study has ended.
Serious adverse events occurring to a patient after the last administration of IMP of that patient 
has ended but before the final study visit (visit 8) should be reported to the sponsor if the 
investigator becomes aware of them.
The serious adverse event form should be sent to the local safety officer (LSO) or designee (a 
contract research organization [CRO] in a country without a sponsor LSO) (contact information 
is in the Clinical Study Personnel Contact Information section); the LSO will forward the report 
to the sponsor’s GPSP.
The following information should be provided to record the event accurately and completely:

study number

investigator and investigational center identification number

patient number

onset date and detailed description of adverse event

investigator’s assessment of the relationship of the adverse event to the test IMP (no 
reasonable possibility, reasonable possibility)
Additional information includes:

age and sex of patient

date of first dose of IMP

date and amount of last administered dose of IMP

action taken

outcome, if known

severity

explanation of assessment of relatedness

relevant concomitant medication (including doses, routes of administration, and 
regimens) and treatment of the event

pertinent laboratory or other diagnostic test data

relevant medical history

results of dechallenge/rechallenge, if known


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
for an adverse event resulting in death

cause of death (whether or not the death was related to test IMP)

autopsy findings (if available)

autopsy report if autopsy was done
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 test IMP, study 
procedures, and to underlying disease.
Additional information (follow-up) about any serious adverse event unavailable at the initial 
reporting should be forwarded by the investigator within 24 hours of when it becomes known to 
the same address as the initial report.
The sponsor’s GPSP will distribute the Council for International Organizations of Medical 
Sciences form/Extensible Markup Language file to the LSO/CRO for submission to the 
competent authorities, Independent Ethics Committee (IEC)/Institutional Review Board (IRB), 
and investigators, according to regulations. The investigator must ensure that the IEC/IRB is also 
informed of the event, in accordance with national and local regulations.
For double-blind studies, blinding will be maintained for all study personnel. Therefore, in case 
of a SUSAR, only the LSO/CRO will receive the unblinded report for regulatory submission; the 
others will receive a blinded report.
Note: Although pregnancy is not a serious adverse event, the process for reporting a pregnancy is 
the same as that for reporting a serious adverse event but using the pregnancy form 
(see Section 7.2).
7.1.5.3.2. Sponsor Responsibility
If a serious unexpected adverse event is believed to be related to the test IMP or study 
procedures, the sponsor will take appropriate steps to notify all investigators participating in the 
sponsored clinical studies of fremanezumab and the appropriate competent authorities (and 
IEC/IRB, as appropriate).
In addition to notifying the investigators and competent authorities (and IEC/IRB, as 
appropriate), other action may be required, including the following:

altering existing research by modifying the protocol

discontinuing or suspending the study

modifying the existing consent form and informing all study participants of new 
findings

modifying listings of expected toxicities to include adverse events newly identified as 
related to fremanezumab
7.1.6.
Protocol-Defined Adverse Events Not for Expedited Reporting
Not applicable.


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7.1.7.
Protocol-Defined Adverse Events of Special Interest
For purposes of this protocol, the following are considered protocol-defined adverse events of 
special interest to be sent to the sponsor’s GPSP for evaluation: ophthalmic-related adverse 
events of at least moderate severity, events of possible drug-induced liver injury (AST or ALT 
≥3× ULN, total bilirubin ≥2× ULN, or international normalized ratio >1.5), Hy’s Law events, or 
events of anaphylaxis and severe hypersensitivity. Refer to Appendix I for guidance regarding 
monitoring of patients with elevated liver function tests. Anaphylaxis and severe hypersensitivity 
will be monitored using the diagnostic criteria for anaphylaxis as outlined by the 2006 Joint 
National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network 
Second Symposium on Anaphylaxis (Sampson et al 2006) (see Appendix J). In the event of 
expected anaphylaxis and severe hypersensitivity, vital signs, including oxygen saturation and 
respiration rate, will be measured. Other assessments will be performed at the discretion of the 
investigator.
The process for reporting a protocol-defined adverse event of special interest is the same as that 
for reporting a serious adverse event (Section 7.1.5.3). These adverse events of special interest to 
be reported to GPSP can be either serious or nonserious, according to the criteria outlined in 
Section 7.1.5.1.
7.1.8.
Protocol Deviations Because of an Adverse Event
If a patient experiences an adverse event or medical emergency, deviations from the protocol 
may be allowed on a case-by-case basis. To ensure patient safety, after the event has stabilized or 
treatment has been administered (or both), the investigator or other physician in attendance must 
contact the physician identified in the Clinical Study Personnel Contact Information section of 
this protocol as soon as possible to discuss the situation. The investigator, in consultation with 
the sponsor, will decide whether the patient should continue to participate in the study.
7.2.
Pregnancy
Any female patient becoming pregnant during the study will discontinue IMP. All pregnancies of 
women participating in the study and female partners of men participating in the study that occur 
during the study or within at least 40 weeks after administration of the first dose of the IMP are 
to be reported immediately to the individual identified in the Clinical Study Personnel Contact 
Information section of this protocol, and the investigator must provide the sponsor (LSO/CRO) 
with the completed pregnancy form. The process for reporting a pregnancy is the same as that for 
reporting a serious adverse event but using the pregnancy form (Section 7.1.5.3).
The investigator is not required to report patients who are found to be pregnant between 
screening and baseline, provided no protocol-related procedures were applied.
All female patients or female partners of men participating in the study who become pregnant 
will be monitored for the outcome of the pregnancy (including spontaneous, elective, or 
voluntary abortion). Female partners of men participating in the study who become pregnant will 
be asked to sign an ICF. If the pregnancy continues to term, the outcome (health of the infant up 
to 8 weeks of age), including details of birth and presence or absence of any birth defect, 
congenital abnormalities, or maternal and newborn complications, will be reported to the 
sponsor. Any complication of pregnancy during the study and any complication of pregnancy 


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that the investigator becomes aware of after withdrawal from the study will be reported as an 
adverse event or serious adverse event, as appropriate.
If the pregnancy in the woman participating in the study and/or the female partners of men 
participating in the study does not continue to term, one of the following actions will be taken:

For a spontaneous abortion, report as a serious adverse event.

For an elective abortion due to developmental anomalies, report as a serious adverse 
event.

For an elective abortion not due to developmental anomalies, report on the pregnancy 
form; do not report as an adverse event.
7.3.
Medication Error and Special Situations Related to the 
Investigational Medicinal Products
Any administration of IMP that is not in accordance with the study protocol should be reported 
on the drug administration CRF, regardless of whether or not an adverse event occurred as a 
result. 
The following are types of medication errors and special situations:
1. Medication error: Any unintentional error in the prescribing, dispensing, or 
administration of a medicinal product while in the control of the healthcare professional, 
patient, or consumer.
2. Overdose: Administration of a quantity of a medicinal product given per administration 
or cumulatively, which is above the maximum recommended dose according to the 
authorized product information. Clinical judgment should always be applied. Any dose of 
IMP (whether the test IMP, reference IMP, or placebo IMP), whether taken intentionally 
or unintentionally, in excess of that prescribed must be immediately reported to the 
sponsor. When the identification of the IMP is required, the investigator must follow the 
procedures for unblinding outlined in Section 5.9.2.
3. Misuse: Situations where the IMP is intentionally and inappropriately used not in 
accordance with the authorized product information.
4. Abuse: Persistent or sporadic, intentional excessive use of IMP, which is accompanied by 
harmful physical or psychological effects.
5. Off-label use: Situations where an IMP is intentionally used for a medical purpose not in 
accordance with the authorized product information.
6. Occupational exposure: Exposure to an IMP, as a result of one’s professional or 
non-professional occupation.
7. Breastfeeding: Suspected adverse reactions that occur in infants following exposure to a 
medicinal product from breast milk.


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7.4.
Clinical Laboratory Tests
All clinical laboratory test results outside of the reference range will be judged by the 
investigator as belonging to one of the following categories:

abnormal and not clinically significant

abnormal and clinically significant
A laboratory test result that is judged by the investigator as clinically significant will be recorded 
both on the source documentation and the CRF as an adverse event and monitored as described 
in Section 7.1.2. An event may include a laboratory or diagnostic test abnormality (once 
confirmed by repeated testing) that may result in the withdrawal of the patient from the study, 
the temporary or permanent withdrawal of IMP or medical treatment, or further diagnostic 
work-up. (Note: Abnormal laboratory or diagnostic test results at the screening visit that preclude 
a patient from entering the study or receiving IMP are not considered adverse events.)
In addition, potentially clinically significant values may be predefined by the sponsor for 
selected laboratory test variables and, if so, will be documented in the statistical analysis plan or 
other relevant documents (eg, medical monitoring plan or laboratory analysis plan).
7.4.1.
Serum Chemistry, Hematology, and Urinalysis
Clinical laboratory tests (serum chemistry, hematology and coagulation, and urinalysis) will be 
performed at the time points detailed in Table 1. Clinical laboratory tests will be performed using 
the central laboratory. Specific laboratory tests to be performed are provided in Appendix K.
7.4.2.
Other Clinical Laboratory Tests
7.4.2.1.
Human Chorionic Gonadotropin Tests
A serum β-HCG test will be performed for all WOCBP at screening (visit 1), and EOT or early 
termination (visit 8), and urine β-HCG tests will be performed for WOCBP at time points 
specified in Table 1. Any female patient who becomes pregnant during the study will be 
withdrawn. Procedures for reporting pregnancy are provided in Section 7.2.
7.4.2.2.
Follicle-Stimulating Hormone Tests
Postmenopausal women will have a follicle-stimulating hormone (FSH) test at screening 
(visit 1). 
7.4.2.3.
Saliva Collection
Saliva samples (~1 mL) will be collected using a standardized protocol available in the 
laboratory manual at time points described in Table 1. Care should be taken to freeze (at -70°C) 
the properly collected saliva samples as soon as possible (3-5 minutes) after collection from the 
patient. For additional details see Appendix N.
7.5.
Physical Examinations
Physical examinations, including height (to be obtained at the screening visit only) and weight, 
will be performed at the time points detailed in Table 1. A full physical examination will include 


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the following: general appearance, head, eyes, ears, nose, throat, chest and lungs, heart, 
abdomen, musculoskeletal, skin, lymph nodes, and neurological systems. Any physical 
examination finding that is judged by the investigator as a potentially clinically significant 
change (worsening) compared with a baseline value will be considered an adverse event, 
recorded on the CRF, and monitored as described in Section 7.1.2.
7.6.
Vital Signs
Vital signs (blood pressure [systolic/diastolic], body temperature, and pulse) will be measured 
before other assessments (eg, blood draws and administration of questionnaires) at the time 
points detailed in Table 1. All vital signs results outside of the reference ranges will be judged by 
the investigator as belonging to one of the following categories:

abnormal and not clinically significant

abnormal and clinically significant
Oxygen saturation and respiratory rate will be measured in cases of suspected anaphylaxis and 
severe hypersensitivity. 
Before blood pressure and pulse are measured, the patient must rest in a supine or 
semi-erect/seated position for at least 5 minutes. The same position and arm should be used each 
time vital signs are measured for a given patient. For any abnormal vital sign value, 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 both on the source documentation and the CRF, and 
monitored as described in Section 7.1.2.
7.7.
Electrocardiography
A 12-lead ECG will be conducted prior to other assessments (eg, blood draws and administration 
of questionnaires) at the time points detailed in Table 1. The ECGs should be performed in 
triplicate with approximately 1 to 5 minutes between recordings after the patient has been supine 
for at least 5 minutes.
A qualified physician at a central diagnostic center will be responsible for interpreting all ECGs. 
ECGs, including those for unscheduled visits, 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 investigational centers. 
Although the ECG interpretation will be performed centrally, the clinical evaluation remains the 
responsibility of the investigator. 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. 
All ECG results outside of the reference ranges will be judged by the investigator as belonging to 
one of the following categories:

abnormal and not clinically significant

abnormal and clinically significant
When potentially clinically significant findings are detected by the investigator, a cardiologist 
should be consulted for a definitive interpretation. Any abnormal findings assessed by the 


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investigator as a clinically significant change (worsening) compared with a baseline value will be 
considered an adverse event, recorded on the source documentation and in the CRF, and 
monitored as described in Section 7.1.2. 
7.8.
Immunogenicity 
Blood samples (fremanezumab-treated patients only) for serum ADA assessment will be 
collected at the time points detailed in Table 1. Blood samples for ADA assessment will also be 
collected upon observation of any severe hypersensitivity reaction (eg, anaphylaxis). 
Bioanalytical personnel should be made aware of anaphylaxis occurrence as soon as possible in 
the event that an anti-fremanezumab immunoglobulin E assay is needed. 
7.9.
Assessment of Local Tolerability and Pain
Injection site assessments will be performed immediately (+10 minutes) and 1 hour 
(±15 minutes) after administration of each dose of the IMP (Table 1). The injection sites will be 
assessed for erythema, induration, and ecchymosis.
Severity will be graded according to the following criteria: 

Injection-site erythema, induration, and ecchymosis will be graded according to 
measurements: absent, 5 to ≤50 mm (mild), >50 to ≤100 mm (moderate), and 
>100 mm (severe). Induration must be assessed by careful superficial palpation, 
avoiding pressuring or squeezing the injection site.

Spontaneous report of local pain after the injection will be measured as described in 
Table 4.
Table 4:
Severity of Pain Scale for Injection Site Assessments
Symptom
Severity grade
Assessment
Pain
0
Absent
1
Mild 
2
Moderate
3
Severe
If a patient has severe injection site erythema, induration, ecchymosis, or pain at 1 hour after 
completion of IMP administration, the patient will be reassessed at 3 hours (±15 minutes) after 
completion of IMP administration and hourly (±15 minutes) thereafter, until the reaction is of 
moderate or less severity. 
Appropriate treatment may be provided if necessary, in which case it must be recorded as 
concomitant medication. 
Injection site reactions (injection site erythema, induration, ecchymosis, and pain) should be 
recorded as adverse events as described in Section 7.1.


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7.10.
Sport Concussion Assessment Tool 3rd Edition
The SCAT-3 is a standardized tool for the evaluation of injured athletes for concussion 
(McCrory et al 2009). It includes 8 metrics to measure concussion symptoms, including GCS, 
Maddocks Score, symptom evaluation, cognitive assessment, neck examination, balance 
examination, coordination examination, and Standardized Assessment of Concussion delayed 
recall. An adapted version of the SCAT-3 tool will be used.
Patients will complete the SCAT-3 questionnaire at the time points detailed in Table 1.
7.11.
Two-Item Patient Health Questionnaire/Nine-Item Patient Health 
Questionnaire
The Patient Health Questionnaire is a 9-item questionnaire with each item corresponding to 
1 criterion of the Diagnostic and Statistical Manual for Mental Disorders 4th edition diagnostic 
criteria for major depressive disorder. Each of the items is scored on a scale of 0 (“not at all”) to 
3 (“nearly every day”) based on the frequency of symptoms (Spitzer et al 1999). The PHQ-2 was 
developed from the PHQ-9 to rapidly screen for depression. The PHQ-2 and the PHQ-9 are 
validated measures for detecting and monitoring depression, anxiety, and somatization (Kroenke 
et al 2010). 
Patients will complete the PHQ-2 at the screening visit (visit 1) and the end of treatment or early 
termination visit (visit 8). If the PHQ-2 is positive (ie, a score of ≥3), patients will complete the 
PHQ-9. 
7.12.
Assessment of Suicidality
The study population being administered fremanezumab should be monitored appropriately and 
observed closely for suicidal ideation and behavior or any other unusual changes in behavior. 
Consideration should be given to discontinuing fremanezumab in participants who experience 
signs of suicidal ideation or behavior.
Families and caregivers of participants being treated with fremanezumab should be instructed to 
monitor participants for the emergence of unusual changes in behavior, as well as the emergence 
of suicidal ideation and behavior, and to report such symptoms immediately to the study 
investigator.
The C-SSRS will be used to assess the patient’s suicidal ideation (severity and intensity) and 
behavior (Posner et al 2011). The C-SSRS Baseline/Screening version will be completed by the 
patient at visit 1, and will be completed by the patient at every subsequent visit thereafter, 
including unscheduled visits. Any positive findings on the C-SSRS Since Last Visit version will 
require evaluation by a physician or doctoral-level psychologist.
A positive finding will be defined as a score ≥4: current suicide ideation with some intent to act, 
but no specific plan. In the case of a positive finding, the investigator, based on his medical 
judgment, will determine if the patient should be seen by a mental health specialist and if the 
patient should continue participation in the study. If the patient scores a 5: current suicide 
ideation with specific plan and intent, then the patient should be discontinued from the study 
immediately and seen by a mental health specialist. 


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7.13.
Concomitant Therapy or Medication
Concomitant therapy or medication use will be monitored throughout the study. Details of 
prohibited medications are found in Section 5.6.


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8.
ASSESSMENT OF PHARMACOKINETICS, BIOMARKERS, AND 
IMMUNOGENICITY 
8.1.
Pharmacokinetic Assessment
Sampling for pharmacokinetics will be sparse. Thus, the fremanezumab pharmacokinetic 
samples will be analyzed using a population pharmacokinetic approach and will be reported 
separately to the clinical study report (CSR). 
Blood samples (approximately 4 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 the date and time of each pharmacokinetic 
sample will be recorded both on the source documentation and the CRF.
Samples from patients who receive IMP will be analyzed for concentration of fremanezumab 
using a validated method. Samples from patients who were randomized to receive placebo will 
not be analyzed (relevant only for double blind period). Details on sample handling, storage, 
shipment, and analysis are given in Appendix L.
8.2.
Pharmacodynamics Assessment
Pharmacodynamics parameters are not evaluated in this study.
8.3.
Immunogenicity Testing 
Blood samples (approximately 5 mL) will be collected via venipuncture or indwelling catheter at 
the time points detailed in Table 1. 
Samples from patients who receive active IMP will be analyzed for ADA using a validated 
method. Samples from patients who receive placebo will not be analyzed. 
Details on sample handling, storage, shipment, and analysis are provided in Appendix M.
 
 
 
 
 


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9.
STATISTICS
This section describes the statistical analysis as foreseen at the time of planning the study. 
Changes, additions, and further details about the analyses will be described in the statistical 
analysis plan. After finalization of the statistical analysis plan, any additional analyses or 
changes to analyses that may be required will be fully disclosed in the CSR.
 
 
 
 
 
 
 
 
9.2.
Analysis Sets
9.2.1.
Intent-to-Treat Analysis Set
The intent-to-treat (ITT) analysis set will include all randomized patients.
In the ITT analysis set, treatment will be assigned based on the treatment to which patients were 
randomized, regardless of which treatment they actually received.
9.2.2.
Full Analysis Set
The full analysis set (FAS) is a subset of the ITT analysis set including only patients who receive 
at least 1 dose of IMP and have at least 1 post-baseline efficacy assessment on the primary 
endpoint.
9.2.3.
Safety Analysis Set
The safety analysis set will include all randomized patients who receive at least 1 dose of IMP.
In the safety analysis set, treatment will be assigned based on the treatment patients actually 
received, regardless of the treatment to which they were randomized, unless otherwise specified.
9.2.4.
Per-Protocol Analysis Set
The per-protocol (PP) analysis set is a subset of the ITT analysis set including only patients 
without any major protocol deviations. Major protocol deviations will be determined before 
unblinding and database lock. 


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9.3.
Data Handling Conventions
Efficacy variables from patients who do not have diary entries completed for the entire study 
period will be imputed. Detailed data imputation rules will be described in the statistical analysis 
plan.
9.4.
Study Population
The study population will be composed of male and female patients aged 18 to 70 years, 
inclusive, with a history of PTH (as defined by ICHD-3 [beta version] criteria).
This population will include patients with headache attributed to mild, traumatic injury of the 
head and patients with headache attributed to whiplash. 
The ITT analysis set (Section 9.2) will be used for all study population summaries, unless 
otherwise specified. Summaries will be presented by treatment group and for all patients.
9.4.1.
Patient Disposition
Data from patients screened; patients screened but not randomized and reason for not 
randomized; patients who are randomized; patients randomized but not treated; patients in the 
ITT, safety, and other analysis sets; patients who complete the study; and patients who withdraw 
from the study will be summarized using descriptive statistics. Data from patients who withdraw 
from the study will also be summarized by reason for withdrawal using descriptive statistics.
9.4.2.
Demographic and Baseline Characteristics
Patient demographic and baseline characteristics, including medical history, prior medications 
and therapies, and ECG findings, will be summarized using descriptive statistics. For continuous 
variables, descriptive statistics (number [n], mean, SD, median, minimum, and maximum) will 
be provided. For categorical variables, patient counts and percentages will be provided. 
Categories for missing data will be presented if necessary.
Treatment groups will be compared for all continuous variables using an analysis of variance 
(ANOVA) with treatment group as a factor. The categorical variables of patient sex and race will 
be summarized using descriptive statistics for each variable category. Missing categories will be 
presented if necessary. Treatment groups will be compared for all categorical variables using a 
Pearson’s chi-square (or Fisher’s exact test if cell sizes are too small).
9.5.
Efficacy Analysis
The primary efficacy endpoint for this study will be derived from PTH data (presence of 
headache [yes/no] and peak severity [mild/moderate/severe]) collected daily using an electronic 
headache diary application.
For the purposes of this study, a PTH will be confirmed when the following situations occur:

Headache is reported to have developed within 7 days of trauma or injury (including 
whiplash [with or without neck pain]), within 7 days after regaining consciousness, or 
within 7 days of discontinuation of medication(s) that impair ability to sense or report 
headache following injury to the head.


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
Headache persists for >1 month after the injury (including whiplash [with or without 
neck pain]) to the head. 
9.5.1.
Primary Endpoint
The primary efficacy endpoint is the mean change from baseline (baseline period) in the monthly 
average number of headache days of at least moderate severity during the 12-week period after 
the first dose of the IMP. The baseline parameters for each patient will be established during the 
baseline period.
9.5.2.
Secondary Endpoints
The secondary endpoints to further demonstrate efficacy are:

proportion of patients reaching at least 50% reduction from baseline (baseline period) 
in the monthly average number of headache days of at least moderate severity during 
the 12-week period of treatment with the IMP

proportion of patients reaching at least 50% reduction from baseline (baseline period) 
in the monthly average number of headache days of at least moderate severity during 
the first 4-week period after the first dose of the IMP

proportion of patients reaching at least 50% reduction from baseline (baseline period) 
in the monthly average number of headache days of at least moderate severity during 
the 5- to 8-week period after the first dose of the IMP

proportion of patients reaching at least 50% reduction from baseline (baseline period) 
in the monthly average number of headache days of at least moderate severity during 
the 9- to 12-week period after the first dose of the IMP

mean change from baseline (baseline period) in the number of headache days of at 
least moderate severity during the first 4-week period after the first dose of the IMP

mean change from baseline (baseline period) in the number of headache days of at 
least moderate severity during the 5- to 8 week period after the first dose of the IMP

mean change from baseline (baseline period) in the number of headache days of at 
least moderate severity during the 9- to 12-week period after the first dose of the IMP

mean change from baseline (visit 2) in disability score, as measured by the 6 item 
Headache Impact Test (HIT 6) at week 12 after the first dose of the IMP

mean change from baseline (visit 2) in the assessment of patient satisfaction, as 
measured by the Patient Global Impression of Change scale, at 4, 8, and 12 weeks 
after the first dose of the IMP
9.5.3.
Immunogenicity Endpoints
The immunogenicity endpoints are ADA incidence and characteristics (eg, titer, kinetics, and 
neutralizing activities).


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9.5.5.
Planned Method of Analysis
The FAS (Sections 9.2.2) will be used for all efficacy analyses. Summaries will be presented by 
treatment group.


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9.5.5.1.
Primary Efficacy Analysis
The primary efficacy endpoint for this study will be derived from PTH data (ie, presence of 
headache [yes/no] and peak severity [mild/moderate/severe]) collected daily using an electronic 
headache diary application. 
The primary endpoint will be analyzed using an analysis of covariance (ANCOVA) method. The 
model will include treatment as fixed effect and the baseline number of headache days of at least 
moderate severity and the PTH onset (<12 months and ≥12 months) as covariate. A 95% 
confidence interval will be constructed for the least squares mean difference between the 
fremanezumab group and the placebo group, and the p-value will be presented.
The primary estimand for this study is defined by the following attributes:

The target population includes male and female patients aged 18 to 70 years, 
inclusive, with a history of PTH (as defined by the ICHD-3 [beta version] criteria).

The primary outcome measure is the mean change from baseline (baseline period) in 
the monthly average number of headache days of at least moderate severity during the 
12-week period after the first dose of IMP.

The FAS will be used for efficacy analyses. FAS is a subset of the ITT analysis set 
and includes only patients who receive at least 1 dose of IMP and have at least 
1 postbaseline efficacy assessment on the primary endpoint. In the FAS, treatment 
will be assigned based on the treatment to which patients were randomized, 
regardless of which treatment they actually received.

Treatment effect will be measured via ANCOVA method, including treatment as 
fixed effect and the baseline number of headache days of at least moderate severity 
and the PTH onset (<12 months and ≥12 months) as covariates.
For patients assigned to active treatment who discontinue the study due to lack of efficacy, death, 
or adverse event, the proportion of headache days in the remainder of the analysis window will 
be imputed as the mean monthly average of headache days in the same analysis window for 
patients assigned to placebo. All other missing data for patients in either treatment group will be 
handled as follows:

For patients who have ≥10 days of e-diary data in an analysis window, the monthly 
average number of headache days will be calculated based on data available in that 
analysis window and prorated to 28 days.

For patients who have <10 days of e-diary data in an analysis window, the monthly 
average number of headache days will be imputed as the mean monthly average of 
headache days in the same analysis window for patients assigned to the same 
treatment group and having ≥10 days of e-diary data. Sensitivity analyses will be 
conducted as defined in the statistical analysis plan.
9.5.5.2.
Sensitivity Analysis
Sensitivity analysis will be conducted to explore the impact of missing data in the primary 
efficacy analysis. In particular, endpoints analyzed using an ANCOVA method will be analyzed 


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using a mixed model for repeated measures method. The details will be described in the 
statistical analysis plan.
9.5.5.3.
Secondary Efficacy Analysis
The continuous secondary efficacy endpoints will be analyzed using an ANOVA method or a 
mixed-model for repeated measures. For the proportion of responders defined as 50% or more 
reduction from baseline in the monthly average headache days, the Cochran-Mantel-Haenszel 
test will be used stratified by PTH onset (<12 months and ≥12 months). For the key secondary 
endpoints, a 95% confidence interval will be constructed to compare the treatment effect
between the fremanezumab group and the placebo group, and the p-value will be presented.
 
 
9.6.
Multiple Comparisons and Multiplicity
Testing of statistical significance at a 2-sided alpha of 0.05 will be performed for the primary 
endpoint. If the primary endpoint meets statistical significance, then each of the key secondary 
endpoints will be tested for significance in a pre-specified order at a 2-sided alpha of 0.05. If and 
when any p>0.05, no further comparisons will be interpreted inferentially. Details will be 
presented in the statistical analysis plan.
9.7.
Safety Analysis
Safety analyses will be performed on the safety analysis set (Section 9.2.3).
Safety assessments and time points are provided in Table 1.
All adverse events will be coded using the Medical Dictionary for Regulatory Activities. Each 
patient will be counted only once in each preferred term or system organ class category for the 
analyses of safety. Summaries will be presented for all adverse events (overall and by severity), 
adverse events determined by the investigator to be related to test IMP (ie, reasonable possibility; 
see Section 7.1.4) (defined as related or with missing relationship) (overall and by severity), 
serious adverse events, and adverse events causing withdrawal from the study. Summaries will 
be presented by treatment group and for all patients. Patient listings of serious adverse events and 
adverse events leading to withdrawal will be presented.
Changes in laboratory, ECG, and vital signs measurements data will be summarized 
descriptively. All values will be compared with predefined criteria to identify potentially 
clinically significant values or changes, and such values will be listed.
The use of concomitant medications will be summarized by therapeutic class using descriptive 
statistics. Concomitant medications will include all medications taken while the patient is treated 
with test IMP.
Safety data will be summarized descriptively overall and by treatment group. For continuous 
variables, descriptive statistics (n, mean, SD, median, minimum, and maximum) will be provided 
for actual values and changes from baseline to each time point. For categorical variables, patient 


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counts and percentages will be provided. Descriptive summaries of serious adverse events, 
patient withdrawals due to adverse events, and potentially clinically significant abnormal values 
(clinical laboratory or vital signs) based on predefined criteria will be provided as well.
If any patient dies during the study, a listing of deaths will be provided and all relevant 
information will be discussed in the patient narrative included in the CSR.
9.8.
Tolerability Analysis
Injection site reaction assessments will be listed and summarized descriptively. 
9.9.
Pharmacokinetic Analysis
Pharmacokinetic plasma concentration results for fremanezumab will be tabulated descriptively 
at each planned sampling time point. At the open-label period, pharmacokinetic plasma 
concentration results will be tabulated descriptively at each planned sampling time point 
treatment group.
In addition, the most appropriate population pharmacokinetic model may be developed, and 
covariates that may affect it will be tested for inclusion in the model. If performed, this analysis 
will be reported separately.
9.10.
Pharmacokinetic/Pharmacodynamic Analysis
The pharmacokinetic/pharmacodynamics relationship may be estimated by compartmental 
techniques. The pharmacokinetic parameters will be based on fremanezumab measurements. The 
pharmacodynamic endpoints will be the efficacy/safety response(s). 
The pharmacokinetic/pharmacodynamic relationship may be estimated using the most 
appropriate model after comparing different candidate models for their quality of fit. Covariates 
that may affect the pharmacokinetic/pharmacodynamic relationship will be tested for inclusion in 
the model. If performed, this analysis will be reported separately.
 
 
.
9.12.
Pharmacogenomic Analysis
Pharmacogenomic analysis will be conducted to correlate clinical observations 
(pharmacokinetic, safety, efficacy, or other effects) with genotypes observed in the study. 
Pharmacogenomic analysis may be conducted at a later time and will be reported in a separate 
addendum report.
9.13.
Immunogenicity Analysis
A summary of immunogenicity results will be provided, and the incidence of immunogenicity 
will be calculated. The impact of immunogenicity on the pharmacokinetic profile, fremanezumab 
efficacy, and clinical safety will be evaluated. This analysis will be reported separately. 


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9.14.
Planned Interim Analysis
There will be no formal interim analysis. However, a database lock from the double-blind period 
will occur following the completion of visit 5 by the last patient. Unblinding will occur after the 
database lock from the double-blind period.
9.15.
Reporting Deviations from the Statistical Plan
Deviations from the statistical plan, along with the reasons for the deviations, will be described 
in protocol amendments, the statistical analysis plan, the CSR, or any combination of these, as 
appropriate, and in accordance with applicable national, local, and regional requirements and 
regulations.


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10.
QUALITY CONTROL AND QUALITY ASSURANCE
Refer to Appendix B for information regarding quality control and quality assurance. This 
includes information about protocol amendments, deviations, responsibilities of the investigator 
to study personnel, study monitoring, and audit and inspection.
Refer to Appendix O for the definition of a clinical product complaint and investigator 
responsibilities in the management of a clinical product complaint.


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11.
COMPLIANCE STATEMENT
This study will be conducted in full accordance with the ICH Harmonised Tripartite Guideline 
for GCP E6 and any applicable national and local laws and regulations (eg, Title 21 Code of 
Federal Regulations [21CFR] Parts 11, 50, 54, 56, 312, and 314, Directive 2001/20/EC of the 
European Parliament and of the Council on the approximation of the laws, regulations, and 
administrative provisions of the Member States relating to the implementation of good clinical 
practice in the conduct of clinical trials on medicinal products for human use). Any episode of 
noncompliance will be documented.
The investigator is responsible for performing the clinical study in accordance with this protocol 
and the applicable GCP guidelines referenced above for collecting, recording, and reporting the 
data accurately and properly. Agreement of the investigator to conduct and administer this 
clinical study in accordance with the protocol will be documented in separate clinical study 
agreements with the sponsor and other forms, as required by national competent authorities in 
the country where each investigational center is located.
The investigator is responsible for ensuring the privacy, health, and welfare of the patients during 
and after the clinical study and must ensure that trained personnel are immediately available in 
the event of a medical emergency. The investigator and the involved clinical study personnel 
must be familiar with the background and requirements of the study and with the properties of 
the IMPs as described in the IB or prescribing information.
The principal investigator at each investigational center has the overall responsibility for the 
conduct and administration of the clinical study at that investigational center and for contacts 
with study management, with the IEC/IRB, and with competent authorities.
See Appendix C for the ethics expectations of informed consent or assent, competent authorities 
and IEC and IRB, confidentiality regarding study patients, and requirements for registration of 
the clinical study.


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12.
DATA MANAGEMENT AND RECORD KEEPING
See Appendix P for information regarding data management and record keeping. This includes 
direct access to source data and documents, data collection, data quality control, and archiving of 
CRFs and source documents.


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13.
FINANCING AND INSURANCE
A separate clinical study agreement, including a study budget, will be signed between each 
principal investigator and the sponsor (or the CRO designated by the sponsor) before the IMP is 
delivered.
The patients in this clinical study are insured in accordance with applicable legal provisions. The 
policy coverage is subject to the full policy terms, conditions, extensions, and exclusions. 
Excluded from the insurance coverage are, inter alia, damages to health and worsening of 
previous existing disease that would have occurred or continued if the patient had not taken part 
in the clinical study.
The policy of Clinical Trials Insurance will be provided to the investigational centers by the 
sponsor.
For covered clinical studies (see 21CFR54), the investigator will provide the sponsor with 
financial information required to complete Food and Drug Administration 3454 form. Each 
investigator will notify the sponsor of any relevant changes during the conduct of the study and 
for 1 year after the study has been completed.


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14.
PUBLICATION POLICY
See Appendix Q for information regarding the publication policy.


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15.
REFERENCES
Anttila V, Winsvold BS, Gormley P, Kurth T, Bettella F, McMahon G, et al. Genome-wide 
meta-analysis identifies new susceptibility loci for migraine. Nat Genet 2013;45(8):912-7.
Bigal ME, Dodick DW, Rapoport AM, Silberstein SD, Ma Y, Yang R, et al. Safety, tolerability, 
and efficacy of TEV-48125 for preventive treatment of high-frequency episodic migraine: a 
multicentre, randomised, double-blind, placebo-controlled, phase 2b study. Lancet Neurol 
2015a;14:1081-90.
Bigal ME, Edvinsson L, Rapoport AM, Lipton RB, Spierings ELH, Diener H, et al. Safety, 
tolerability, and efficacy of TEV-48125 for preventive treatment of chronic migraine: a 
multicentre, randomised, double-blind, placebo-controlled, phase 2b study. Lancet Neurol 
2015b;14:1091-100.
D’Onofrio F, Russo A, Conte F, Casucci G, Tessitore A, Tedeschi, G. Posttraumatic headaches: 
an epidemiological overview. Neurol Sci 2014; 35:S203-6.
Finkel A, Yerry J, Klaric J, Ivins B, Scher A, Choi Y. Headache in military service members 
with a history of mild traumatic brain injury: a cohort study of diagnosis and classification. 
Cephalalgia 2017;37(6):548-59.
Food and Drug Administration (FDA). Guidance for Industry: Drug Interaction Studies – Study 
Design, Data Analysis, Implications for Dosing, and Labeling Recommendations. 2012. 
Available at: 
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm 
292362.pdf.
Headache Classification Committee of the International Headache Society (IHS). The 
International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia 
2013;33(9):629-808.
Kosinski M, Bayliss MS, Bjorner JB, Ware JE Jr, Garber WH, Batenhorst A, et al. A six-item 
short-form survey for measuring headache impact: the HIT-6. Qual Life Res 2003;12:963–74.
Kroenke K, Spitzer RL, Williams JB, Löwe B. The Patient Health Questionnaire somatic, 
anxiety, and depressive symptom scales: a systematic review. Gen Hosp Psychiatry 
2010;32(4):345-59.
Lipton RB, Micieli G, Russell D, Solomon S, Tfelt-Hansen P, Waldenlind E. Guidelines for 
controlled trials of drugs in cluster headache. Cephalalgia 1995;15(6):452-62.
Lucas S. Posttraumatic headache: clinical characterization and management. Curr Pain Headache 
Rep 2015;19(10):48.
McCrory P, Meeuwisse W, Johnston K, Dvorak J, Aubry M, Molloy M, et al. Consensus 
Statement on Concussion in Sport: the 3rd International Conference on Concussion in Sport held 
in Zurich, November 2008. Br J Sports Med 2009;43(Suppl 1):i76–i84.
Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, et al. The 
Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings from 
three multisite studies with adolescents and adults. Am J Psychiatry 2011;168(12):1266-77.


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Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF, Jr, Bock SA, Branum A, et al. 
Second symposium on the definition and management of anaphylaxis: summary report-Second 
National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network 
Symposium. J Allergy Clin Immunol 2006;117(2):391-7.
Spitzer RL, Kroenke K, Williams JB. Validation and utility of self-report version of 
PRIME-MD: the PHQ primary care study. Primary care evaluation of metal disorders. Patient 
health questionnaire. JAMA 1999;282(18):1737-44.
Ware J Jr, Kosinski M, Keller SD. A 12-Item Short-Form Health Survey: construction of scales 
and preliminary tests of reliability and validity. Med Care 1996;34(3):220-33.


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16.
SUMMARY OF CHANGES TO PROTOCOL
16.1.
Amendment 02 Dated 30 March 2020
The primary reason for this amendment is to revise the planned number of patients as study 
recruitment was discontinued at 87 patients due to challenges to enrollment. Additionally, 
revisions have been made to the justification of the primary endpoint, including the primary 
analysis method, revise the secondary endpoints, 
. 
This amendment is considered to be substantial (ie, requires approval by CA, 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.
Table 1 (Study Procedures and Assessments) has been revised to reflect changes described 
below.


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Original text with changes shown
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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 02 Approval Date: 
30 March 2020
Protocol with Amendment 02 Approval Date: 
30 March 2020
To update for Amendment 02
Teva Branded Pharmaceutical Products R&D, Inc. 
41 Moores Road 145 Brandywine Parkway
FrazerWest Chester, Pennsylvania 1935519380
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
Section 1.1 Introduction
Most often tThey can resemble a range of primary 
headache conditions such as those of migraine (ie, 
moderate to severe intensity, pulsating, associated 
nausea or vomiting, light or sound sensitivity, and 
worsened with activity) or tension-type headache 
(ie, mild to moderate intensity, non-pulsating, light 
or sound sensitivity, but no nausea or vomiting), or 
one of a number of more uncommon headache 
syndromes (Finkel et al 2017). 
ConsequentlyRather, the diagnosis of PTH is 
largely dependent on the close temporal 
relationship between the trauma or injury and 
headache onset. PTH requires that the headache 
must be reported to have developed within 7 days 
of trauma or injury, or within 7 days of having 
regained consciousness, and/or ability to report pain 
when these have been lost following trauma or 
injury. During the first 3 months from onset, these 
headaches are considered acute. A PTH that 
continues beyond the first 3 months from onset is 
designated as a persistent posttraumatic headache 
(PPTH) (IHS 2013).
They can resemble a range of primary headache 
conditions such as migraine (ie, moderate to severe 
intensity, pulsating, associated nausea or vomiting, 
light or sound sensitivity, and worsened with 
activity) or tension-type headache (ie, mild to 
moderate intensity, non-pulsating, light or sound 
sensitivity, but no nausea or vomiting), or one of a 
number of more uncommon headache syndromes 
(Finkel et al 2017). Rather, the diagnosis of PTH is 
largely dependent on the close temporal 
relationship between the trauma or injury and 
headache onset. PTH requires that the headache 
must be reported to have developed within 7 days 
of trauma or injury, or within 7 days of having 
regained consciousness, and/or ability to report pain 
when these have been lost following trauma or 
injury (IHS 2013).


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Reason/Justification for change
The pathogenesis of PTH is often unclear most 
commonly in the absence of overt brain injury.
The pathogenesis of PTH is most commonly in the 
absence of overt brain injury.
It is recommended that treatment for secondary 
headache types, such as PTH, be consistent with the 
treatment of the primary headache type it most 
resembles, in this case, migraine (Lucas 2015).
It is recommended that treatment for secondary 
headache types, such as PTH, be consistent with the 
treatment of the primary headache type it most 
resembles (Lucas 2015).
These results suggest that fremanezumab may be 
successful for the prevention of PTH.
-
Section 2.1 Primary and Secondary Study Objectives and Endpoints (Other sections affected by this change: Section 9.5.2)
See new changes column.
The secondary efficacy endpoints are:

proportion of patients reaching at least 50% 
reduction from baseline (baseline period) in the 
monthly average number of headache days of 
at least moderate severity during the 12-week 
period of treatment with the IMP

proportion of patients reaching at least 50% 
reduction from baseline (baseline period) in the 
monthly average number of headache days of 
at least moderate severity during the first 4-
week period after the first dose of the IMP

proportion of patients reaching at least 50% 
reduction from baseline (baseline period) in the 
monthly average number of headache days of 
at least moderate severity during the 5- to 8-
week period after the first dose of the IMP

proportion of patients reaching at least 50% 
reduction from baseline (baseline period) in the 
monthly average number of headache days of 
at least moderate severity during the 9- to 12-
week period after the first dose of the IMP

mean change from baseline (baseline period) in 
the number of headache days of at least 
moderate severity during the first 4-week 
Criteria changed from monthly average number of 
headache days of any severity to headache days of 
at least moderate severity for the first secondary 
endpoint.
,
 
 
 


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period after the first dose of the IMP

mean change from baseline (baseline period) in 
the number of headache days of at least 
moderate severity during the 5- to 8 week 
period after the first dose of the IMP

mean change from baseline (baseline period) in 
the number of headache days of at least 
moderate severity during the 9- to 12-week 
period after the first dose of the IMP

mean change from baseline (visit 2) in 
disability score, as measured by the 6 item 
Headache Impact Test (HIT 6) at week 12 after 
the first dose of the IMP

mean change from baseline (visit 2) in the 
assessment of patient satisfaction, as measured 
by the Patient Global Impression of Change 
scale, at 4, 8, and 12 weeks after the first dose 
of the IMP
Section 2.1.1 Justification of Primary Endpoint
For this study of patients with PTH, the primary 
efficacy endpoint is the mean change from baseline 
(baseline period) in the monthly average number of 
headache days of at least moderate severity during 
the 12-week period after the first dose of the IMP. 
A headache day is defined as a day when a patient 
reports at least 4 hours of a headache (not 
necessarily consecutive) and at its worst at any 
point has of at least moderate severity; or when a 
patient has a headache and takes a prescription 
abortive medication with intent to alleviate the 
headache (regardless of duration or severity).. This 
measure allows the use of a relatively simple 
headache diary. The patient will indicate the 
presence of headache (yes/no), its peak severity 
(mild/moderate/severe), its duration (<4 hours/4 
hours), and whether or not prescription medication 
For this study of patients with PTH, the primary 
efficacy endpoint is the mean change from baseline 
(baseline period) in the monthly average number of 
headache days of at least moderate severity during 
the 12-week period after the first dose of the IMP. 
A headache day is defined as a day when a patient 
reports a headache of at least moderate severity. 
This measure allows the use of a relatively simple 
headache diary.
The definition of a headache day was revised for 
the primary endpoint analysis to better align with 
measures used in patients with PTH. 


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was taken to alleviate the headache daily during the 
baseline period to establish the baseline parameters 
and daily through the 12-week treatment period.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Reason/Justification for change
the number of headache days of at least 
moderate severity in patients with at least 4 
hours of a headache (not necessarily 
consecutive) or who took a prescription 
abortive medication with intent to alleviate the 
headache (regardless of duration or severity) 
during the first 4-week period after the first 
dose of the IMP

mean change from baseline (baseline period) in 
the number of headache days of at least 
moderate severity in patients with at least 4 
hours of a headache (not necessarily 
consecutive) or who took a prescription
abortive medication with intent to alleviate the 
headache (regardless of duration or severity) 
during the 5- to 8 week period after the first 
dose of the IMP

mean change from baseline (baseline period) in 
the number of headache days of at least 
moderate severity in patients with at least 4 
hours of a headache (not necessarily 
consecutive) or who took a prescription 
abortive medication with intent to alleviate the 
headache (regardless of duration or severity) 
during the 9- to 12-week period after the first 
dose of the IMP

proportion of patients reaching at least 50% 
reduction from baseline (baseline period) in the 
monthly average number of headache days of 
at least moderate severity in patients with at 
least 4 hours of a headache (not necessarily 
consecutive) or who took a prescription 
abortive medication with intent to alleviate the 
headache (regardless of duration or severity) 
during the 12 week period after the first dose of 
the IMP


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Reason/Justification for change
Section 3.2 Planned Number of Patients and Countries
The total number of patients planned iswas 172 (86 
patients per treatment group). Study recruitment 
was discontinued at 87 patients due to challenges to 
enrollment and not for any safety concerns.
The total number of patients planned was 172 (86 
patients per treatment group). Study recruitment 
was discontinued at 87 patients due to challenges to 
enrollment and not for any safety concerns.
Clarification to the sample size as study enrollment 
was discontinued due to challenges to recruitment 
prior to reaching the target sample size.
The study is planned to be conducted in the United 
States in approximately 32 25 study centers. The 
study is expected to be executed between the period 
of Q4 2017 and Q2 2020.
The study is planned to be conducted in the United 
States in approximately 32 study centers. The study 
is expected to be executed between the period of 
Q4 2017 and Q2 2020.
Text was updated to reflect change in study centers 
that was made throughout protocol in protocol 
amendment 01, but omitted in Section 3.2, as 
detailed in Letter of Clarification 06.
Section 3.5 Schedule of Study Procedures and Assessments
See new wording column
Table 1 has been modified as described below:
Footnote “a” added on visit 1 column heading
Correction. Footnote “a” was inadvertently omitted 
from the column heading
m Patients will enter headache days of any severity 
(mild, moderate, or severe), their duration, and 
prescription medication use into the electronic diary 
application daily throughout the pretreatment 
period and double-blind treatment periods. Eligible 
patients will upload the application to their own 
device or use the provisioned device and will be 
trained in its use and compliance requirements on 
the day of screening (visit 1). Patients will be asked 
to return the provisioned device electronic diary 
device on visit 5 and the electronic tablet on visit 8
to the investigational center at the EOT or early 
termination visit (visit 5).
m Patients will enter headache days of any severity 
(mild, moderate, or severe), their duration, and 
prescription medication use into the electronic diary 
application daily throughout the pretreatment 
period and double-blind treatment periods. Eligible 
patients will upload the application to their own 
device or use the provisioned device and will be 
trained in its use and compliance requirements on 
the day of screening (visit 1). Patients will be asked 
to return the provisioned electronic diary device on 
visit 5 and the electronic tablet on visit 8 to the 
investigational center.
Clarification, as detailed in Letter of Clarification 
06.
o Blood samples for serum ADA assessment (5 mL) 
will be collected prior to dosing at each applicable 
visit and will also be collected upon observation of 
any anaphylaxis or severe hypersensitivity reaction.
o Blood samples for serum ADA assessment (5 mL) 
will be collected prior to dosing at each applicable 
visit and will also be collected upon observation of 
any anaphylaxis or severe hypersensitivity reaction.
Clarification, as detailed in Letter of Clarification 
07.


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v Patients will complete the Special Protocol 
Headache questionnaire for visits 5 and 8 following 
all other procedures at visits 5 and 8. Patients will 
be instructed to return the provisioned devices
electronic diary device on visit 5 and the electronic 
tablet on visit 8 to the investigational center after 
collection of the Special Protocol Headache 
Questionnaire (visit 8).
v Patients will complete the Special Protocol 
Headache questionnaire for visits 5 and 8 following 
all other procedures at visits 5 and 8. Patients will 
be instructed to return the electronic diary device 
on visit 5 and the electronic tablet on visit 8 to the 
investigational center after collection of the Special 
Protocol Headache Questionnaire.
Clarification, as detailed in Letter of Clarification 
06.
Section 4.2 Patient Exclusion Criteria
h. The patient is not currently being treated with 
onabotulinmumtoxinA (eg, Botox, Dysport, 
Xeomin) application in the head or neck or has 
received any such injection during the 3 months 
prior to the screening visit.
h. The patient is currently being treated with 
onabotulinumtoxinA (eg, Botox, Dysport, Xeomin) 
application in the head or neck or has received any 
such injection during the 3 months prior to the 
screening visit.
Correction of a typo as patients will be excluded 
from the study if they are currently being treated 
with onabotulinumtoxinA.
Section 4.3 Withdrawal Criteria and Procedures for the Patient
See Appendix FAppendix E for information 
regarding how the study will define and address 
lost to follow up patients to help limit the amount 
and impact of missing data.
See Appendix E for information regarding how the 
study will define and address lost to follow up 
patients to help limit the amount and impact of 
missing data.
Correction to appendix hyperlinking, as described 
in Letter of Clarification 09.
All assessments should be performed at the early 
withdrawal visit according to the protocol 
(Appendix B Appendix H).
All assessments should be performed at the early 
withdrawal visit according to the protocol 
(Appendix H).
Correction to appendix hyperlinking.
Section 5.5.3 Pregnancy
Restrictions in regards to contraception methods are 
given in Appendix E Appendix D.
Restrictions in regards to contraception methods are 
given in Appendix D.
Correction to appendix hyperlinking.
Section 5.10 Total Blood Volume (Other sections affected by this change: Appendix G)
The total blood volume to be collected for each 
patient in this study is approximately 140.5210 mL. 
Details are provided in Appendix G.
The total blood volume to be collected for each 
patient in this study is approximately 210 mL. 
Details are provided in Appendix G.
Correction to the total blood volume, as detailed in 
Letter of Clarification 07.
Section 6.5 Special Protocol Headache Questionnaire


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Reason/Justification for change
Patients will be instructed to return the provisioned 
deviceselectronic diary device on visit 5 and the 
electronic tablet on visit 8 to the investigational 
center after collection of the Special Protocol
Headache Questionnaire (visit 8).
Patients will be instructed to return the electronic 
diary device on visit 5 and the electronic tablet on 
visit 8 to the investigational center after collection 
of the Special Protocol Headache Questionnaire.
Text updated to reflect collection of the electronic 
diary device and the electronic tablet will be at visit 
5 and visit 8, respectively, as detailed in Letter of 
Clarification 06.
Section 7.1.7 Protocol-Defined Adverse Events of Special Interest
Refer to Appendix H Appendix I for guidance 
regarding monitoring of patients with elevated liver 
function tests.
Refer to Appendix I for guidance regarding 
monitoring of patients with elevated liver function 
tests.
Correction to appendix hyperlinking.
Section 9.1 Sample Size and Power Considerations
A sample size of 154 patients (77 evaluable patients 
per treatment group) willwas calculated to provide 
80% power to detect a treatment difference of 2.0 
days in the monthly average (assuming a common 
SD of 4.4 days) at a 2-sided alpha level of 0.05. 
Assuming a 10% discontinuation rate, 172 patients 
(86 patients per treatment group) willwere planned 
to be randomized in the study.
Study recruitment was discontinued at 87 patients 
due to challenges to enrollment and not for any 
safety concerns.
A sample size of 154 patients (77 evaluable patients 
per treatment group) was calculated to provide 80% 
power to detect a treatment difference of 2.0 days in 
the monthly average (assuming a common SD of 
4.4 days) at a 2-sided alpha level of 0.05. Assuming 
a 10% discontinuation rate, 172 patients (86 
patients per treatment group) were planned to be 
randomized in the study.
Study recruitment was discontinued at 87 patients 
due to challenges to enrollment and not for any 
safety concerns.
Clarification to the sample size as study enrollment 
was discontinued due to challenges to recruitment 
prior to reaching the target sample size.
Section 9.2.4 Per-Protocol Analysis Set
The per-protocol (PP) analysis set is a subset of the 
ITT analysis set including only patients without any 
major protocol deviations or unexpected drug 
concentration findings. Major protocol deviations 
will be determined before unblinding and database 
lock. 
In the PP analysis set, treatment will be assigned 
based on the treatment patients actually received, 
regardless of the treatment to which they were 
randomized.
The per-protocol (PP) analysis set is a subset of the 
ITT analysis set including only patients without any 
major protocol deviations. Major protocol 
deviations will be determined before unblinding 
and database lock.
The definition of the per-protocol analysis set was 
modified as this is a subset of patients who 
completed the study as intended, only with a lack of 
major protocol deviations.
Section 9.5 Efficacy Analysis


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The primary efficacy endpoint for this study will be 
derived from PTH data (presence of headache 
[yes/no], and peak severity [mild/moderate/severe], 
and duration [<4 hours/4 hours]) collected daily 
using an electronic headache diary application.
The primary efficacy endpoint for this study will be 
derived from PTH data (presence of headache 
[yes/no] and peak severity [mild/moderate/severe]) 
collected daily using an electronic headache diary 
application.
Update to the primary efficacy analysis to coincide 
with the updated definition of a headache day in 
Section 2.1.1.
Section 9.5.5.1 Primary Efficacy Analysis
The primary efficacy endpoint for this study will be 
derived from PTH data (ie, presence of headache 
[yes/no], and peak severity [mild/moderate/severe], 
duration [<4 hours/4 hours], and prescription 
medication use [yes/no]) collected daily using an 
electronic headache diary application.
The primary efficacy endpoint for this study will be 
derived from PTH data (ie, presence of headache 
[yes/no] and peak severity [mild/moderate/severe]) 
collected daily using an electronic headache diary 
application.
Update to the primary efficacy analysis to coincide 
with the updated definition of a headache day in 
Section 2.1.1.
Section 10 Quality Control and Quality Assurance
Refer to Appendix CAppendix B for information 
regarding quality control and quality assurance. 
This includes information about protocol 
amendments, deviations, responsibilities of the 
investigator to study personnel, study monitoring, 
and audit and inspection.
Refer to Appendix B for information regarding 
quality control and quality assurance. This includes 
information about protocol amendments, 
deviations, responsibilities of the investigator to 
study personnel, study monitoring, and audit and 
inspection.
Correction to appendix hyperlinking, as described 
in Letter of Clarification 09.
Section 11 Compliance Statement
See Appendix DAppendix C for the ethics 
expectations of informed consent or assent, 
competent authorities and IEC and IRB, 
confidentiality regarding study patients, and 
requirements for registration of the clinical study.
See Appendix C for the ethics expectations of 
informed consent or assent, competent authorities 
and IEC and IRB, confidentiality regarding study 
patients, and requirements for registration of the 
clinical study.
Correction to appendix hyperlinking, as described 
in Letter of Clarification 09.
Section 15 References
See new changes column.
Finkel A, Yerry J, Klaric J, Ivins B, Scher A, Choi 
Y. Headache in military service members with a 
history of mild traumatic brain injury: a cohort 
study of diagnosis and classification. Cephalalgia
2017;37(6):548-59..
New reference cited in the introduction.
Section 16.2 Letter of Clarification 09 Dated 30 October 2019


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Reason/Justification for change
This letter rectified the incorrect links (field codes) 
to some of the appendices and to update the 
sponsor’s medical expert/contact in Appendix A.
This letter rectified the incorrect links (field codes) 
to some of the appendices and to update the 
sponsor’s medical expert/contact in Appendix A.
This section was added to reflect the changes 
described in Letter of Clarification 09.
Section 16.3 Letter of Clarification 08 Dated 24 September 2019
This letter clarified that the use of temperature 
loggers for the transport of pharmacokinetic 
samples was not needed in Appendix L 
(Pharmacokinetics Samples) as premium, next day 
couriers will be used and, thus, a temperature log 
will not be needed and the wording was removed.
This letter clarified that the use of temperature 
loggers for the transport of pharmacokinetic 
samples was not needed in Appendix L 
(Pharmacokinetics Samples) as premium, next day 
couriers will be used and, thus, a temperature log 
will not be needed and the wording was removed.
This section was added to reflect the changes 
described in Letter of Clarification 08.
16.4 Letter of Clarification 07 Dated 01 August 2019
This letter clarified the total number of samples and 
the total volume of blood in Appendix G of the 
protocol. In Amendment 01, the number of samples 
(and the total volume) for clinical laboratory tests, 
pharmacokinetics, and biomarkers was revised. 
However, the number of samples and the associated 
blood volumes were not updated in Appendix G.
This letter clarified the total number of samples and 
the total volume of blood in Appendix G of the 
protocol. In Amendment 01, the number of samples 
(and the total volume) for clinical laboratory tests, 
pharmacokinetics, and biomarkers was revised. 
However, the number of samples and the associated 
blood volumes were not updated in Appendix G.
This section was added to reflect the changes 
described in Letter of Clarification 07.
16.5 Letter of Clarification 06 Dated 18 April 2019
This letter clarified a typo in Appendix H, the Final 
Visit Day should read "168±3 days" instead of 
"16±3 days", the number of study centers was 
changed from 25 to 32 in Section 3.2 for 
consistency, footnote “v” in Table 1 was changed 
so that the provisioned electronic diary device 
should be returned at visit 5 to match footnote “m”, 
and footnote “a” in Table 1 on the visit 1 column 
was put back in row 2 after being inadvertently 
omitted.
This letter clarified a typo in Appendix H, the Final 
Visit Day should read "168±3 days" instead of 
"16±3 days", the number of study centers was 
changed from 25 to 32 in Section 3.2 for 
consistency, footnote “v” in Table 1 was changed 
so that the provisioned electronic diary device 
should be returned at visit 5 to match footnote “m”, 
and footnote “a” in Table 1 on the visit 1 column 
was put back in row 2 after being inadvertently 
omitted.
This section was added to reflect the changes 
described in Letter of Clarification 06.
Appendix A Clinical Laboratories and Other Departments and Institutions


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Reason/Justification for change
Andrew Ahn, MD, PhD 
Vice President of Clinical Development, Headache
Teva Branded Pharmaceutical Products R&D, Inc.
Tel: (610) 727-6128(610) 883-5503
Cell: (484) 983-9544
Andrew Ahn, MD, PhD 
Vice President of Clinical Development, Headache
Teva Branded Pharmaceutical Products R&D, Inc.
Tel: (610) 883-5503
Cell: (484) 983-9544
Update to sponsor contact information.
Jimmy Schiemann, Juline Bryson, MD
Senior Director
Clinical Development, Migraine and Headache
Teva Branded Pharmaceutical Products R&D, Inc.
Tel: 610-727-6305610-786-7079
Fax: 610-786-7061
Cell: 484-502-6359484-401-2044
Juline Bryson, MD
Director
Clinical Development, Migraine and Headache
Teva Branded Pharmaceutical Products R&D, Inc.
Tel: 610-786-7079
Fax: 610-786-7061
Cell: 484-401-2044
Update to reflect the new sponsor medical expert.
Michael BurczynskiConrad Cowan
Director, Translational Medicine
Personalized & Precision Medicine and Big Data
Analytics
Teva Branded Pharmaceuticals R&D, Inc.
Tel: 215-850-4392610-883-5843
Cell: 862-200-8781484-484-8259
Email: 
Michael.Burczynski@tevapharm.comConrad.Cowa
n01@tevapharm.com
Conrad Cowan
Director, Translational Medicine
Teva Branded Pharmaceuticals R&D, Inc.
Tel: 610-883-5843
Cell: 484-484-8259
Email: Conrad.Cowan01@tevapharm.com
Update to reflect the new sponsor biomarker 
evaluator.
Appendix H Detailed Description of Assessments and Study Procedures
Final Visit (End-of-Treatment/Early 
Termination/End-of-Study [Visit 8, Day 16168±3 
days])
Final Visit (End-of-Treatment/Early 
Termination/End-of-Study [Visit 8, Day 168±3 
days])
Correction to the study day number, as detailed in 
Letter of Clarification 06.
Appendix L Pharmacokinetics Samples (Other sections affected by this change: Appendix M)
Set A samples will be transported with a 
temperature data logger and frozen with dry ice 
sufficient for 4 days, by next day courier to the 
central laboratory.
Set A samples will be transported frozen with dry 
ice sufficient for 4 days, by next day courier to the 
central laboratory.
The use of temperature data loggers are not needed 
as next day couriers are used.


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Appendix G Total Blood volume
See new wording column.
Total Blood Volumes table has been modified as 
follows:

“Clinical laboratory tests and pregnancy” row:
o
Footnote “a” added
o
Total number of samples updated 
from 6 to 8
o
Total volume (mL) updated from 36 
to 48

“FSH” row:
o
Footnote “b” added

“Pharmacokinetics” row:
o
Total number of samples updated 
from 5 to 7
o
Total volume (mL) updated from 20 
to 28

“ADA” row:
o
Footnote “c” added

“Biomarkers” row:
o
Footnote “d” added
o
Total number of samples updated 
from 3 to 6
o
Total volume (mL) updated from 55.5 
to 111

“Total” row:
o
Total number of samples updated 
from 19 to 26
o
Total volume (mL) updated from 
134.5 to 210

Footnote “c” updated to coincide with the 
changes made to Table 1 footnote “o”

“AE=adverse event;” added to the table 
Updates to the blood volumes as described in Letter 
of Clarification 07.


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abbreviations.


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16.2.
Letter of Clarification 09 Dated 30 October 2019
This letter rectified the incorrect links (field codes) to some of the appendices and to update the 
sponsor’s medical expert/contact in Appendix A.
16.3.
Letter of Clarification 08 Dated 24 September 2019
This letter clarified that the use of temperature loggers for the transport of pharmacokinetic 
samples was not needed in Appendix L (Pharmacokinetics Samples) as premium, next day 
couriers will be used and, thus, a temperature log will not be needed and the wording was 
removed.
16.4.
Letter of Clarification 07 Dated 01 August 2019
This letter clarified the total number of samples and the total volume of blood in Appendix G of 
the protocol. In Amendment 01, the number of samples (and the total volume) for clinical 
laboratory tests, pharmacokinetics, and biomarkers was revised. However, the number of 
samples and the associated blood volumes were not updated in Appendix G.
16.5.
Letter of Clarification 06 Dated 18 April 2019
This letter clarified a typo in Appendix H, the Final Visit Day should read "168±3 days" instead 
of "16±3 days", the number of study centers was changed from 25 to 32 in Section 3.2 for 
consistency, footnote “v” in Table 1 was changed so that the provisioned electronic diary device 
should be returned at visit 5 to match footnote “m”, and footnote “a” in Table 1 on the visit 1 
column was put back in row 2 after being inadvertently omitted.
16.6.
Amendment 01 Dated 25 March 2019
The primary reason for this amendment is to incorporate the changes indicated from several 
administrative letters, to add language that specifies the estimand framework for the primary 
endpoint, and to specify key secondary endpoints. This amendment is considered to be 
substantial (ie, requires approval by CA, 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.
Table 1 (Study Procedures and Assessments) and Figure 1 (Overall Study Schematic Diagram) 
have been revised to reflect changes described below.


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Clinical Study Protocol Synopsis
Is this study conducted to investigate the New Use of an 
approved, marketed product? YesNo
Is this study conducted to investigate the New 
Use of an approved, marketed product? Yes
This change was made because the 
investigational product was approved in 
the United States after the previous 
version of the protocol was written. 
Number of Investigational Centers Planned: This study is 
planned to be conducted in approximately 2532 investigational 
centers.
Number of Investigational Centers Planned: 
This study is planned to be conducted in 
approximately 32 investigational centers.
This change was made to increase the 
number of investigational centers planned 
in the study from 25 to 32. 
Section 1.1 Introduction (Other sections affected by this change: Sections 2.1, 3.1, 3.3, 4.1, 4.2, 5.1.1, 5.3.1, 5.3.2, 6.1, 9.4, 9.5, 9.5.5)
PPTHPTH
PTH
This change was made to remove 
“persistent” from “persistent 
posttraumatic headache” throughout the
protocol to expand eligibility.
Section 2.1 Primary and Secondary Study Objectives and Endpoints (Other sections affected by this change: Sections 2.1.1, 2.2, 3.1, 3.5, 4.1, 5.8, 6.1, 6.5, 
9.5.1, 9.5.2, 9.5.4, Appendix H)
The primary efficacy endpoint is the mean change from 
baseline (run-in baseline period) in the monthly average 
number of headache days of at least moderate severity during 
the 12-week period after the first dose of the IMP.
The primary efficacy endpoint is the mean 
change from baseline (baseline period) in the 
monthly average number of headache days of at 
least moderate severity during the 12-week 
period after the first dose of the IMP.
The term “run-in” period was changed to 
“baseline” period throughout the protocol 
due to team preference in terminology.
Baseline was determined to be more 
appropriate. 
Section 2.1 Primary and Secondary Study Objectives and Endpoints (Other sections affected by this change: Sections 3.1, 3.5, 5.1.1.1, 9.9, Appendix H)
A secondary objective of the study is to evaluate the safety 
and tolerability of fremanezumab administered sc in adult 
patients with PPTH compared with placebo and during the 
open-label period.
A secondary objective of the study is to 
evaluate the safety and tolerability of 
fremanezumab administered sc in adult patients 
with PTH compared with placebo and during the 
open-label period.
This change was made because an 
open-label period was added to this study.
Section 2.1.1 Primary and Secondary Study Objectives and Endpoints (Other sections affected by this change: Sections 4.1, 5.8)
A headache day is defined as a day when a patient reports at 
least 4 hours of headache (not necessarily consecutive) and at 
its worst at any point has at least moderate severity; or when a 
patient has a headache and takes a prescription abortive
medication with intent to alleviate the headache (regardless of 
duration or severity).
A headache day is defined as a day when a 
patient reports at least 4 hours of headache (not 
necessarily consecutive) and at its worst at any 
point has at least moderate severity; or when a 
patient has a headache and takes a prescription 
abortive medication with intent to alleviate the 
headache (regardless of duration or severity).
The term “abortive” was added to specify 
the type of prescription medication taken 
by patients to alleviate headache. 


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Reason/Justification for change
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Section 3.1 General Study Design and Study Schematic Diagram 
The study will consist of a screening visit, a run-in baseline 
period, and a double-blind treatment period lasting 
approximately 12 weeks, and an open-label period lasting 
approximately 12 weeks. Follow-up visits will take place 
approximately 24 weeks (phone visit) and approximately 
40 weeks after the first dose of the IMP.
The study will consist of a screening visit, a 
baseline period, a double-blind treatment period 
lasting approximately 12 weeks, and an 
open-label period lasting approximately 
12 weeks. 
This change was made to include the 
open-label period of approximately 
12 weeks and to remove all follow-up 
visits from the study. 
The total duration of patient participation in the study is 
planned to be approximately 4428 weeks.
The total duration of patient participation in the 
study is planned to be approximately 28 weeks.
This change was made to adjust the study 
duration from 44 weeks to 28 weeks to 
reflect the new study schedule and the 
addition of an open-label period. .
Patients will complete a screening visit (visit 1) after providing 
informed consent, and eligible patients will enter a 
run-inbaseline period lasting approximately 4 weeks 
(28+3 days), during which time they will enter their baseline 
PTH information into ana daily electronic headache diary 
application daily. The diagnosis will be prospectively 
confirmed via a review of headache data recorded daily during 
a 28-day run-in period in an electronic headache diary device.
Patients will complete a screening visit (visit 1) 
after providing informed consent, and eligible 
patients will enter a baseline period lasting 
approximately 4 weeks (28+3 days), during 
which time they will enter their baseline PTH 
information into a daily electronic headache 
diary. 
Information was removed regarding 
confirmation of the diagnosis from the 
e-diary review. 
Patients meeting eligibility requirements will be randomly 
assigned to 1 of 2 treatment groups with fremanezumab or 
Patients meeting eligibility requirements will be 
randomly assigned to 1 of 2 treatment groups 
These changes were made to specify the 
2 possible treatment groups in the study: 


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placebo in a 1:1 ratio. Treatment assignment will take place
with stratification based on the duration of the patient’s history 
of posttraumatic headache onset (<12 months and ≥12 months 
since the brain injury) to 1 of 2 treatment groups with 
fremanezumab or placebo in a 1:1 ratio.duration). 
with fremanezumab or placebo in a 1:1 ratio. 
Treatment assignment will take place with 
stratification based on the duration of the 
patient’s history of posttraumatic headache 
(<12 months and ≥12 months duration). 
fremanezumab and placebo. Changes 
were also made to specify that patients 
will be randomly assigned in a 1:1 ratio. 
Specifications for duration of the patient’s 
history of posttraumatic headache were 
generalized for clarification. 
Baseline procedures andScreening results will be reviewed for 
eligibility, additional baseline assessments will be 
administered, and the first treatment administration will occur 
at visit 2. 
Screening results will be reviewed for eligibility, 
additional baseline assessments will be 
administered, and the first treatment 
administration will occur at visit 2. 
This change was made to replace baseline 
procedures with screening results. 
Patients will return to the study center approximately every 4 
weeks (visit 3 and visit 4) for a continuation of the blinded 
treatment administered sc; for safety and efficacy assessments; 
and for blood and urine sampling for pharmacokinetics, 
immunogenicity, biomarkers, and pharmacogenomics (unless 
prohibited by local regulations) analyses.biomarker analysis.
Patients will return to the study center 
approximately every 4 weeks (visit 3 and visit 4) 
for a continuation of the blinded treatment 
administered sc; for safety and efficacy 
assessments; and for blood and urine sampling 
for pharmacokinetics, immunogenicity, and 
biomarker analysis.
This change was made to clarify that 
patients will return to the study center 
during an open-label period of the study. 
Pharmacogenomics was removed from the 
study endpoints. 
At visit 5, all patients will proceed directly to an open-label 
treatment phase, with fremanezumab administered sc. Patients 
will then return to the study center approximately every 4 
weeks (visits 6, and 7) for continued open-label treatment and 
safety tolerability and efficacy assessments. Final study 
assessments will be performed on visit 8, at the end of 
treatment or early termination visit (visit 5), approximately 
1224 weeks after first administration of the IMP.
At visit 5, all patients will proceed directly to an 
open-label treatment phase, with fremanezumab 
administered sc. Patients will then return to the 
study center approximately every 4 weeks (visits 
6 and 7) for continued open-label treatment and 
safety tolerability and efficacy assessments. Final 
study assessments will be performed on visit 8, 
at the end of treatment or early termination visit, 
approximately 24 weeks after first administration 
of the IMP.
Visit 5 was changed to the first visit of the 
open-label period. Visits 6, 7, and 8 were 
added to the open-label period, with 
approximately 4 weeks between visits. 
Visits 6 and 7 were added as dosing visits, 
and Visit 8 is the EOS visit. 
FollowingFor all patients in the study, the end-of -treatment 
visit (visit 5),8) is defined as the final visit of the study and the 
conclusion of all study activities for the patient; patients will 
not receive any further treatments with IMP and shouldwill be 
treated according to guidelines and treating physicians’ 
discretion.
For all patients in the study, the end-of-treatment 
visit (visit 8) is defined as the final visit of the 
study and the conclusion of all study activities 
for the patient; patients will not receive any 
further treatments with IMP and will be treated 
according to guidelines and treating physicians’ 
discretion.
This change was made to define the 
end-of-treatment visit. 
Patients will be contacted by telephone for a follow-up visit 
(visit 6) approximately 24 weeks after the first dose of IMP to 
have efficacy procedures completed and will report to the 
investigational center for a final follow-up visit (visit 7) 
However, a final database lock will occur 
following the end-of-treatment visit (visit 8) of 
the last patient for analysis of the study data.
The telephone visit was removed from 
this study. The final follow-up visit was 
changed to visit 8 to account for the 
addition of visits 6 and 7 in the open-label 


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approximately 40 weeks following the first dose of IMP to 
have final procedures and assessments performed. The end of 
study is defined as the last follow-up visit. However, a finalan 
interim database lock will occur following the end-of-treatment 
visit (visit 58) of the last patient for analysis of the study data. 
period. 
This change supersedes the alterations 
requested in the letter of clarification 
dated 01 October 2018.
Section 3.1 General Study Design and Study Schematic Diagram (Other sections affected by this change: Section 3.2)
The total duration of the study will be approximately 2 years 
from Q4 of 2017 until approximately Q4Q2 of 20192020.
The total duration of the study will be 
approximately 2 years from Q4 of 2017 until 
approximately Q2 of 2020.
This change was made to extend the total 
duration of the study from Q4 2019 to Q2 
2020. 
Section 3.1 General Study Design and Study Schematic Diagram (Other sections affected by this change: Section 9.14)
Final study assessments will be performed on visit 8, at the end 
of treatment or early termination visit, approximately 24 weeks 
after first administration of the IMP.
A database lock from the double-blind period will occur 
following the completion of visit 5 by the last patient. 
Unblinding will occur after the database lock from the 
double-blind period.
Final study assessments will be performed on 
visit 8, at the end of treatment or early 
termination visit, approximately 24 weeks after 
first administration of the IMP. 
A database lock from the double-blind period 
will occur following the completion of visit 5 by 
the last patient. Unblinding will occur after the 
database lock from the double-blind period.
This change was made to clearly state the 
intent to analyze data following the 
completion of visit 5 by the last patient.
Section 3.3 Justification for Study Design and Selection of Population (Other sections affected by this change: Sections 4.1, 4.5, 9.5)
PPTHPTH is a headache with >3 months1 month duration
PTH is a headache with >1 month duration
This change was made to reduce the 
length of headache duration from 3 
months to 1 month. 
Section 3.4 Stopping Rules for the Study
The investigator and/or sponsor can withdraw a patient from 
the study at any time for any reason (eg, protocol violation or
deviation as defined in Section 10, noncompliance, or adverse 
event). 
The investigator and/or sponsor can withdraw a 
patient from the study at any time for any reason 
(eg, protocol deviation as defined in Section 10, 
noncompliance, or adverse event). 
This change was made to remove the term
“protocol violation” language from the 
protocol. Protocol deviation is the 
preferred language. 
Section 4. 1 Patient Inclusion Criteria 
In addition, the following criteria should be met: 
Headache persists for >3 months 1 month after injury to the 
head
And/or
Whiplash has occurred and is associated at the time with neck 
pain and/or headache
Headache has developed within 7 days after the whiplash
Headache persists for >3 months after the whiplash
In addition, the following criteria should be met: 
Headache persists for >1 month after injury to 
the head
This criterion was modified to expand 
patient eligibility by lowering the 
symptom timeframe. Also, whiplash as a 
headache etiology was removed to clarify 
the indication. 


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Women may be included only if they have a negative serum 
beta-human chorionic gonadotropin (β-HCG) test at screening 
and a negative urine pregnancy test at baseline, are sterile, or 
postmenopausal. Definitions of sterile and postmenopausal are 
given in Appendix D.
Women may be included only if they have a 
negative serum beta-human chorionic 
gonadotropin (β-HCG) test at screening and a 
negative urine pregnancy test at baseline, are 
sterile, or postmenopausal. Definitions of sterile 
and postmenopausal are given in Appendix D.
This text was added to clarify that 
Appendix D further elaborates on 
definitions of sterile and postmenopausal. 
Men must be sterile or, if they are potentially fertile or 
reproductively competent (ie, not surgically or congenitally 
sterile), must use, together with their female partners, a 
condom for the duration of the study and for 30 weeks after the 
last IMP administration. Further details are included in 
Appendix D.
Men must be sterile or, if they are potentially 
fertile or reproductively competent (ie, not 
surgically or congenitally sterile) and their 
female partners are of childbearing potential, 
must use, together with their female partners, a 
condom for the duration of the study and for 
30 weeks after the last IMP administration. 
Further details are included in Appendix D.
This text was added to clarify that men in 
the study, or men with female partners 
who are participating in the study, must 
use a condom as a birth control method.  
Definitions of WOCBP, sterile and postmenopausal women, 
male contraception, and highly effective and acceptable birth 
control methods, including examples, are given in Appendix D.
Definitions of WOCBP, sterile and 
postmenopausal women, male contraception, and 
highly effective birth control methods, including 
examples, are given in Appendix D.
This change was made to remove 
acceptable birth control from the protocol. 
Only effective birth control will be used. 
Section 4. 2 Patient Exclusion Criteria 
The patient has a previous history of brain imaging showing 
evidence of intracerebral hemorrhage, subdural or epidural 
hematomas, or subarachnoid hemorrhage as a consequence of 
the traumatic head injury. Brain images with structurally 
insignificant changes, as discussed and approved by the 
sponsor, will be reviewed by the sponsor on a case-by-case 
basis.
The patient has a previous history of brain 
imaging showing evidence of intracerebral 
hemorrhage, subdural or epidural hematomas, or 
subarachnoid hemorrhage as a consequence of 
the traumatic head injury. Brain images with 
structurally insignificant changes, as discussed 
and approved by the sponsor, will be reviewed 
by the sponsor on a case-by-case basis. 
This change was made to include patients 
who have brain images with structurally 
insignificant changes, if agreed upon by 
the sponsor. This will allow for more 
potential study participants. 
The patient has whiplash with only neck pain and no 
persistentsubsequent headache >3 months after whiplashbut no 
history of head injury or concussion. 
The patient has whiplash and subsequent 
headache but no history of head injury or 
concussion.
This change was made to add subsequent 
headache to this exclusion criterion, 
following whiplash. 
The patient has participated in another study of an IMP (or a 
medical device) within the previous 30 days (or 90 days for 
biologics) or 5.5 half-lives, whichever is longer, of the IMP or 
is currently participating in another study of an IMP (or a 
medical device) prior to screening.
The patient has participated in another study of 
an IMP (or a medical device) within the previous 
30 days (or 90 days for biologics) or 5.5 half-
lives, whichever is longer, of the IMP or is 
currently participating in another study of an 
IMP (or a medical device) prior to screening.
This change was made to specify that this 
exclusion criterion refers to the time 
period before screening in this study. 
The patient has had exposure to a mAb targeting the CGRP 
pathway (erenumab, eptinezumab, galcanezumab and 
The patient has had exposure to a mAb targeting 
the CGRP pathway (erenumab, eptinezumab, 
This exclusion criterion was added to 
specify that patients with exposure to a 


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fremanezumab) during the 6 months prior to the day of the 
screening visit.
galcanezumab, and fremanezumab) during the 6 
months prior to the day of the screening visit.
mAb targeting the CGRP pathway during 
the 6 months prior to the study will not be 
included. 
The patient is not currently using or has prior exposure to any 
CGRP antibody, any antibody to the CGRP receptor. The 
patient has received being treated with onabotulinmumtoxinA 
(eg, Botox, Dysport, Xeomin) application in the head or neck 
or has received any such injection during the previous 
3 months beforeprior to the screening visit. 
The patient is not currently being treated with 
onabotulinmumtoxinA (eg, Botox, Dysport, 
Xeomin) application in the head or neck or has 
received any such injection during the previous 
3 months prior to the screening visit. 
These changes were made to clarify that 
patients should not be treated (currently or 
during the 3 months prior to screening) 
with onabotulinmumtoxinA application. 
Xeomin was added to the list of such 
applications. 
The patient has been implanted with any electronic devices for 
headache prophylaxis prevention during the previous 3 months 
before screeningprior to the screening visit or is currently using 
any implanted or externally applied stimulator or device.
The patient has been implanted with any 
electronic devices for headache prevention 
during the 3 months prior to the screening visit 
or is currently using any implanted or externally 
applied stimulator or device.
These changes were made to specify that 
electronic devices implanted for headache 
are not permitted in this study. 
The patient has major depression as assessed by the 2-item 
Patient Health Questionnaire (PHQ-2)/9-item Patient Health 
Questionnaire (PHQ-9) at screening. Any patient with a score 
≥15 should be considered to have major depression and should 
be referred for appropriate treatment. Patients with lower 
scores (5 to 14) may also have major depression, and they 
should be carefully evaluated by the investigator for the 
presence of additional symptoms.
The patient has major depression as assessed by 
the 2-item Patient Health Questionnaire (PHQ-
2)/9-item Patient Health Questionnaire (PHQ-9) 
at screening. Any patient with a score ≥15 should 
be considered to have major depression and 
should be referred for appropriate treatment. 
Patients with lower scores (5 to 14) may also 
have major depression, and they should be 
carefully evaluated by the investigator for the 
presence of additional symptoms. 
This text was added to further elaborate 
on the PHQ scores to describe which 
scores indicate that patients may have 
major depression. 
The patient has a history of alcohol abuse or recreational drug 
abuse or at the discretion of the investigator is suspected of 
abusing alcohol or recreational drugs.
The patient has a history of alcohol abuse or
recreational drug abuse or at the discretion of the 
investigator is suspected of abusing alcohol or 
recreational drugs.
This text was added to include the ability 
of the investigator to suspect alcohol or 
recreational drug abuse in patients to 
exclude them from the study. 
The patient has exhibitedany lifetime history of suicidal 
behaviors (actualsuicide attempts, interrupted attempts, aborted 
attempts, and preparatory actionssuicidal ideation, or 
preparations for suicide). 
The patient has any lifetime history of suicidal 
behaviors (suicide attempts, interrupted attempts, 
aborted attempts, suicidal ideation, or 
preparations for suicide).
These changes were made to clarify 
suicidal behavior. 
Section 4. 3 Withdrawal Criteria and Procedures for the Patient
Each patient is free to withdraw from the study or discontinue 
from IMP at any time, without prejudice to their continued care
Each patient is free to withdraw from the study 
or discontinue from IMP at any time, without 
prejudice to their continued care
This text was added to specify that 
patients may discontinue from the IMP at 
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Investigators should attempt to obtain information on patients 
in the case of withdrawal from the study or discontinuation 
from IMP. 
Investigators should attempt to obtain 
information on patients in the case of withdrawal 
from the study or discontinuation from IMP. 
These changes were made to clarify that 
patients may withdraw from the study or 
discontinue from IMP. 
Section 4.5 Rescreening
Patients who historically screen-failed or have currently failed 
screening as a result of the following previous criteria will be 
rescreened if both conditions apply:
•
headache persists for >1 month after injury to the head
•
e-diary compliance level of 75%.
A patient who is screened and does not meet study inclusion 
and exclusion criteria will not be considered for screening 
again unless approved by the sponsor on a case-by-case basis. 
Patients enrolled after rescreening will be given a new patient 
identification number.
Patients who historically screen-failed or have 
currently failed screening as a result of the 
following previous criteria will be rescreened if 
both conditions apply:
•
headache persists for >1 month after injury 
to the head
•
e-diary compliance level of 75%
A patient who is screened and does not meet 
study inclusion and exclusion criteria will not be 
considered for screening again unless approved 
by the sponsor on a case-by-case basis. 
Patients enrolled after rescreening will be given a 
new patient identification number.
Due to changes in the eligibility criteria, 
this change was made to include sponsor 
approval of rescreening on a case-by-case 
basis and to clarify the criteria for 
rescreening. 
Section 5.1.1.1 Starting Dose and Dose Levels (Other sections affected by this change: Section 3.5)
Patients randomized to fremanezumab will receive 675 mg of 
fremanezumab administered as 3 sc injections (225 mg/1.5 mL 
each) at visit 2 (week 0) , visit 3 (week 4), and visit 4 
(week 8).randomization), visit 3 (week 4), and visit 4 (week 8). 
Patients will then enter the open-label period of the study, 
where they will receive 675 mg of fremanezumab administered 
as 3 sc injections (225 mg/1.5 mL each) at visit 5 (week 12), 
visit 6 (week 16), and visit 7 (week 20).  
Patients randomized to fremanezumab will 
receive 675 mg of fremanezumab administered 
as 3 sc injections (225 mg/1.5 mL each) at visit 2 
(randomization), visit 3 (week 4), and visit 4 
(week 8). Patients will then enter the open-label 
period of the study, where they will receive 675 
mg of fremanezumab administered as 3 sc 
injections (225 mg/1.5 mL each) at visit 5 
(week 12), visit 6 (week 16), and visit 7 (week 
20).  
These changes were made to include the 
injection schedules and doses for both the 
blinded period and the open-label period.  
Section 5.4 Treatment After the End of the Study
A telephone visit will take place approximately 24 weeks 
following administration of the first dose of IMP to assess 
efficacy.
Deleted text
The follow-up telephone visit was 
removed from the study. There will be no 
follow-up visit in the adjusted study. 
Section 5.6 Prior and Concomitant Medication or Therapy 
For daily-prescribed medications and preventative treatments, 
patients must be on a stable dose and regimen for at least 
2 weeks prior to screening and maintained throughout the 
study until the completion of visit 58. 
For daily-prescribed medications and 
preventative treatments, patients must be on a 
stable dose and regimen for at least 2 weeks prior 
to screening and maintained throughout the study 
until the completion of visit 8. 
This change was made to include the 
allowance of preventative treatments 
concomitantly with the dosing regimen. 


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Section 5.8 Randomization and Blinding (Other sections affected by this change: Section 4.1, 4.5, and 6.1)
Electronic diary card completion must be at least 8575% 
during the run-inbaseline period for randomization eligibility 
and at least 75% during the double-blind treatment period, 
during which the patient cannot miss more than 7 days of 
recording nor more than 4 days in a row.
Electronic diary completion must be at least 75% 
during the baseline period for randomization 
eligibility and at least 75% during the double-
blind treatment period, during which the patient 
cannot miss more than 7 days of recording nor 
more than 4 days in a row.
These changes were made to adjust the 
electric diary completion percentage from 
85% to 75%. 
Section 5.9.1 Maintenance of Randomization 
At the time of analysisAfter all patients have completed visit 
5(after the end of the study), after receiving and an unblinding 
request from the Teva statistician has been received, the third-
party vendor will provide the unblinded IMP assignments 
according to the processes defined in the relevant Standard 
Operating Procedure.
After all patients have completed visit 5 and an 
unblinding request from the Teva statistician has 
been received, the third-party vendor will 
provide the unblinded IMP assignments 
according to the processes defined in the relevant 
Standard Operating Procedure.
These changes were made to clarify that 
unblinding will occur after all patients 
have completed visit 5. 
Section 5.9.2 Blinding and Unblinding 
the investigator may unblind the patient’s IMP assignment 
before the open-enrollment period as deemed necessary
the investigator may unblind the patient’s IMP 
assignment before the open-enrollment period as 
deemed necessary
This text has been added to clarify that the 
IMP assignment may be unblinded before 
the open-enrollment period. 
Section 6.5 Special Protocol Headache Questionnaire 
Patients will then be contacted by telephone for a follow-up 
visit (visit 6) approximately 12 weeks following the last study 
visit (visit 5) and will be asked if they had any headaches since 
the last study visit. For those who experienced headache(s), an 
additional 12 questions will be asked regarding the number, 
severity, frequency, and duration of the headache(s) and their 
effect on daily activities and sleep.Patients will be instructed to 
return the provisioned devices to the investigational center 
after collection of the Special Protocol Headache 
Questionnaire (visit 8).
Patients will be instructed to return the 
provisioned devices to the investigational center 
after collection of the Special Protocol Headache 
Questionnaire (visit 8). 
This text was modified to clarify the 
instructions on returning devices to the 
investigational center. End of study was 
changed from visit 6 to visit 8 to reflect 
the addition of the open-label period. All 
text relating to the follow-up telephone 
visit has been removed from the protocol. 
There will no longer be a telephone 
follow-up visit. 
Section 9.2.4 Per-Protocol Analysis Set
The per-protocol (PP) analysis set is a subset of the ITT 
analysis set including only patients without any major protocol 
deviationsdeviations or who have unexpected drug 
concentration findings. 
The per-protocol (PP) analysis set is a subset of 
the ITT analysis set including only patients 
without any major protocol deviations or 
unexpected drug concentration findings. 
This change was made to clarify which 
patients are included in the per-protocol
analysis set. 
Section 9.5.5.1 Primary Efficacy Analysis
The primary estimand for this study is defined by the following 
attributes:
The primary estimand for this study is defined by 
the following attributes:
This change was made as part of a 
recommendation to include the estimand 
framework.


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Original text with changes shown
New wording
Reason/Justification for change

The target population includes male and female 
patients aged 18 to 70 years, inclusive, with a 
history of PTH (as defined by the ICHD-3 [beta 
version] criteria).

The primary outcome measure is the mean 
change from baseline (baseline period) in the 
monthly average number of headache days of at 
least moderate severity during the 12-week 
period after the first dose of IMP.

The FAS will be used for efficacy analyses. FAS 
is a subset of the ITT analysis set and includes 
only patients who receive at least 1 dose of IMP 
and have at least 1 postbaseline efficacy 
assessment on the primary endpoint. In the FAS, 
treatment will be assigned based on the treatment 
to which patients were randomized, regardless of 
which treatment they actually received.

Treatment effect will be measured via ANCOVA 
method, including treatment as fixed effect and 
the baseline number of headache days of at least 
moderate severity and the PTH onset 
(<12 months and ≥12 months) as covariates.
For patients assigned to active treatment who discontinue the 
study due to lack of efficacy, death, or adverse event, the 
proportion of headache days in the remainder of the analysis 
window will be imputed as the mean monthly average of 
headache days in the same analysis window for patients 
assigned to placebo. All other missing data for patients in 
either treatment group will be handled as follows:

For patients who have ≥10 days of e-diary data in 
an analysis window, the monthly average number 

The target population includes male 
and female patients aged 18 to 
70 years, inclusive, with a history 
of PTH (as defined by the ICHD-3 
[beta version] criteria).

The primary outcome measure is 
the mean change from baseline 
(baseline period) in the monthly 
average number of headache days 
of at least moderate severity during 
the 12-week period after the first 
dose of IMP.

The FAS will be used for efficacy 
analyses. FAS is a subset of the 
ITT analysis set and includes only 
patients who receive at least 1 dose 
of IMP and have at least 
1 postbaseline efficacy assessment 
on the primary endpoint. In the 
FAS, treatment will be assigned 
based on the treatment to which 
patients were randomized, 
regardless of which treatment they 
actually received.

Treatment effect will be measured 
via ANCOVA method, including 
treatment as fixed effect and the 
baseline number of headache days 
of at least moderate severity and 
the PTH onset (<12 months and 
≥12 months) as covariates.
For patients assigned to active treatment who 


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Original text with changes shown
New wording
Reason/Justification for change
of headache days will be calculated based on data 
available in that analysis window and prorated to 
28 days.

For patients who have <10 days of e-diary data in 
an analysis window, the monthly average number 
of headache days will be imputed as the mean 
monthly average of headache days in the same 
analysis window for patients assigned to the same 
treatment group and having ≥10 days of e-diary 
data. Sensitivity analyses will be conducted as 
defined in the statistical analysis plan.
discontinue the study due to lack of efficacy, 
death, or adverse event, the proportion of 
headache days in the remainder of the analysis 
window will be imputed as the mean monthly 
average of headache days in the same analysis 
window for patients assigned to placebo. All 
other missing data for patients in either treatment 
group will be handled as follows:

For patients who have ≥10 days of 
e-diary data in an analysis window, 
the monthly average number of 
headache days will be calculated 
based on data available in that 
analysis window and prorated to 
28 days.

For patients who have <10 days of 
e-diary data in an analysis window, 
the monthly average number of 
headache days will be imputed as 
the mean monthly average of 
headache days in the same analysis 
window for patients assigned to the 
same treatment group and having 
≥10 days of e-diary data. 
Sensitivity analyses will be 
conducted as defined in the 
statistical analysis plan.


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Original text with changes shown
New wording
Reason/Justification for change
Section 9.5.5.2 Sensitivity Analysis
Sensitivity analysis may be performedwill be conducted to 
explore the impact of missing data in the primary efficacy 
analysis. In particular, endpoints analyzed using an ANCOVA 
method will be analyzed using a mixed model for repeated 
measures method. The details will be described in the 
statistical analysis plan.
Sensitivity analysis will be conducted to explore 
the impact of missing data in the primary 
efficacy analysis. In particular, endpoints 
analyzed using an ANCOVA method will be 
analyzed using a mixed model for repeated 
measures method. The details will be described 
in the statistical analysis plan.
This change was made as part of a 
recommendation to include the estimand 
framework.
Section 9.5.5.3 Secondary Efficacy Analysis
For the proportion of responders defined as 50% or more 
reduction from baseline in the monthly average headache days, 
the Cochran-Mantel-Haenszel test will be used stratified by 
PTH onset (<12 months and ≥12 months).
For the proportion of responders defined as 50% 
or more reduction from baseline in the monthly 
average headache days, the Cochran-Mantel-
Haenszel test will be used stratified by PTH 
onset (<12 months and ≥12 months).
This change was made as part of a 
recommendation to include the estimand 
framework.
Section 9.6 Multiple Comparisons and Multiplicity
Testing of statistical significance at a 2-sided alpha of 0.05 will 
be performed for the primary endpoint. If the primary endpoint 
meets statistical significance, then each of the key secondary 
endpoints will be tested for significance in a pre-specified 
order at a 2-sided alpha of 0.05. If and when any p>0.05, no 
further comparisons will be interpreted inferentially. Details 
will be presented in the statistical analysis plan.
Testing of statistical significance at a 2-sided 
alpha of 0.05 will be performed for the primary 
endpoint. If the primary endpoint meets 
statistical significance, then each of the key 
secondary endpoints will be tested for 
significance in a pre-specified order at a 2-sided 
alpha of 0.05. If and when any p>0.05, no further 
comparisons will be interpreted inferentially. 
Details will be presented in the statistical 
analysis plan.
This change was made as part of a 
recommendation to include the estimand 
framework.
Section 9.9 Pharmacokinetic Analysis
Pharmacokinetic plasma concentration results for 
fremanezumab will be tabulated descriptively at each planned 
sampling time point. At the open-label period, pharmacokinetic 
plasma concentration results will be tabulated descriptively at 
each planned sampling time point treatment group.
Pharmacokinetic plasma concentration results for 
fremanezumab will be tabulated descriptively at 
each planned sampling time point. At the open-
label period, pharmacokinetic plasma 
concentration results will be tabulated 
descriptively at each planned sampling time 
point treatment group.
This text was added to clarify that 
pharmacokinetic plasma concentration 
results will be tabulated descriptively at 
sampling time points. 


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16.7.
Letter of Clarification 05 Dated 01 October 2018
This letter clarified the requirements for the telephone call in Section 6.5. However, this 
paragraph was removed during review of the amendment due to the removal of the phone call.
16.8.
Letter of Clarification 04 Dated 06 February 2018
This letter clarified the requirements for the exclusion criterion related to major depression; at 
what PHQ-2/PHQ-9 score a patient would be excluded.
16.9.
Letter of Clarification 03 Dated 11 December 2017
This letter specified in inclusion criterion ‘f’ which prescription medications support the 
determination of moderate severity. However, this criterion was further modified during review 
of the amendment.
16.10.
Letter of Clarification 02 Dated 16 November 2017
This letter clarified the requirements for prior or concomitant medication or therapies in 
Section 5.6 and Appendix F.
16.11.
Letter of Clarification 01 Dated 10 November 2017
This letter clarified the use of the word “capsule” in the model ICF.


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APPENDIX A. CLINICAL LABORATORIES AND OTHER 
DEPARTMENTS AND INSTITUTIONS
Sponsor’s Authorized Representative
Andrew Ahn, MD, PhD 
Vice President of Clinical Development, 
Headache
Teva Branded Pharmaceutical Products 
R&D, Inc.
Tel: (610) 883-5503
Cell: (484) 983-9544
Sponsor’s Medical Expert/Contact Point Designated by the 
Sponsor for Further Information on the Study
Juline Bryson, MD
Director
Clinical Development, Migraine and 
Headache
Teva Branded Pharmaceutical Products 
R&D, Inc.
Tel: 610-786-7079
Fax: 610-786-7061
Cell: 484-401-2044
Sponsor’s Contact Point Designated by the Sponsor for Further 
Information on the Study
Sarah Swanson 
Sr Manager, Global Clinical Project 
Management
Global Clinical Operations, CNS & Pain
Teva Branded Pharmaceutical Products 
R&D, Inc.
Tel: 610-893-1074
Fax: 610-786-7061
Cell: 484-319-5807
Study Coordinating Investigators
Egilius L.H. Spierings, MD, PhD
Medical Director and Principal Investigator,
MedVadis Research Corporation
Watertown, MA 02472
Tel: 617-777-1310
Fax: 617-744-1285
Cell: 781-588-5430
Stephen Silberstein, MD
Director, Jefferson Headache Center, Dept. 
of Neurology
900 Walnut Street, 2nd floor, Suite #200
Philadelphia, PA 19107
Tel: 215-955-2727
Cell: 215-955-2243


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Sponsor’s Representative of Global Patient Safety and 
Pharmacovigilance
For serious adverse events:
Send by email to the local safety officer/contract research 
organization (LSO/CRO). The email address will be provided in the 
serious adverse event report form. In the event of difficulty 
transmitting the form, contact the sponsor’s study personnel 
identified above for further instruction.
Yoel Kessler, MD, MBA
Safety Physician
Director
Global Patient Safety & Pharmacovigilance 
Tel: +972 9 836 1265
Cell: + 972 54 944 5889
Contract Research Organization
ICON Clinical Research Services
123 Smith Street
Farmingdale, NY 11735
United States
Central Clinical Laboratory
ICON Clinical Research Services
123 Smith Street
Farmingdale, NY 11735
United States
Central Electrocardiogram Evaluation
Spaulding Clinical Research, LLC
525 S. Silverbrook Dr.
West Bend, Wisconsin 53095
Bioanalytical Pharmacokinetics and Immunogenicity Evaluation
Michele Rasamoelisolo, PhD
Director
PK/PD Bioanalytics, Global Bioassays and 
Technology
Teva Branded Pharmaceuticals R&D, Inc.
Tel: 610-738-6111
Email: 
Michele.Rasamoelisolo@tevapharm.com
Orit Cohen-Barak, PhD (pharmacokinetics 
evaluation)
Associate Director
Clinical Pharmacology
Teva Branded Pharmaceuticals R&D, Inc.
Tel: 972-9-892-1799
Email: Orit.Cohen-Barak@teva.co.il
Biomarker Evaluation
Conrad Cowan
Director, Translational Medicine
Teva Branded Pharmaceuticals R&D, Inc.
Tel: 610-883-5843
Cell: 484-484-8259
Email: Conrad.Cowan01@tevapharm.com
Electronic Clinical Outcome Assessment
Medidata Solutions Worldwide
350 Hudson Street
New York, NY 10014
eC-SSRS Scale
eResearch Technology, Inc
1818 Market Street #1000
Philadelphia, PA, 19103


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Web and Phone Integrated Interactive Response Technology
Medidata Solutions Worldwide
350 Hudson Street
New York, NY 10014


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


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Study Monitoring
To ensure compliance with GCP guidelines, the study monitor or representative is responsible 
for ensuring that patients have signed the informed consent form and the study is conducted 
according to applicable Standard Operating Procedures (SOPs), the protocol, and other written 
instructions and regulatory guidelines.
The study monitor is the primary association between the sponsor and the investigator. The main 
responsibilities of the study monitor(s) are to visit the investigator before, during, and after the 
study to ensure adherence to the protocol, that all data are correctly and completely recorded and 
reported, and that informed consent is obtained and recorded for all patients before they 
participate in the study and when changes to the consent form are warranted, in accordance with 
IEC/IRB approvals.
The study monitor(s) will contact the investigator and visit the investigational center according 
to the monitoring plan. The study monitor will be permitted to review and verify the various 
records (case report forms and other pertinent source data records, including specific electronic 
source document relating to the study) to verify adherence to the protocol and to ensure the 
completeness, consistency, and accuracy of the data being recorded.
As part of the supervision of study progress, other sponsor personnel may, on request, 
accompany the study monitor on visits to the investigational center. The investigator and 
assisting personnel must agree to cooperate with the study monitor to resolve any problems, 
errors, or possible misunderstandings concerning the findings detected during the course of these 
monitoring visits or provided in follow-up written communication.
Audit and Inspection
The sponsor may audit the investigational center to evaluate study conduct and compliance with 
protocols, SOPs, GCP guidelines, and applicable regulatory requirements. The sponsor’s Global 
Clinical Quality Assurance, independent of Global Specialty Development, is responsible for 
determining the need for (and timing of) an investigational center audit.
The investigator must accept that competent authorities and sponsor representatives may conduct 
inspections and audits to verify compliance with GCP guidelines.


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APPENDIX C. ETHICS
Informed Consent
The investigator, or a qualified person designated by the investigator, should fully inform the 
patient of all pertinent aspects of the study, including the written information approved by the 
Independent Ethics Committee (IEC)/Institutional Review Board (IRB). All written and oral 
information about the study will be provided in a language as nontechnical as practical to be 
understood by the patient. The patient should be given ample time and opportunity to inquire 
about details of the study and to decide whether or not to participate in the study. The above 
should be detailed in the source documents.
Written informed consent will be obtained from each patient before any study specific 
procedures or assessments are done and after the aims, methods, anticipated benefits, and 
potential hazards are explained. The patient’s willingness to participate in the study will be 
documented in the informed consent form, which will be signed and personally dated by the 
patient and by the person who conducted the informed consent discussion. The investigator will 
keep the original informed consent forms, and copies will be given to the patients. It will also be 
explained to the patients that the patient is free to refuse participation in the study and free to 
withdraw from the study or discontinue from IMP at any time without prejudice to future 
treatment.
Competent Authorities and Independent Ethics Committees/Institutional Review Boards
Before this study starts, the protocol will be submitted to the national competent authority and to 
the respective IEC/IRB for review. As required, the study will not start at a given investigational 
center before the IEC/IRB and competent authority (as applicable) for the investigational center 
give written approval or a favorable opinion.
Confidentiality Regarding Study Patients
The investigator must ensure that the privacy of the patients, including their identity and all 
personal medical information, will be maintained at all times. In case report forms (CRFs) and 
other documents or image material submitted to the sponsor, patients will be identified not by 
their names, but by an identification number.
Personal medical information may be reviewed for the purpose of patient safety or for verifying 
data in the source and the CRF. This review may be conducted by the study monitor, properly 
authorized persons on behalf of the sponsor, Global Quality Assurance, or competent authorities. 
Personal medical information will always be treated as confidential.
Registration of the Clinical Study
In compliance with national and local regulations and in accordance with Teva standard 
procedures, this clinical study will be registered on trials registry websites.


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APPENDIX D.
BIRTH CONTROL METHODS AND PREGNANCY 
TESTING
Assessment of likelihood of possible interaction between investigational medicinal product 
(IMP) or concomitant medications and hormonal contraception should be conducted. Hormonal 
contraception may be susceptible to interaction with the IMP, which may reduce the efficacy of 
the contraception method.
Drug interaction studies have not been conducted with fremanezumab. Like other therapeutic
antibodies, fremanezumab is expected to be metabolized primarily via proteolytic catabolism. 
Therefore, interaction with and impact on drug metabolizing enzymes (eg, cytochrome P-450 
[CYP] isoforms) is considered unlikely in humans.
In addition, fremanezumab is not expected to indirectly influence CYP enzymes. In general, 
protein products that are cytokine modulators have been reported to affect the metabolism or 
disposition of co-administered medication by altering CYP enzymes/transporters (FDA 2012). 
Fremanezumab is an immunoglobulin G2 isotype, which is directed against a non-immunologic 
and soluble (not cell-bound) target. Thus, the risk of cytokine release is considered to be low in 
the clinical setting. Furthermore, fremanezumab was tested for stimulation of pro-inflammatory 
cytokine release in human whole blood (Study 111320). Fremanezumab did no elicit significant 
cytokine release (tumor necrosis factor alpha, interleukin [IL]-6, interferon gamma, or IL-1β) in 
any donor, including at concentrations up to 100 μg/mL. As such, there is no reason to suspect 
that fremanezumab may influence CYP activity. 
Women/Girls of childbearing potential are defined as:

not surgically (documented hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy) or congenitally sterile

not postmenopausal
Postmenopausal women:

1 year postmenopausal (no menses for 12 months without an alternative medical 
cause plus an increased concentration of FSH of more than 35 U/L) in women not 
using hormonal contraception or hormonal replacement therapy
Description of different birth control methods
Highly effective birth control methods:
Highly effective birth control methods are methods that can achieve a failure rate of less than 1% 
per year when used consistently and correctly. Such methods include:

Combined estrogen and progestogen hormonal contraception (oral, intravaginal, 
transdermal) associated with inhibition of ovulation; these should be initiated at least 
1 cycle (for IMPs without suspected teratogenicity/genotoxicity) before the first dose 
of IMP.


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
Progestogen-only hormonal contraception (oral, injectable, implantable) associated 
with inhibition of ovulation; these should be initiated at least 1 cycle (for IMPs 
without suspected teratogenicity/genotoxicity) 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 he is the sole sexual partner and has received medical 
assessment of the surgical process.

Sexual abstinence is only considered a highly effective method if defined as 
refraining from heterosexual intercourse in the defined period. The reliability of 
sexual abstinence needs to be evaluated in relation to the duration of the clinical study 
and the preferred and usual lifestyle of the patient.

Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods), 
declaration of abstinence for the duration of a study, and withdrawal are not 
acceptable methods of contraception (according to Medicines and Healthcare 
Products Regulatory Agency).
Unacceptable birth control methods:
Periodic abstinence (calendar, symptothermal, and post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and lactational amenorrhea method are not acceptable methods of 
contraception. Female condom and male condom should not be used together.
Male contraception:
Male patients must always use a condom.
Vasectomy:
Use of contraceptive methods also applies to vasectomized men because of the risk associated 
with transfer of a drug via seminal fluid.
Contraception for female partners of male study participants:
Male study participants must use a condom if their female partners are of childbearing potential
until the end of relevant systemic exposure.
Pregnant female partners of male study participants:
Male study participants must use condoms during intercourse if their female partners are 
pregnant.


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


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APPENDIX F.
LIST OF PROHIBITED MEDICATIONS AND 
PROCEDURES AND ALLOWED MEDICATIONS WITH 
SPECIAL CONDITIONS
Prohibited Medications and Procedures
The following medications will be prohibited during this study:

analgesic medications containing opioids (including codeine) if used for more than 
15 days per month

a barbiturate if used for more than 15 days per month

calcitonin gene-related peptide (CGRP) antibody or any antibody to the CGRP 
receptor 

OnabotulinumtoxinA (eg, Botox, Dysport, Xeomin)

devices for headache prophylaxis

nerve block for head and/or neck
All patients will be questioned about concomitant medications at each study visit. 
Allowed Medications with Special Conditions
Patients will be allowed to take the following medications during the study only if they were 
started at least 2 months before screening. In that case, the dose regimen should be maintained 
with no modifications until visit 8. These medications should not be started before visit 8. 

atenolol, propranolol, metoprolol, nadolol, timolol, flunarizine, pizotifen, 
amitriptyline, venlafaxine, nortriptyline, duloxetine, topiramate, valproate, 
carbamazepine, fivalproate, candesartan, and lisinopril


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APPENDIX G. TOTAL BLOOD VOLUME
The total blood volume to be collected for each patient in this study is approximately 210 mL.
Total Blood Volumes
Type of samples
Volume per sample (mL)
Total number of samples
Total volume (mL)
Clinical laboratory tests 
and pregnancya
6
8
48
FSHb
3
1
3
Pharmacokinetics
4
7
28
ADAc
5
4
20
Biomarkersd
18.5
6
111
Total
--
26
210
a A serum pregnancy test will be performed for women of childbearing potential only.
b Postmenopausal women only.
c A blood sample for ADA assessment will be collected prior to dosing at each applicable visit and will also be 
collected upon observation of severe hypersensitivity or anaphylaxis or if there is a suspected causal relationship 
of an AE potentially being related to immunogenicity (eg, lack of efficacy).
d Each 18.5 mL sample will be divided into 3 samples: 6 mL each for serum and plasma and 6.5 mL for RNA.
ADA=anti-drug antibody; AE=adverse event; FSH=follicle-stimulating hormone.


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APPENDIX H. DETAILED DESCRIPTION OF ASSESSMENTS AND 
PROCEDURES 
1. Procedures for Screening (Visit 1, Day -28 to -1 [+3 days])
The screening visit (visit 1) will take place 28 days before the randomization visit (visit 2). 
The following procedures will be performed at visit 1:

Obtain written informed consent before any study-related procedures are performed.

Review inclusion and exclusion criteria.

Obtain medical and psychiatric history.

Obtain prior medication and treatment history.

Record demographic characteristics.

Perform clinical laboratory tests (serum chemistry, hematology and coagulation, and 
urinalysis).

Perform a full physical examination (including height and weight).

Perform 12-lead electrocardiogram (ECG) in triplicate.

Perform vital signs measurements (systolic and diastolic blood pressure, pulse, and 
body temperature).

Perform beta-human chorionic gonadotropin (β-HCG) serum pregnancy test (for 
women of childbearing potential).

Perform serum FSH test (for postmenopausal women).

Inform patients of study restrictions and compliance requirements.

Complete electronic headache diary. (Note: This will be completed by the patient 
daily at home during the baseline period.)

Complete the 2-item Patient Health Questionnaire (PHQ-2)/9-item Patient Health 
Questionnaire (PHQ-9).

Complete the Columbia Suicide Severity Rating Scale (C-SSRS) Baseline/Screening 
version.

Inquire about adverse events

Inquire about concomitant medications.
1. Procedures Before Administration of Investigational Medicinal Product (Baseline 
[Visit 2, Day 0±3 days])
Patients who meet the inclusion and exclusion criteria at visit 1 will continue to visit 2, when 
baseline assessments will be conducted.
The following procedures will be performed predose at visit 2:


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
Review inclusion and exclusion criteria.

Assign randomization/treatment number.

Perform clinical laboratory tests (serum chemistry, hematology and coagulation, and 
urinalysis).

Perform a full physical examination (including weight).

Perform 12-lead ECG in triplicate.

Perform vital signs measurements (systolic and diastolic blood pressure, pulse, and 
body temperature).

Perform a urine pregnancy test for women of childbearing potential.

Review study compliance.

Complete and review electronic headache diary. 

Obtain a 4 mL blood sample for plasma concentration of investigational medicinal 
product (IMP).

Obtain a 5 mL blood sample for serum anti-drug antibodies (ADAs) assay.

Obtain an 18.5 mL blood sample and a urine sample for biomarkers analysis.

Collect a 1 mL saliva sample for biomarker analysis.

Inquire about adverse events.

Complete the 6-item Headache Impact Test (HIT-6) questionnaire.

Complete the 12-item Short-Form Health Survey (SF-12) questionnaire.

Complete the Sport Concussion Assessment Tool 3rd edition (SCAT-3) 
questionnaire.

Complete the Patient Global Impression of Change (PGIC) questionnaire.

Complete the C-SSRS Since Last Visit version.

Inquire about concomitant medications.
Patients who meet eligibility criteria will be randomized to 1 of 3 treatment groups.
2. Procedures During Administration of Investigational Medicinal Product 
(Double-Blind Treatment Period [Visits 2 through 4, Days 0 through 84±3 days])
Eligible patients will complete entries of posttraumatic headache information (presence, severity, 
and duration) daily from visit 2 through visit 5. See Section 6.1 of the protocol for additional 
details. 
Visit 2 (Day 0±3 days)
The following procedures and assessments will be performed at visit 2 following predose 
assessments:

Administer IMP.


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
Perform injection site assessments immediately (+10 minutes) and 1 hour 
(±15 minutes) after completing IMP administration. Additional injection site 
assessments may be performed based on the severity of any observed injection site 
reaction and/or injection site pain. See Section 7.9 of the protocol for additional 
details. 

Evaluate for anaphylaxis or hypersensitivity reaction.

Inquire about postdose adverse events before the patient leaves the investigational 
center.
Visit 3 (Day 28±3 days)
The following procedures and assessments will be performed predose at visit 3:

Perform clinical laboratory tests (serum chemistry, hematology and coagulation, and 
urinalysis).

Perform 12-lead ECG in triplicate.

Perform vital signs measurements (systolic and diastolic blood pressure, pulse, and 
body temperature).

Perform a urine pregnancy test for women of childbearing potential.

Review study compliance.

Complete and review electronic headache diary.

Obtain a 4 mL blood sample for plasma concentration of IMP.

Obtain a 5 mL blood sample for serum ADA assay.

Collect a 1 mL saliva sample for biomarker analysis.

Inquire about adverse events. 

Complete the PGIC and C-SSRS Since Last Visit version questionnaires.
The following procedures and assessments will be performed at visit 3 following predose 
procedures and assessments:

Administer IMP.

Perform injection site assessments immediately (+10 minutes) and 1 hour 
(±15 minutes) after completing IMP administration. Additional injection site 
assessments may be performed based on the severity of any observed injection site 
reaction and/or injection site pain. See Section 7.9 of the protocol for additional 
details. 

Evaluate for anaphylaxis or hypersensitivity reactions. 

Inquire about concomitant medication. 

Inquire about postdose adverse events before the patient leaves the investigational 
center.


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Visit 4 (Day 56±3 days)
The following procedures and assessments will be performed predose at visit 4:

Perform clinical laboratory tests (serum chemistry, hematology and coagulation, and 
urinalysis).

Perform 12-lead ECG in triplicate.

Perform vital signs measurements (systolic and diastolic blood pressure, pulse, and 
body temperature).

Perform a urine pregnancy test for women of childbearing potential.

Review study compliance.

Complete and review electronic headache diary.

Obtain a 4 mL blood sample for plasma concentration of IMP.

Obtain an 18.5 mL blood sample and a urine sample for biomarkers analysis.

Collect a 1 mL saliva sample for biomarker analysis.

Inquire about adverse events. 

Complete the PGIC and C-SSRS Since Last Visit version questionnaires.
The following procedures and assessments will be performed at visit 4 following predose 
procedures and assessments:

Administer IMP.

Perform injection site assessments immediately (+10 minutes) and 1 hour (±15 
minutes) after completing IMP administration. Additional injection site assessments 
may be performed based on the severity of any observed injection site reaction and/or 
injection site pain. See Section 7.9 of the protocol for additional details. 

Evaluate for anaphylaxis or hypersensitivity reactions. 

Inquire about concomitant medication.

Inquire about postdose adverse events before the patient leaves the investigational 
center.
3. Procedures During Administration of Investigational Medicinal Product
(Open-Label Treatment Period [Visits 5 through 7, Days 84±3 through 140±3])
Visit 5, Day 84±3 days
The following procedures and assessments will be performed predose at visit 5:

Perform clinical laboratory tests (serum chemistry, hematology and coagulation, and 
urinalysis).

Perform a full physical examination (including weight).

Perform 12-lead ECG in triplicate.


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
Perform vital signs measurements (systolic and diastolic blood pressure, pulse, and 
body temperature).

Perform a serum β-HCG test for women of childbearing potential.

Review study compliance.

Complete and review electronic headache diary.

Obtain a 4 mL blood sample for plasma concentration of IMP.

Obtain a 5 mL blood sample for serum ADA assay.

Obtain an 18.5 mL blood sample and a urine sample for biomarkers analysis.

Collect a 1 mL saliva sample for biomarker analysis.

Inquire about adverse events. 

Complete HIT-6, SF-12, SCAT-3, PGIC, and C-SSRS Since Last Visit version 
questionnaires.
The following procedures and assessments will be performed at visit 5 following predose 
procedures and assessments:

Administer IMP.

Perform injection site assessments immediately (+10 minutes) and 1 hour 
(±15 minutes) after completing IMP administration. Additional injection site 
assessments may be performed based on the severity of any observed injection site 
reaction and/or injection site pain. See Section 7.9 of the protocol for additional 
details. 

Evaluate for anaphylaxis or hypersensitivity reactions. 

Inquire about concomitant medication.

Inquire about postdose adverse events before the patient leaves the investigational 
center.

Complete the Special Protocol Headache questionnaire. (to be completed at visit 5 
and as the last study procedure at visit 8.) 
Visit 6, Day 112±3 days 
The following procedures and assessments will be performed predose at visit 6:

Perform clinical laboratory tests (serum chemistry, hematology and coagulation, and 
urinalysis).

Perform 12-lead ECG in triplicate.

Perform vital signs measurements (systolic and diastolic blood pressure, pulse, and 
body temperature).

Obtain a 4 mL blood sample for plasma concentration of IMP.

Obtain an 18.5 mL blood sample for biomarker analysis.


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
Collect a 1 mL saliva sample for biomarker analysis.

Inquire about adverse events. 

Complete the HIT-6, SF-12, PGIC and C-SSRS Since Last Visit version 
questionnaires.
The following procedures and assessments will be performed at visit 6 following predose 
procedures and assessments:

Administer IMP.

Perform injection site assessments immediately (+10 minutes) and 1 hour 
(±15 minutes) after completing IMP administration. Additional injection site 
assessments may be performed based on the severity of any observed injection site 
reaction and/or injection site pain. See Section 7.9 of the protocol for additional 
details. 

Evaluate for anaphylaxis or hypersensitivity reactions. 

Inquire about concomitant medication.

Inquire about postdose adverse events before the patient leaves the investigational 
center.
Visit 7, Day 140±3 days 
The following procedures and assessments will be performed predose at visit 7:

Perform clinical laboratory tests (serum chemistry, hematology and coagulation, and 
urinalysis).

Perform 12-lead ECG in triplicate.

Perform vital signs measurements (systolic and diastolic blood pressure, pulse, and 
body temperature).

Obtain a 4 mL blood sample for plasma concentration of IMP.

Obtain an 18.5 mL blood sample for biomarker analysis. 

Collect a 1 mL saliva sample for biomarker analysis.

Inquire about adverse events. 

Complete the HIT-6, SF-12, PGIC and C-SSRS Since Last Visit version 
questionnaires.
The following procedures and assessments will be performed at visit 7 following predose 
procedures and assessments:

Administer IMP.

Perform injection site assessments immediately (+10 minutes) and 1 hour 
(±15 minutes) after completing IMP administration. Additional injection site 
assessments may be performed based on the severity of any observed injection site 


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reaction and/or injection site pain. See Section 7.9 of the protocol for additional 
details. 

Evaluate for anaphylaxis or hypersensitivity reactions. 

Inquire about concomitant medication.

Inquire about postdose adverse events before the patient leaves the investigational 
center.
Final Visit (End-of-Treatment/Early Termination/End-of-Study [Visit 8, Day 168±3 
days])
The following procedures and assessments will be performed at the final visit 8:

Perform clinical laboratory tests (serum chemistry, hematology and coagulation, and 
urinalysis).

Perform 12-lead ECG in triplicate.

Perform vital signs measurements (systolic and diastolic blood pressure, pulse, and 
body temperature).

Perform beta-human chorionic gonadotropin (β-HCG) serum pregnancy test (for 
women of childbearing potential).

Perform a urine pregnancy test for women of childbearing potential.

Obtain a 4 mL blood sample for plasma concentration of IMP.

Obtain an 18.5 mL blood sample and a urine sample for biomarkers analysis.

Obtain a 5 mL blood sample for serum ADA assay.

Collect a 1 mL saliva sample for biomarker analysis.

Inquire about adverse events. 

Complete the C-SSRS Since Last Visit version questionnaire.

Complete HIT-6, PHQ-2/PHQ-9, SF-12, SCAT-3, PGIC, and Special Protocol 
Headache Questionnaire. 

Inquire about concomitant medications.
4. Unscheduled Visits
An unscheduled visit may be performed at any time during the study at the patient’s request 
and as deemed necessary by the investigator. The date and reason for the unscheduled visit 
will be recorded on the case report form, as well as any other data obtained from procedures 
and assessments.
Procedures performed during unscheduled visits include:

Review electronic diary data.

Review study compliance.


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
Perform vital signs measurements (including systolic and diastolic blood pressure, 
pulse, and body temperature).

Inquire about adverse events.

Inquire about concomitant medications

Complete the C-SSRS Since Last Visit version.
Other procedures and assessments may be performed at the discretion of the investigator.


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APPENDIX I.
GUIDANCE ON SAFETY MONITORING
Guidance on Monitoring Patients with Elevated Liver Function Tests
Liver enzymes (alanine aminotransferase [ALT], aspartate aminotransferase [AST], 
gamma-glutamyl transpeptidase [GGT], and alkaline phosphatase [ALP]), as well as total, direct, 
and indirect bilirubin, will be measured at each study visit.
In any case of elevated ALT or AST to a level exceeding ≥2× the upper limit of normal (ULN) 
(including subjects whose baseline ALT or AST levels are ≥2× and ≤3× the ULN, who may be 
enrolled in the study), a thorough medical history and physical examination with a focus on liver 
disease should be undertaken1. In addition, the subject should be instructed to refrain from 
alcoholic beverages.
In case of symptoms compatible with drug-induced liver injury during the study, subjects will be 
instructed to return to the study center for an unscheduled visit or to go to the emergency room to 
measure liver enzymes as soon as possible. Solitary elevations of total, direct, or indirect 
bilirubin not accompanied by elevations of ALT or AST should be managed according to the 
discretion of the treating physician.
Elevation of Either ALT or AST to ≥3× ULN
Confirmation is required prior to study drug discontinuation in cases of elevation of either ALT 
or AST ≥3× ULN. (Note: In cases of elevation of ALT or AST ≥8× the ULN, no confirmation is 
required prior to study drug discontinuation, but the assessments below should be performed.) 
The following procedures should be followed:

The day in which the abnormal value is received from the laboratory will be 
considered as day 0.

The investigator should repeat the test for confirmation purposes (this may be 
performed in a local laboratory along with complete blood count [CBC] and 
differential to assess for eosinophilia; in general, in case a blood sample is sent to a 
local laboratory, the following assessments [and reference ranges] are mandatory: 
ALT [serum glutamic pyruvic transaminase], AST [serum glutamic oxaloacetic 
transaminase], ALP, bilirubin [total, direct, and indirect], CBC [with differential for 
eosinophil count, separate tube], and international normalized ratio (INR) [separate 
tube; not to be sent in a confirmatory test]). The investigator should also question the 
subject regarding symptoms.
                                                
1 Thorough medical history with a focus on liver disease: personal or family history of liver disease; personal history 
of a systemic disease with potential liver involvement; exposure to alcohol, medications (prescription or over the 
counter), herbal preparations, dietary supplements, recreational drugs, special diets, or environmental chemical 
agents; potential exposure to infectious agents (eg, travel to developing countries, history of potential exposure to 
blood or blood products, high-risk sexual relations); and any additional information deemed relevant by the 
investigator. Physical examination, including signs of chronic liver disease.


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The 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 case report form (CRF):

Serology for hepatitis A (antibody and immunoglobulins M and G), B (core antibody 
total, core immunoglobulin M, and surface antigen), and C viruses (central 
laboratory).

Serology for autoimmune hepatitis: anti-nuclear antibodies (titer), anti-smooth muscle 
antibodies, and anti-liver kidney microsomal antibodies (central laboratory); further 
testing may be required in case of a positive result for hepatitis B or C.

Ultrasound examination of the liver and biliary tract at the investigator’s discretion.

Other diagnostic tests/consultations as deemed necessary by the investigator 
(eg, serology for hepatitis E virus in case of travel to endemic geography).

Observation and follow-up (to be performed after the abnormality was confirmed as 
above).
ALT or AST ≥3× (>3.5× the ULN if the Baseline Value is >2.5× the ULN) but <5× the ULN
In addition to the above procedures required for any elevation to levels >3× the ULN:

ALT, AST, GGT, ALP, total bilirubin, direct bilirubin, indirect bilirubin, CBC and 
differential (to assess for eosinophilia), and INR should be monitored on days 5 
(±2 days), 8 (±2 days), 14 (±3 days), and 28 (±3 days). On at least one 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 subject will be followed according to the investigator’s discretion, 
but a blood sample for ALT; AST; GGT; ALP; and total, direct, and indirect bilirubin 
should be sent to the central laboratory at least once a month.
ALT or AST ≥5× but <8× the ULN
In addition to the above procedures required for any elevation to levels >3× the ULN:

ALT, AST, GGT, ALP, total bilirubin, direct bilirubin, indirect bilirubin, CBC and 
differential count (to assess for eosinophilia), and INR should be monitored twice a 
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
At least for every other measurement, the tests should be sent to the central 
laboratory. The rest of the tests may be sent to a local laboratory. The INR should 
always be sent to a local laboratory.
ALT or AST ≥8× the ULN
In addition to the above procedures required for any elevation to levels >3× the ULN:

The study drug should be discontinued immediately, and the early withdrawal visit 
should be performed.

For follow-up guidance, please see below section “Follow-Up of Liver Enzymes 
After Stopping Rules Are Met.”
Stopping Rules
In the following circumstances, the study drug will be discontinued immediately:

Any increase in ALT or AST to ≥3× the ULN, combined with INR >1.5× the ULN or 
total bilirubin >2× the ULN

Any increase in ALT or AST to ≥3× the ULN, which is accompanied by symptoms 
clearly associated with impaired liver function (eg, vomiting, nausea, fever, rash, and 
eosinophilia) and not deemed related to other diseases (eg, vomiting or nausea 
triggered by cluster headache)

Any increase in ALT or AST to levels ≥5 but <8× the ULN, which is persistent for 
≥2 weeks of repeated measurements

Any increase in ALT or AST to levels ≥8× the ULN

In any case where monitoring of liver enzymes cannot be performed according to the 
protocol guidance
Follow-Up of Liver Enzymes After Stopping Rules Are Met

Early withdrawal visit activities should be performed as soon as possible.

Liver enzymes should be monitored until normalization or stabilization of the 
abnormality, according to the discretion of the investigator.

In any case, following the early withdrawal visit, the minimal follow-up period will 
be 30 days and will include measurement of liver enzymes at least once weekly (may 
be performed in local laboratory, with at least 1 test being sent to the central 
laboratory).

Every effort should be made to complete the additional tests/evaluations, as described 
above.


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APPENDIX J.
CLINICAL CRITERIA FOR DIAGNOSING 
ANAPHYLAXIS
As detailed by Sampson et al 20062, anaphylaxis is broadly defined as “a serious allergic reaction 
that is rapid in onset and may cause death.” Diagnostic criteria defined by the National Institute 
of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network during the second 
symposium on the definition and management of anaphylaxis, modified from Sampson el al 
2006, are as follows: 
Anaphylaxis is highly likely when any of the following 3 criteria is fulfilled:
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (eg, generalized hives, pruritus or flushing, swollen 
lips-tongue-uvula) and at least one of the following:
a.
respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced peak 
expiratory flow, hypoxemia)
b. reduced blood pressure or associated symptoms of end-organ dysfunction 
(eg, hypotonia [collapse], syncope, incontinence)
2. Two or more of the following that occur rapidly after exposure to a likely allergen for 
that patient (minutes to several hours):
a.
involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, swollen 
lips-tongue-uvula)
b. respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced peak 
expiratory flow, hypoxemia)
c.
reduced blood pressure or associated symptoms (eg, hypotonia [collapse], syncope, 
incontinence)
d. persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting)
3. Reduced blood pressure after exposure to known allergen for that patient (minutes to 
several hours):
a.
adult: systolic blood pressure <90 mm Hg or >30% decrease from that person’s 
baseline
In the event of suspected anaphylaxis or severe hypersensitivity, vital signs, including oxygen 
saturation and respiration rate, will be measured. Other assessments will be performed at the 
discretion of the investigator. As a precaution, each investigational center should have a 
resuscitation cart nearby. 
                                                
2 Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF, Jr, Bock SA, Branum A, et al. Second symposium 
on the definition and management of anaphylaxis: summary report-Second National Institute of Allergy and 
Infectious Disease/Food Allergy and Anaphylaxis Network Symposium. J Allergy Clin Immunol 2006;117(2):391-
7.


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APPENDIX K. CLINICAL LABORATORY TESTS
Clinical Laboratory Tests
Serum chemistry
Hematology and coagulation
Urinalysis
Calcium
Phosphate
Sodium
Potassium
Chloride
Creatinine
Glucose
Blood urea nitrogen (BUN)
Low density lipoprotein (LDL)
High density lipoprotein (HDL)
Triglycerides
Urate
Alanine aminotransferase (ALT)
Aspartate aminotransferase (AST)
Lactate dehydrogenase (LDH)
Gamma-glutamyl transpeptidase (GGT)
Alkaline phosphatase
Bicarbonate
Carbon dioxide
Protein
Albumin
Bilirubin
Direct bilirubin
Indirect bilirubin
Hemoglobin
Hematocrit
Erythrocytes
Platelets
Leucocytes
Neutrophils
Lymphocytes
Eosinophils
Monocytes
Basophils
Lymphocytes atypical
Prothrombin International Normalized 
Ratio (INR)
Color and appearance
Protein
Glucose
Albumin
Ketones
Leukocyte esterase
Nitrite
Bilirubin
Hemoglobin
pH
Specific gravity
Microscopic tests
Bacteria
Erythrocytes
Leucocytes
Crystals
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APPENDIX L. PHARMACOKINETICS SAMPLES
Specimen Sampling and Handling
For plasma collection, samples will be collected in anticoagulant tubes, inverted slowly 
6 to 8 times to mix the contents, and placed on water/ice (approximately 4°C). Blood samples 
will be centrifuged (1500 g, approximately 10 minutes, at 2 to 8°C) between 5 minutes and 
1 hour after sampling. If a refrigerated centrifuge is not available, samples should be chilled 
before centrifugation. Other measures should be taken as appropriate to prevent samples from 
heating significantly during centrifugation. Separated plasma will be transferred in 
approximately equal portions in 2 labeled, polypropylene tubes (Sets A and B).
Labels for samples should include study number, patient randomization number, nominal 
collection time (visit number), Set A or B, and indication that they are pharmacokinetic samples. 
Samples will be stored at a temperature of -70 ±20°C in an upright position until they are 
shipped to the central laboratory.
Shipment and Analysis of Samples
Plasma samples for all patients will be shipped from the investigational center to the central 
laboratory where they will be stored until shipped to the sponsor or designee for analysis. 
Samples will be stored in an upright position at –70ºC until assayed. The central laboratory will 
be notified before the shipment of the samples and will be sent the shipping information when 
the samples are shipped. An electronic file containing sample demographics will be emailed to 
the bioanalytical laboratory and the sponsor’s representatives from bioanalytical departments for 
each shipment.
Set A samples will be transported frozen with dry ice sufficient for 4 days, by next-day courier to 
the central laboratory.
Set B samples will be sent either to the same laboratory as that for Set A samples on a 
subsequent day by next-day courier or be retained at the investigational center until the study is 
completed and the clinical study report has been issued (unless shipment to another facility is 
requested by the sponsor). Instructions as to the disposition of the Set B samples will be provided 
by the sponsor.
Sample shipments should be sent no later in the week than Wednesday morning for next-day 
delivery. Samples are not to arrive on the weekend.
Samples will be analyzed using an appropriate validated method. Timing of the initiation of 
sample analysis will be determined by the sponsor’s representatives of bioanalytical departments 
responsible for the bioanalysis while keeping the study blinding, if any, intact.


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APPENDIX M. IMMUNOGENICITY SAMPLES
Blood Sampling and Handling 
For serum collection, samples will be collected in Vacutainer tubes containing no anticoagulant 
and allowed to set at room temperature for between 1 and 1.5 hours to allow for serum separation 
to occur. Samples will then be centrifuged (1500 g, approximately 10 minutes, at 2 to 8°C). If a 
refrigerated centrifuge is not available, samples should be chilled before centrifugation. Other 
measures should be taken as appropriate to prevent samples from heating significantly during 
centrifugation. Separated serum will be transferred in approximately equal portions in 2 labeled 
polypropylene tubes (Sets A and B).
Label of samples should include study number, patient randomization number, nominal 
collection time (visit number), Set A or B, and indication that they are anti-drug antibody 
samples. Serum samples will be stored at a temperature of -70 ±20°C in an upright position until 
they are shipped to the central laboratory.
Shipment and Analysis of Samples
Serum samples for all patients will be shipped from the investigational center to the central 
laboratory where they will be stored until shipped to the sponsor or designee for analysis. 
Samples will be stored in an upright position at –70ºC until analysis. The central laboratory will 
be notified before the shipment of the samples and will be sent the shipping information when 
the samples are shipped. An electronic file containing sample demographics will be emailed to 
the central laboratory for each shipment. The same will be copied to the sponsor’s 
representatives of bioanalytical departments responsible for the bioanalysis.
Set A samples will be transported frozen with dry ice sufficient for 4 days, by next-day courier to 
the central laboratory.
Set B samples will be sent either to the same laboratory as that for Set A on a subsequent day by 
next-day courier, or be retained at the investigational center until the study is completed and the 
clinical study report has been issued (unless shipment to another facility is requested by the 
sponsor). Instructions as to the disposition of the Set B samples will be provided by the sponsor.
Sample shipments should be sent no later in the week than Wednesday morning for next-day 
delivery. Samples are not to arrive on the weekend.
Samples will be analyzed using an appropriate validated method. Timing of the initiation of 
sample analysis will be determined by the sponsor’s representatives of bioanalytical departments 
responsible for the bioanalysis while keeping the study blinding, if any, intact.


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APPENDIX O. PRODUCT COMPLAINTS
Clinical Product Complaints
A clinical product complaint is defined as a problem or potential problem with the physical 
quality or characteristics of clinical investigational medicinal product (IMP) supplies or clinical 
device supplies used in a clinical research study sponsored by Teva. Examples of a product 
complaint include, but are not limited to:

suspected contamination

questionable stability (eg, color change, flaking, crumbling, etc)

defective components

missing or extra units (eg, primary container is received at the investigational center 
with more or less than the designated number of units inside)

incorrect packaging or incorrect or missing labeling/labels

unexpected or unanticipated taste or odor, or both

device not working correctly or appears defective in some manner
Each investigational center will be responsible for reporting a possible clinical product complaint 
by completing the product complaint form provided by Teva and emailing it to 
clinical.productcomplaints@tevapharm.com within 48 hours of becoming aware of the issue.
For complaints involving a device or other retrievable item, it is required that the device (or 
item) be sent back to the sponsor for investigative testing whenever possible. For complaints 
involving an IMP, all relevant samples (eg, the remainder of the patient’s IMP supply) should be 
sent back to the sponsor for investigative testing whenever possible.
1. Product Complaint Information Needed from the Investigational Center
In the event that the product complaint form cannot be completed, the investigator will provide 
the following information, as available:

investigational center number and principal investigator name

name, phone number, and address of the source of the complaint

clinical protocol number

patient identifier (patient study number) and corresponding visit numbers, if 
applicable

product name and strength for open-label studies

patient number, bottle, and kit numbers (if applicable) for double-blind or open-label 
studies

product available for return (yes/no)

product was taken or used according to protocol (yes/no)


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
description or nature of complaint

associated serious adverse event (yes/no)

clinical supplies unblinded (for blinded studies) (yes/no)

date and name of person receiving the complaint
Note: Reporting a product complaint must not be delayed even if not all the required information 
can be obtained immediately. Known information must be reported immediately. The sponsor 
will collaborate with the investigator to obtain any outstanding information.
2. Handling of Investigational Medicinal Product(s) at the Investigational Center(s)
The investigator is responsible for retaining the product in question in a location separate from 
the investigator’s clinical study supplies. The sponsor may request that the investigator return the 
product for further evaluation and/or analysis. If this is necessary, the clinical study monitor or 
designee will provide the information needed for returning the IMP.
If it is determined that the investigational center must return all IMP, the sponsor will provide the 
information needed to handle the return.
The integrity of the randomization code and corresponding blinded clinical supplies will be 
maintained whenever possible. A serious adverse event or the potential for a product quality 
problem existing beyond the scope of the complaint may be a reason to unblind the clinical 
supplies for an affected patient.
3. Adverse Events or Serious Adverse Events Associated with a Product Complaint
If there is an adverse event or serious adverse event due to product complaint, the protocol 
should be followed for recording and reporting (Section 7.1.2 and Section 7.1.5.3 of the protocol, 
respectively).
4. Documenting a Product Complaint
The investigator will record in the source documentation a description of the product complaint 
and any actions taken to resolve the complaint and to preserve the safety of the patient. Once the 
complaint has been investigated by the sponsor and the investigator, if necessary, an event 
closure letter may be sent to the investigational center where the complaint originated or to all 
investigational centers using the product.
Medical device incidents, including those resulting from malfunctions of the device, must be 
detected, documented, and reported by the investigator throughout the study.


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APPENDIX P.
DATA MANAGEMENT AND RECORD KEEPING
Direct Access to Source Data and Documents
All patient data must have supportive original source documentation in the medical records, or 
equivalent, before they are transcribed to the case report form (CRF). Data may not be recorded 
directly on the CRF and considered as source data unless the sponsor provides written 
instructions specifying which data are permitted to be recorded directly to the CRF.
The medical experts, study monitors, auditors, Independent Ethics Committee (IEC)/Institutional 
Review Board (IRB), and inspectors from competent authority (or their agents) will be given 
direct access to source data and documents (eg, medical charts/records, laboratory test results, 
printouts, videotapes) for source data verification, provided that patient confidentiality is 
maintained in accordance with national and local requirements.
The investigator must maintain the original records (ie, source documents) of each patient’s data 
at all times. The investigator must maintain a confidential patient identification list that allows 
the unambiguous identification of each patient.
Data Collection
Data will be collected using CRFs that are specifically designed for this study. The data collected 
on the CRFs will be captured in a clinical data management system (CDMS) that meets the 
technical requirements described in 21CFR Part 11 (USA) and documents of other concerned 
competent authorities. Before using the CDMS, it will be fully validated and all users will 
receive training on the system and study-specific training. After they are trained, users will be 
provided with individual system access rights.
Data will be collected at the investigational center by appropriately designated and trained 
personnel, and CRFs must be completed for each patient who provided informed consent. Patient 
identity should not be discernible from the data provided on the CRF.
If data are processed from other sources (eg, central laboratory, bioanalytical laboratory, central 
image center, electronic diary data, electronic patient-reported outcome tablet), these data will be 
sent to the investigational center, where they will be retained but not transcribed to the CRF, 
unless otherwise noted in the protocol. These data may also be sent electronically to the sponsor 
(or organization performing data management). All patient data must have supportive original 
source documentation in the medical records, or equivalent, before they are transcribed to the 
CRF. Data may not be recorded directly on the CRF and considered as source data unless the 
sponsor provides written instructions specifying which data are permitted to be recorded directly 
to the CRF.
For patients who enter a study but do not meet entry criteria, at a minimum, data for screening 
failure reason, demography, and adverse events from the time of informed consent will be 
entered in the CRF.
Data Quality Control
Data Management is responsible for the accuracy, quality, completeness, and internal 
consistency of the data from this study. Oversight will be carried out as described in the 
sponsor’s SOPs for clinical studies. Day-to-day data management tasks for this study are 


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delegated to a contract organization, and these functions may be carried out as described in the 
SOPs for clinical studies at that organization. These SOPs will be reviewed by the sponsor before 
the start of data management activities.
Data will be verified by the study monitor using the data source and reviewed by Data 
Management using both automated logical checks and manual review. Data identified as 
erroneous or data that are missing will be referred to the investigational center for resolution 
through data queries. Any necessary changes will be made in the clinical database, and data 
review and validation procedures will be repeated as needed. Data from external sources will be 
compared with the information available in the CDMS, and any discrepancies will be queried.
Applicable terms will be coded according to the coding conventions for this study.
A final database lock will occur following the end-of-treatment visit (visit 8) of the last patient. 
At the conclusion of the study, the CDMS and all other study data will be locked to further 
additions or corrections. Locking the study data represents the acknowledgement that all data 
have been captured and confirmed as accurate. All data collected will be approved by the 
investigator at the investigational center. This approval acknowledges the investigator’s review 
and acceptance of the data as being complete and accurate.
Archiving of Case Report Forms and Source Documents
Sponsor Responsibilities
The original CRFs will be archived by the sponsor. Investigational center-specific CRFs will be 
provided to the respective investigational centers for archiving.
Investigator Responsibilities
The investigator must maintain all written and electronic records, accounts, notes, reports, and 
data related to the study and any additional records required to be maintained under country, 
state/province, or national and local laws, including, but not limited to:

full case histories

signed informed consent forms

patient identification lists

case report forms for each patient on a per-visit basis

data from other sources (eg, central laboratory, bioanalytical laboratory, central image 
center, electronic diary)

safety reports

financial disclosure reports/forms

reports of receipt, use, and disposition of the investigational medicinal products

copies of all correspondence with sponsor, the IEC/IRB, and any competent authority
The investigator will retain all records related to the study and any additional records required, as 
indicated by the protocol and according to applicable laws and regulations, until the contract 
research organization or sponsor notifies the institution in writing that records may be destroyed. 
If, after 25 years from study completion, or earlier in the case of the investigational center 


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closing or going out of business, the investigator reasonably determines that study record 
retention has become unduly burdensome, and sponsor has not provided written notification of 
destruction, then the investigator may submit a written request to sponsor at least 60 days before 
any planned disposition of study records. After receipt of such request, the sponsor may make
arrangements for appropriate archival or disposition, including requiring that the investigator 
deliver such records to the sponsor. The investigator shall notify the sponsor of any accidental 
loss or destruction of study records.


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APPENDIX Q. PUBLICATION POLICY
All unpublished information given to the investigator by the sponsor shall not be published or 
disclosed to a third party without the prior written consent of the sponsor.
The results of this study may be published or presented at scientific meetings. If this is foreseen, 
the investigator agrees to submit all manuscripts or abstracts to the sponsor before submission. 
This allows the sponsor to protect proprietary information and to provide comments.
The sponsor will comply with the requirements for publication of study results: 
“Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly Work in 
Medical Journals” (www.ICMJE.org). Publication of the results will occur in a timely manner 
according to applicable regulations. In accordance with standard editorial and ethical practice, 
the sponsor will generally support publication of multicenter studies only in their entirety and not 
as individual investigational center data. In this case, a coordinating investigator will be 
designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International Committee of 
Medical Journal Editors authorship requirements:

substantial contributions to the conception or design of the work; or the acquisition, 
analysis, or interpretation of data for the work

drafting the work or revising it critically for important intellectual content

final approval of the version to be published

agreement to be accountable for all aspects of the work in ensuring that questions 
related to the accuracy or integrity of any part of the work are appropriately 
investigated and resolved
The publications committee established by the sponsor will oversee this process. Additional 
publications may follow. Policies regarding the publication of the study results are defined in the 
financial agreement.
No patent applications based on the results of the study may be made by the investigator nor may 
assistance be given to any third party to make such an application without the written 
authorization of the sponsor.

SAP_001.pdf: 
 
 
 
 
Statistical Analysis Plan 
 
 
A Phase 2, Multicenter, Randomized, Proof-of-Concept, Double-Blind, Placebo-
Controlled, Parallel-Group Study, Including an Open-Label Period, Evaluating the 
Efficacy and Safety of 1 Subcutaneous Dose Regimen of Fremanezumab for the 
Treatment of Posttraumatic Headache (PTH) 
 
 
Study Number TV48125-CNS-20024 
 
 
NCT03347188 
 
 
SAP Approval Date: 06 April 2020 


 
 
 
 
Statistical Analysis Plan 
 
 
A Phase 2, Multicenter, Randomized, Proof-of-Concept, Double-Blind, Placebo-
Controlled, Parallel-Group Study, Including an Open-Label Period, Evaluating the 
Efficacy and Safety of 1 Subcutaneous Dose Regimen of Fremanezumab for the 
Treatment of Posttraumatic Headache (PTH) 
 
 
Study Number TV48125-CNS-20024 
 
 
NCT03347188 
 
 
SAP Approval Date: 06 April 2020 


Placebo-Controlled Study–PTH
Statistical Analysis Plan
Study TV48125-CNS-20024
1
pfmmef6f TITL
TITLE PAGE
Statistical Analysis Plan
Study TV48125-CNS-20024
A Phase 2, Multicenter, Randomized, Proof-of-Concept, Double-Blind, Placebo-Controlled, 
Parallel-Group Study, Including an Open-Label Period, Evaluating the Efficacy and Safety 
of 1 Subcutaneous Dose Regimen of Fremanezumab for the Treatment of Posttraumatic 
Headache (PTH)
Phase 2
IND number: 106533;     EudraCT number: Not Applicable
Approval Date: 06 April 2020
Sponsor
Teva Branded Pharmaceutical
Products R&D, Inc.
145 Brandywine Parkway
West Chester, Pennsylvania 19380
United States of America
Prepared by:


Placebo-Controlled Study–PTH
Statistical Analysis Plan
Study TV48125-CNS-20024
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STATISTICAL ANALYSIS PLAN APPROVAL


Placebo-Controlled Study–PTH
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3
TABLE OF CONTENTS
TITLE PAGE...................................................................................................................................1
STATISTICAL ANALYSIS PLAN APPROVAL..........................................................................2
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..................................................9
INTRODUCTION .........................................................................................................................11
1.
STUDY ENDPOINTS................................................................................................12
1.1.
Primary Efficacy Endpoints........................................................................................12
1.2.
Secondary Efficacy Endpoints....................................................................................12
1.3.
Safety Endpoints.........................................................................................................12
1.4.
Immunogenicity Assessment Endpoints.....................................................................13
1.5.
................................................................................................13
1.6.
Estimand for Primary Efficacy Endpoint ...................................................................15
2.
STUDY DESIGN .......................................................................................................17
2.1.
General Design ...........................................................................................................17
2.2.
Randomization and Blinding......................................................................................18
2.3.
Data Monitoring Committee.......................................................................................19
2.4.
Sample Size and Power Considerations .....................................................................19
2.5.
Sequence of Planned Analyses ...................................................................................19
2.5.1.
Planned Interim Analyses...........................................................................................19
2.5.2.
Final Analyses and Reporting.....................................................................................19
3.
ANALYSIS SETS ......................................................................................................20
3.1.
Intent-to-Treat Analysis Set........................................................................................20
3.2.
Open-Label Intend-to-Treat Analysis Set...................................................................20
3.3.
Safety Analysis Set.....................................................................................................20
3.4.
Full Analysis Set.........................................................................................................20
3.5.
Per-Protocol Analysis Set...........................................................................................20
3.6.
Patients in Extension or Open-Label Period...............................................................20
4.
GENERAL ISSUES FOR DATA ANALYSIS..........................................................21
4.1.
General........................................................................................................................21
4.2.
Specification of Baseline Values................................................................................21
4.3.
Handling Withdrawals and Missing Data...................................................................21
4.4.
Study Days and Visits.................................................................................................21


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5.
STUDY POPULATION.............................................................................................23
5.1.
General........................................................................................................................23
5.2.
Patient Disposition......................................................................................................23
5.3.
Demographics and Baseline Characteristics...............................................................23
5.4.
Medical History ..........................................................................................................23
5.5.
Prior Therapy and Medication....................................................................................24
5.6.
Childbearing Potential and Methods of Contraception ..............................................24
5.7.
Physical Examinations................................................................................................24
5.8.
Study Protocol Deviations..........................................................................................24
6.
EFFICACY ANALYSIS ............................................................................................25
6.1.
General........................................................................................................................25
6.1.1.
Posttraumatic Headache Data from E-diary ...............................................................25
6.1.2.
Data Derivation...........................................................................................................26
6.1.3.
Analysis Windows for E-diary Data...........................................................................26
6.1.4.
Handling Missing E-diary Data..................................................................................27
6.2.
Primary Efficacy Endpoint and Analysis ...................................................................28
6.2.1.
Definition....................................................................................................................28
6.2.2.
Primary Efficacy Analysis..........................................................................................28
6.2.3.
Sensitivity Analysis for the Primary Efficacy Endpoint.............................................29
6.3.
Secondary Efficacy Endpoints and Analyses .............................................................30
6.3.1.
Proportion of Patients Reaching at Least 50% Reduction From Baseline in 
the Monthly Average Number of Headache Days of at Least Moderate 
Severity During 12-Week Period of Treatment with the IMP....................................30
6.3.2.
Proportion of Patients Reaching at Least 50% Reduction From Baseline in 
the Monthly Average Number of Headache Days of at Least Moderate 
Severity During First 4-Week, 5- to 8-Week, and 9- to 12-Week Periods of 
Treatment with the IMP..............................................................................................30
6.3.3.
Mean Change from Baseline in the Number of Headache Days of at Least 
Moderate Severity During the First 4-Week, 5- to 8-Week, and 9- to 12-
Week Periods after the First Dose of the IMP............................................................31
6.3.4.
Mean Change From Baseline in Disability Score, as Measured by the 6-Item 
Headache Impact Test (HIT-6) at Week 12 After the First Dose of the IMP ............31
6.3.5.
Mean Change From Baseline in the Assessment of Patient Satisfaction, as 
Measured by the Patient Global Impression of Change Scale, at 4, 8, and 
12 Weeks after the First Dose of the IMP ..................................................................32


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6.4.
............................................................32
6.4.1.
Mean Change from Baseline in the Monthly Average Number of Headache 
Days of Any Severity During the 12-Week Period after the First Dose of The 
IMP .............................................................................................................................33
6.4.2.
Mean Change from Baseline in the Monthly Average Number of Headache 
Days of Any Severity During the First 4-Week,  5- to 8-Week, and 9- to 12-
Week Periods after the First Dose of the IMP............................................................33
6.4.3.
Proportion of Patients Reaching at Least 50% Reduction from Baseline in 
the Monthly Average Number of Headache Days of Any Severity During 
12-Week Period After the First Dose of the IMP.......................................................33
6.4.4.
Mean Change from Baseline in the Monthly Average Number of Headache 
Days of at Least Moderate Severity in Patients with at Least 4 Hours of 
Headache (Not Necessarily Consecutive) or Who Took a Prescription 
Abortive Medication with Intent to Alleviate the headache (regardless of 
duration or severity) During the 12-Week Period after the First Dose of The 
IMP .............................................................................................................................33
6.4.5.
Mean Change from Baseline in the Monthly Average Number of Headache 
Days of at Least Moderate Severity in Patients with at Least 4 Hours of 
Headache (Not Necessarily Consecutive) or Who Took a Prescription 
Abortive Medication with Intent to Alleviate the headache (regardless of 
duration or severity) During First 4-Week,  5- to 8-Week, and 9- to 12-Week 
Period after the First Dose of The IMP ......................................................................33
6.4.6.
Proportion of Patients Reaching at Least 50% Reduction from Baseline in 
the Monthly Average Number of Headache Days of at Least Moderate 
Severity in Patients with at Least 4 Hours of Headache (Not Necessarily 
Consecutive) or Who Took a Prescription Abortive Medication with Intent 
to Alleviate the headache (regardless of duration or severity) During the 12-
Week Period after the First Dose of The IMP ............................................................34
6.4.7.
Mean Change From Baseline for Patients with Neck Pain in the Monthly 
Average Number of Neck Pain Days of Any Severity During the 12-Week 
Period After the First Dose of the IMP.......................................................................34
6.4.8.
Mean Change from Baseline in the Monthly Average Number of Days of 
Use of Any Acute Headache Medications During the 12-Week Period After 
Administration of the First Dose of the IMP..............................................................35
6.4.9.
Mean Change From Baseline in the Monthly Average Number of Days 
Associated with Use of Opioid Analgesics for Headache During the 
12-Week Period After the First Dose of the IMP.......................................................35
6.4.10.
Mean Change From Baseline in Health Status as Measured by the 12-Item 
Short-Form Health Survey Physical and Mental Health at Weeks 12 and 24 
After the First Dose of the IMP ..................................................................................35


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6
6.4.11.
Mean Change From Baseline in the Sport Concussion Assessment Tool 3rd 
Edition Scores at Week 12 After the First Dose of the IMP ......................................36
6.4.12.
Mean Change From Visit 5 in Health Status, as Measured by the SF-12 
Physical and Mental Health at Weeks 16, 20, and 24 After the Last Dose of 
IMP .............................................................................................................................36
6.4.13.
Mean Change From Visit 5 in the Assessment of Patient Satisfaction, as 
Measured by the PGIC Scale, at Weeks 16, 20, And 24 after the Last Dose 
of IMP.........................................................................................................................37
6.4.14.
Mean Change from Visit 5 in Disability Score, as Measured by the HIT-6 at 
Weeks 16, 20, and 24 after the Last Dose of IMP......................................................37
6.4.15.
Mean Change from Visit 5 in Patient Perception of Frequency and Severity 
of Headaches, as Measured by the Special Protocol Headache Questionnaire, 
at Week 24 after the last Dose of the IMP..................................................................37
6.4.16.
Mean Change From Baseline in The Average Severity of Headaches During 
The 12-Week Period After The First Dose of The IMP .............................................38
6.4.17.
Mean Change From Baseline in the Average Daily Peak Headache Severity 
During the 12-Week Period After the First Dose of the IMP.....................................38
7.
MULTIPLE COMPARISONS AND MULTIPLICITY ............................................40
8.
SAFETY ANALYSIS ................................................................................................41
8.1.
General........................................................................................................................41
8.2.
Duration of Exposure to Study Drug..........................................................................41
8.2.1.
Double-Blind Treatment Period .................................................................................41
8.2.2.
Open-Label Treatment Period ....................................................................................41
8.3.
Adverse Events ...........................................................................................................42
8.4.
Injection Site Assessments .........................................................................................42
8.5.
Hypersensitivity/Anaphylaxis.....................................................................................43
8.6.
Electronic Columbia Suicide Severity Rating Scale ..................................................43
8.7.
Deaths .........................................................................................................................43
8.8.
Clinical Laboratory Tests ...........................................................................................43
8.8.1.
Laboratory Values Meeting Hy’s Law Criteria..........................................................45
8.9.
Physical Examinations................................................................................................45
8.10.
Vital Signs ..................................................................................................................45
8.11.
Electrocardiography....................................................................................................46
8.12.
Concomitant Medications or Therapies......................................................................46
9.
TOLERABILITY VARIABLES AND ANALYSIS..................................................47


Placebo-Controlled Study–PTH
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10.
PHARMACOKINETIC ANALYSIS.........................................................................48
11.
PHARMACOGENOMIC ANALYSIS ......................................................................49
12.
PHARMACOKINETIC/PHARMACODYNAMIC ANALYSIS..............................50
........................................................................................51
14.
IMMUNOGENICITY ANALYSIS............................................................................52
15.
PLANNED INTERIM ANALYSIS ...........................................................................53
16.
STATISTICAL SOFTWARE ....................................................................................54
17.
CHANGES TO ANALYSES SPECIFIED IN THE STUDY PROTOCOL..............55
18.
REFERENCES ...........................................................................................................56
..........................................................................57
............................................................59
..................................60
.............................62


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LIST OF TABLES
Table 1:
Study Visits.................................................................................................................22
Table 2:
Criteria for Potentially Clinically Significant Laboratory Values..............................44
Table 3:
Criteria for Potentially Clinically Significant Vital Signs..........................................46


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
ADA
antidrug antibodies
ANCOVA
analysis of covariance
β-HCG
beta-human chorionic gonadotropin
CMH
Cochran-Mantel-Haenszel
CNS
central nervous system
CRF
case report form
CV
coefficient of variation
e-diary 
electronic diary
ECG
electrocardiogram/electrocardiography
eC-SSRS
electronic Columbia Suicide Severity Rating Scale
EOS
end of study
EOT
end of treatment
EODBT
end of double-blind treatment
ET
early termination
DB
Double-blind
FAS
full analysis set
GCS
Glasgow coma scale
HIT-6
6-item Headache Impact Test 
IMP
investigational medicinal product
IRT
interactive response technology
ITT
intent-to-treat
LS
least square
MCS
Mental Health Composite Scores
MedDRA
Medical Dictionary for Regulatory Activities
NSAID
non-steroidal anti-inflammatory drug
OL-ITT 
Open-label intent-to-treat
PCS
Physical Composite Scores
PDAESI
protocol-defined adverse events of special interest
PGIC
Global Impression of Change
PP
per-protocol
PTH
posttraumatic headache


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Abbreviation
Term
R&D
Research and Development
MMRM
mixed model for repeated measures
SAC
Standardized Assessment of Concussion
SAP
statistical analysis plan
sc
subcutaneous(ly)
SCAT-3
Sport Concussion Assessment Tool 3rd edition
SD
standard deviation
SE
standard error
SF-12
12-Item Short-Form Health Survey
SI
standard international
SOC
system organ class
SOP
standard operating procedure
ULN
upper limit of normal
UN
unstructured covariance
WHO Drug
World Health Organization Drug Dictionary


Placebo-Controlled Study–PTH
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INTRODUCTION
This Statistical Analysis Plan describes the planned analysis and reporting for Teva Branded 
Pharmaceutical Products R&D, Inc. study TV48125-CNS-20024, [a phase 2, multicenter, 
randomized, proof-of-concept, double-blind, placebo-controlled, parallel-group study, including 
an open-label period, evaluating the efficacy and safety of 1 subcutaneous dose regimen of 
fremanezumab for the treatment of posttraumatic headache (PTH)], and was written in 
accordance with GSD_SOP_702 (Statistical Analysis Plan).
The reader of this SAP is encouraged to read the study protocol for details on the conduct of this 
study, the operational aspects of clinical assessments, and the timing for completing the 
participation of a patient in this study.
The SAP is intended to be in agreement with the protocol, especially with regard to the primary 
and all secondary endpoints and their respective analyses. However, the SAP may contain more 
details regarding these particular points of interest, or other types of analyses (eg, other 
endpoints). When differences exist in descriptions or explanations provided in the study protocol 
and this SAP, the SAP prevails; the differences will be explained in the clinical study report.


Placebo-Controlled Study–PTH
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12
1.
STUDY ENDPOINTS
1.1.
Primary Efficacy Endpoints
The primary efficacy endpoint is the mean change from baseline (baseline period) in the 
monthly average number of headache days of at least moderate severity during the 12-week 
period after the first dose of the IMP.
1.2.
Secondary Efficacy Endpoints
The secondary efficacy endpoints are:

proportion of patients reaching at least 50% reduction from baseline (baseline period) 
in the monthly average number of headache days of at least moderate severity during 
the 12-week period of treatment with the IMP

proportion of patients reaching at least 50% reduction from baseline (baseline period) 
in the monthly average number of headache days of at least moderate severity during 
the first 4-week period after the first dose of the IMP

proportion of patients reaching at least 50% reduction from baseline (baseline period) 
in the monthly average number of headache days of at least moderate severity during 
the 5- to 8-week period after the first dose of the IMP

proportion of patients reaching at least 50% reduction from baseline (baseline period) 
in the monthly average number of headache days of at least moderate severity during 
the 9- to 12-week period after the first dose of the IMP

mean change from baseline (baseline period) in the number of headache days of at 
least moderate severity during the first 4-week period after the first dose of the IMP

mean change from baseline (baseline period) in the number of headache days of at 
least moderate severity during the 5- to 8-week period after the first dose of the IMP

mean change from baseline (baseline period) in the number of headache days of at 
least moderate severity during the 9- to 12-week period after the first dose of the IMP

mean change from baseline (visit 2) in disability score, as measured by the 6-item 
Headache Impact Test (HIT-6) at week 12 after the first dose of the IMP

mean change from baseline (visit 2) in the assessment of patient satisfaction, as 
measured by the Patient Global Impression of Change scale, at 4, 8, and 12 weeks 
after the first dose of the IMP
1.3.
Safety Endpoints
The safety and tolerability endpoints are as follows:

occurrence of adverse events during the study

clinically significant changes in physical examinations, including body weight


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
clinical laboratory (serum chemistry, hematology and coagulation, and urinalysis) test 
results at each visit

vital signs (blood pressure, respiratory rate, body temperature, and pulse) 
measurements at each visit
Note: Oxygen saturation and respiratory rate will be measured in cases of suspected 
anaphylaxis and severe hypersensitivity.

12-lead electrocardiogram (ECG) findings at each visit

use of concomitant medication during the study

number (%) of patients who did not complete the study (day 168, end of study)

number (%) of patients who did not complete the study due to adverse events

local tolerability at the injection site (ie, erythema, induration, ecchymosis, and pain) 
at the following time points postdose: day 0, day 28, and day 56

hypersensitivity reaction assessment

Columbia Suicide Severity Rating Scale (C-SSRS)
1.4.
Immunogenicity Assessment Endpoints
The immunogenicity endpoints are antidrug antibodies (ADA) incidence and characteristics (eg, 
titer, kinetics, and neutralizing activities). 
1.5.

 
 
 
 
 
 
 
 
 
 
 


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
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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
 
 
 
 
 
 
 
 
 
 
 
1.6.
Estimand for Primary Efficacy Endpoint
The primary estimand for this study is defined by the following 4 components:
1. Target population: male and female patients aged 18 to 70 years, inclusive, with a 
history of PTH (as defined by International Classification of Headache Disorders 3rd 
revision [ICHD-3] (beta version) criteria).
2. Outcome measure: mean change from baseline (baseline period) in the monthly average 
number of headache days of at least moderate severity during the 12 week period after 
the first dose of the IMP.
3. Analysis set and handling of intercurrent events: The full analysis set (FAS) will be 
used for efficacy analyses.  FAS is a subset of the ITT analysis set including only patients 
who received at least 1 dose of IMP and had at least 1 post-baseline efficacy assessment 
on the primary endpoint. In the FAS, treatment will be assigned based on the treatment to 
which patients were randomized, regardless of which treatment they actually received.  
For patients randomized to active treatment who did not complete the double-blind treatment 
period due to lack of efficacy, death, or adverse event, the average number of headache days 
in the remainder of the analysis window will be imputed as the mean monthly average of 
headache days in the same analysis window for patients assigned to placebo.  
All other missing data for patients in either treatment group will be handled as follows: 

For patients who have ≥10 days of e-diary data in an analysis window, the monthly 
average number of headache days will be calculated based on data available in that 
analysis window and prorated to 28 days

For patients who have <10 days of e-diary data in an analysis window, the monthly 
average number of headache days will be imputed using the mean monthly average of 


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headache days in the same analysis window for patients assigned to the same 
treatment group and having ≥10 days of e-diary data. 
More details are provided in Section 6.1.4. 
4. Measure of treatment effect: analysis of covariance model including treatment as fixed 
effect and the baseline number of headache days of at least moderate severity and the 
posttraumatic headache onset (<12 months and ≥12 months) as covariates.


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2.
STUDY DESIGN
2.1.
General Design
This is a multicenter, randomized, proof-of-concept, double-blind, placebo-controlled, 
parallel-group study, including an open-label period, evaluating the efficacy and safety of 
1 subcutaneous (sc) dose regimen of fremanezumab in adult patients with PTH. The study will 
consist of a screening visit, a baseline period, a double-blind treatment period lasting 
approximately 12 weeks, and an open-label period lasting approximately 12 weeks. 
The total duration of patient participation in the study is planned to be approximately 28 weeks.
Patients will complete a screening visit (visit 1) after providing informed consent, and eligible 
patients will enter a baseline period lasting approximately 4 weeks (28+3 days), during which 
time they will enter their baseline PTH information into a daily electronic headache diary
(e-diary). Patients meeting eligibility requirements will be randomly assigned to 1 of 2 treatment 
groups with fremanezumab or placebo in a 1:1 ratio. Treatment assignment will take place with 
stratification based on the duration of the patient’s history of PTH (<12 months and ≥12 months 
duration). 
Screening results will be reviewed for eligibility, additional baseline assessments will be 
administered, and the first treatment administration will occur at visit 2. Patients will return to 
the study center approximately every 4 weeks (visit 3 and visit 4) for a continuation of the 
blinded treatment administered subcutaneously (sc); for safety and efficacy assessments; and for 
blood and urine sampling for pharmacokinetics, immunogenicity, and biomarker analysis. At 
visit 5, all patients will proceed directly to an open-label treatment phase, with fremanezumab 
administered sc. Patients will then return to the study center approximately every 4 weeks (visits 
6 and 7) for continued open-label treatment and safety tolerability and efficacy assessments. 
Final study assessments will be performed on visit 8, at the end of treatment or early termination 
visit, approximately 24 weeks after first administration of the IMP.
A database lock from the double-blind period will occur following the completion of visit 5 by 
the last patient. Unblinding will occur after the database lock from the double-blind period.
Patients who complete all scheduled visits will have procedures and assessments performed at 
visit 8. Patients who withdraw from the study before completing either the double-blind or the 
open-label treatment phases will have visit 8 procedures and assessments performed at their final 
visit. For all patients in the study, the end-of-treatment visit (visit 8) is defined as the final visit 
of the study and the conclusion of all study activities for the patient; patients will not receive any 
further treatments with IMP and will be treated according to guidelines and treating physicians’ 
discretion.
In the open-label period patients will receive 675 mg of fremanezumab administered as 3 sc 
injections (225 mg/1.5 mL each) at visit 5 (week 12), visit 6 (week 16), and visit 7 (week 20).
The end of study is defined as the last safety visit. However, a final database lock will occur 
following the end-of-treatment visit (visit 8) of the last patient for analysis of the study data.


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The study schematic diagram is presented in Figure 1. Study procedures and assessments with 
their timing are summarized in Table 1 of the study protocol.
Figure 1:
Overall Study Schematic Diagram
PBO=placebo; SC=subcutaneous; V=visit.
2.2.
Randomization and Blinding
Patients meeting eligibility requirements will be randomized into one of the following treatment 
groups:
1. Arm A: Fremanezumab 675-mg sc treatment group 
Patients randomized to fremanezumab will receive 675 mg of fremanezumab administered as 
3 sc injections (225 mg/1.5 mL each) at visit 2 (randomization), visit 3 (week 4), and visit 4 
(week 8).
2. Arm B: Placebo treatment group
Patients randomized to placebo will receive placebo administered as 3 sc injections (1.5 mL 
each) at visit 2 (randomization), visit 3 (week 4), and visit 4 (week 8).
The randomization code will be generated by the interactive response technology (IRT)
third-party vendor according to specifications from the Biostatistics Department. A Teva 
statistician will be responsible for reviewing the dummy randomization codes, and the final 
randomization code will be maintained by the third-party vendor in a secure location.
After all patients have completed visit 5 and an unblinding request from the Teva statistician has 
been received, the third-party vendor will provide the unblinded IMP assignments according to
the processes defined in the relevant Standard Operating Procedure (SOP).


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The sponsor, investigators, study staff (except for staff involved in bioanalytical analyses), and 
patients will be blinded to treatment assignment during the double-blind treatment period of the 
study.
2.3.
Data Monitoring Committee
Not applicable.
 
 
 
 
 
 
 
 
 
2.5.
Sequence of Planned Analyses
2.5.1.
Planned Interim Analyses
There will be no interim analysis. However, a database lock from the double-blind period will 
occur following the completion of visit 5 by the last patient. Unblinding will occur after the 
database lock from the double-blind treatment period.
2.5.2.
Final Analyses and Reporting
A database lock from the double-blind treatment period will occur following the completion of 
visit 5 by the last patient. Unblinding will occur after the database lock from the double-blind 
treatment period. This SAP will be finalized before the database lock.
All endpoints related to the double-blind treatment period will be analyzed, including data up to 
visit 5.
Data collected from open-label treatment period (visit 5 and after) will be analyzed separately 
after study completion.


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3.
ANALYSIS SETS
3.1.
Intent-to-Treat Analysis Set
The intent-to-treat (ITT) analysis set will include all randomized patients.
In the ITT analysis set, treatment will be assigned based on the treatment to which patients were 
randomized, regardless of which treatment they actually received.
3.2.
Open-Label Intend-to-Treat Analysis Set
The open-label ITT (OL-ITT) analysis set is a subset of the ITT analysis set including only 
patients who receive at least 1 dose of study drug during the open-label treatment period.
Note, OL-ITT will be used for open-label analysis. 
3.3.
Safety Analysis Set
The safety analysis set will include all randomized patients who receive at least 1 dose of the 
IMP.
In the safety analysis set, treatment will be assigned based on the treatment patients actually 
received in the double-blind treatment period, regardless of the treatment to which they were 
randomized, unless otherwise specified.
Patients randomized to placebo group but received any number of injection of fremanezumab in 
error will be analyzed in a separated group (Other) in the safety analyses if applicable. 
3.4.
Full Analysis Set
The full analysis set (FAS) is a subset of the ITT analysis set including only patients who receive 
at least 1 dose of the IMP and have at least 1 post-baseline efficacy assessment on the primary 
endpoint.
In the FAS, treatment will be assigned based on the treatment to which patients were
randomized, regardless of which treatment they actually received.
3.5.
Per-Protocol Analysis Set
The per-protocol (PP) analysis set is a subset of the ITT analysis set including only patients 
without any major protocol deviations. Major protocol deviations will be determined before 
unblinding and database lock. 
3.6.
Patients in Extension or Open-Label Period
This will include patients continued in the extension or open-label period.


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4.
GENERAL ISSUES FOR DATA ANALYSIS
4.1.
General
Descriptive statistics for continuous variables include count (n), mean, SD, standard error (SE),
median, minimum, and maximum. In addition, for fremanezumab concentration, percentage 
coefficient of variation (%CV) and geometric mean will also be calculated. Descriptive statistics 
for categorical variables include patient counts and percentages, and a missing category will be 
displayed as appropriate.
Summaries of potentially clinically significant abnormal values for clinical laboratory tests and 
vital signs values will include all postbaseline values (including scheduled, unscheduled, and 
early withdrawal visits).
4.2.
Specification of Baseline Values
For analyses of the double-blinded treatment period, baseline is the last observed data before the 
administration of the first dose of the IMP, unless otherwise noted. For data collected in the e-
diary daily, baseline will be derived from the baseline period (from the day of the informed 
consent to before the administration of the first dose of the IMP) and prorated to 28 days if the 
number of days in the baseline period is not equal to 28. Details are provided in Section 6.1.
For analyses of the open label treatment period, the baseline is the observed data at visit 5, unless 
otherwise noted.  
4.3.
Handling Withdrawals and Missing Data
For efficacy analyses based on e-diary data, the missing data handling methods are provided in 
Section 6.1.4. For the efficacy analyses based on non-e-diary data, missing data handling 
methods, if applicable, will be provided in the efficacy analysis section for that endpoint.
Dates that have incomplete information (ie. only month and year or only year recorded) will be 
estimated for the purpose of calculating variables that are dependent on time if necessary. Day 
will be estimated as the first day (01) of the month (if month and year of partial date are 
available) or middle (July 1) of the year (if only year is available), unless otherwise noted. If no 
date information is recorded, the date will not be imputed.
The imputations for partial dates are only for calculation purpose. Original date variables will not 
be modified. Listings will present dates as collected. If no date information is recorded, the date 
will not be imputed.
4.4.
Study Days and Visits
For by-visit summaries, if there are multiple assessments at a postbaseline visit then the last 
non-missing assessment at that visit will be used for the summary (this includes scheduled and 
unscheduled assessments), except for triplicate ECG assessments (see Section 8.11 for further 
details).
Study visits are detailed in Table 1.


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Table 1:
Study Visits
Visit #
V1
(Screening)
Double-Blinded Treatment Period
Open-Label Period
V21
V3
V4
V52
V6
V7
V8
Day
-28 to-1
0±3
28±3
56±3
84±3
112±3
140±3
168±3
Week 
-
0
4
8
12
16
20
24
Visit 1
Visit 2
Dose 1
Visit 3/
Dose 2
Visit 4/
Dose 3
Visit 5/
Dose 4/
EODBT
Visit 6/
Dose 5
Visit 7/
Dose 6
Visit 8/
EOT/EOS/ET3
1 Baseline/Randomization
2 Visit 5 is the end of double-blind treatment period and the beginning of open-label period
3 EOT=the end of treatment; EOS=end of study; ET=early termination
The end of double-blind treatment period (EODBT) is defined as Visit 5/Week 12 or early 
termination (ET) visit for patients did not complete double-blind treatment period and did not 
continue in open-label period.
‘Last Assessment’ may be derived for analysis purpose for safety data and is defined as the last 
observed postbaseline data during the double-blind treatment period for double-blind period or 
the last observed postbaseline data during the open-label treatment period for open-label period. 
For patients who withdraw from the study early, their data at the early withdrawal visit will be 
excluded from the by-visit summaries but will be included in the ‘Last Assessment’ summaries.
Study days are numbered relative to the first day of the IMP administration. The start of 
treatment (day 1) is defined as the date on which a patient takes the first dose of the IMP, as 
recorded on the case report form (CRF). Days will be numbered relative to treatment start (ie, ..., 
–2, –1, 1, 2, ...; with day 1 being the day of the first IMP administration and day –1 being the day 
before the day of the first IMP administration).
For data from the e-diary, monthly analysis windows [Month 1 (weeks 1 to 4), Month 2 (weeks 5
to 8), and Month 3 (weeks 9 to 12)] will be derived for the purpose of efficacy endpoint analyses. 
Details are provided in Section 6.1.3.


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5.
STUDY POPULATION
5.1.
General
The ITT analysis set (see Section 3.1) will be used for all study population summaries unless 
otherwise specified. Summaries will be presented by treatment group and all patients.
5.2.
Patient Disposition
Data from patients screened; patients screened but not randomized and reason not randomized; 
patients randomized (ITT); patients randomized but not treated; patients in the safety and other 
analysis sets; patients who completed the double-blind treatment; patients who enter open-label 
treatment period; patients who did not compete double-blind treatment will be summarized using 
descriptive statistics. Data from patients who did not complete double-blind treatment will also 
be summarized by reason using descriptive statistics.
This summary will include all patients.
Patients who completed study or patients withdrew from the study by reason will be summarized 
once the study is completed. 
5.3.
Demographics and Baseline Characteristics
The demographic data will be collected at the screening visit after the patient signs the informed 
consent form. Patient demographic data including age, age group (<65 or ≥65 years old), gender, 
race, race group (white or other), ethnicity, baseline weight (kg), baseline height (cm), and 
baseline body mass index (kg/m2) will be summarized using descriptive statistics for all analysis 
sets. 
Baseline characteristics including time since the head trauma, duration of PTH history (less than 
12 month since the brain injury versus greater or equal to 12 month since the brain injury),
diagnosis of PTH, preventive medication use (yes or no) at screening or baseline, use of any 
acute headache medication (opioid, barbiturate, triptan, and NSAIDS) during the baseline period
(yes or no), use of prescription abortive headache medication (opioid, barbiturate, and triptan)
during the baseline period (yes or no), and monthly average number of headache days of at least 
moderate severity during the baseline period will be summarized for the ITT analysis set using 
descriptive statistics. No inferential analyses will be performed.
The time (in year) since the head trauma will be calculated as (the date of informed consent – the 
date of head trauma + 1)/365.25. Rules for handling partial head trauma date are in Section 4.3.
5.4.
Medical History
All medical history abnormalities will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA). The incidence of medical history abnormalities will be summarized using 
descriptive statistics by system organ class (SOC) and preferred term. Patients are counted only 
once in each SOC and only once in each preferred term.


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5.5.
Prior Therapy and Medication
All prior medications or therapy will be coded using the World Health Organization Drug
Dictionary of medical codes (WHO Drug). The incidence of prior medications or therapy will be 
summarized by therapeutic class and preferred term using descriptive statistics. Patients are 
counted only once in each therapeutic class category, and only once in each preferred term
category. Prior medications will include all medications taken within 3 months prior to the 
administration of the first dose of the IMP.
The prior medications will be summarized by the following indications categories: 

butalbital for post traumatic headache

butalbital for other reason than post traumatic headache

ergots for post traumatic headache

ergots for other reason than post traumatic headache

NSAIDS for post traumatic headache

NSAIDS for other reason than post traumatic headache

opioids for post traumatic headache

opioids for other reason than post traumatic headache

preventive medication from the study protocol for post traumatic headache

preventive medication from the study protocol for other reason than post traumatic 
headache

triptans for post traumatic headache

triptans for other reason than post traumatic headache

other
5.6.
Childbearing Potential and Methods of Contraception
Information related to reproductive system findings will be collected at the screening visit. Data 
will be listed.
5.7.
Physical Examinations
Patients with at least 1 abnormal finding (overall) and abnormal findings for each category will 
be summarized.
5.8.
Study Protocol Deviations
Data from patients with any important protocol deviations during the study will be summarized 
overall and for each category using descriptive statistics.


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6.
EFFICACY ANALYSIS
6.1.
General
The FAS will be used for all efficacy analyses unless otherwise noted. Analyses of the primary 
and secondary endpoints will be repeated for the PP analysis set.
Analyses for endpoints related to double-blind treatment (up to visit 5/12-week) will be 
performed after DB lock for double-blind treatment. The analyses will be by treatment groups.
Analyses for endpoints related to open-label treatment (from visit 5/12-week to the end of the 
study) will be performed after study completion.
For data not collected daily, baseline is the last observed data before the administration of the 
first dose of the IMP. For data collected daily in the e-diary, baseline will be derived from the 
baseline period (from the day of the informed consent to before the administration of the first 
dose of the IMP). Details are provided in Section 6.1.3. 
For patients who do not have Visit5/Week 12 assessment and do not continue in the open-label
period but have assessment at EOS, the assessment at EOS will be used as Visit 5/Week 12. 
Derived efficacy variables are 

monthly average number of headache days of at least moderate severity

monthly average number of headache days of any severity

monthly average number of neck pain days of any severity

monthly average number of days of use of any acute headache medication 

monthly average number of days of use of opioid analgesics for headache 

average severity of headache 

average daily peak headache severity
Summaries will be presented by treatment group as randomized unless otherwise noted. In 
addition to inferential statistics, descriptive statistics will be presented in by-visit or 
by-analysis-window summaries. A missing category will be presented if applicable. Derived 
endpoints will be listed.
6.1.1.
Posttraumatic Headache Data from E-diary
Information about PTH will be recorded in the e-diary daily. Corresponding PTH questions are 
in Appendix A (questions A1, B1 through B3, and C1 through C9). Patients will record
headache(s) occurred during last 24 hours. The recording window on e-diary device is 
“Yesterday morning 6:00 am to today at 5:59 am”. Patients can record missed entry for “the day 
before yesterday morning 6:00 am to yesterday at 5:59 am”, maximum 48 hours recall window is 
allowed.
Date of a headache is derived as the following


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
headache report date -1 day if the recording is for 24 hours recall

headache report date – 2 days if the recording is for 48 hours recall
Baseline and postbaseline monthly average number of headache days for a patient within an 
analysis window will be calculated based on data available and prorated to 28 days using 
formula A.
6.1.2.
Data Derivation 
The monthly average of an efficacy variable will be calculated and prorated to 28 days as 
follows:
The “efficacy endpoint data” will be “number of headache days of at least moderate severity”, 
“number of headache days of any severity”, “number of neck pain days of any severity”, 
“number of days of use of any acute headache medication”, and “number of days associated with 
use of opioid analgesics for headache” observed during a treatment period. 
The “period” will be the baseline period for baseline calculation or 12-week double-blind 
treatment period or monthly analysis window [eg. Month 1 (weeks 1 to 4), Month 2 (weeks 5 to
8), Month 3 (weeks 9 to 12)] for post-baseline calculations.
The percentage of reduction from baseline in the monthly average number of headache days
will be calculated as follows:
where baseline value and postbaseline value are the monthly average calculated using formula A.
6.1.3.
Analysis Windows for E-diary Data
Baseline window is the period from the day of the informed consent to before the administration 
of the first dose of the IMP. The baseline monthly average value for an efficacy variable will be 
calculated based on data recorded in the baseline window and prorated to 28 days using
formula A.
Postbaseline 4-week (monthly) analysis windows will be determined based on the actual 
dosing date as follows:

Month 1 (weeks 1 to 4): from the day of the first dose of the IMP administration to 
the day before the IMP administration at visit 3 (week 4/dose 2) or to the end of 
e-diary in the double-blind treatment period if a patient only receives dose 1;

Month 2 (weeks 5 to 8): from the day of the IMP administration at visit 3 (week 
4/dose 2) to the day before the IMP administration at visit 4 (week 8/dose 3) or to the 
end of e-diary in the double-blind treatment period if a patient only receives dose 1 
and dose 2;


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
Month 3 (weeks 9 to 12): from the day of the IMP administration at visit 4 (week 8/ 
dose 3) to the end of e-diary of the double-blind treatment period.
Notes:
1. The end of e-diary of the double-blind treatment period is defined as the date of last IMP 
administration + 27 days.
2. There will be no double-blind IMP administration at visit 5; 
3. A 4-week analysis window may contain <28, 28, or >28 days.
The monthly average of an efficacy variable for each analysis window will be calculated based 
on data recorded in the e-diary and prorated to 28 days using formula A. Missing data handling 
methods are provided in Section 6.1.4.
6.1.4.
Handling Missing E-diary Data
This section includes missing data handling for e-diary data. For other type of data, the missing
data handling methods are provided in the analysis section for the endpoint if applicable.
For analyses using ANCOVA or mixed model for repeated measures (MMRM) based on 
monthly averages the missing data handling methods are as follows:  
For patients randomized to active treatment group and did not completed the double-blind
treatment period due to lack of efficacy, death, or adverse event, the number of headaches in an 
analysis window will be imputed as the following
∑ (observed headaches during a analysis window) + (N-X)*(placebo average/N)
Where
N denotes the number of days in the analysis window, 84 days for 12-week analysis window and 
28 days for 4-week analysis window;
X (X>0) denotes the number of days with e-diary within the analysis window;
“Placebo average” is the monthly average of number of headache during the analysis window 
from placebo patients who completed study.
For 12-week analysis window, the monthly average of the number of headaches will be prorated 
to 28 days using formula A;
All other missing data for patients in either treatment group will be handled as follows: 

For patients who have ≥10 days of e-diary data in an analysis window, the monthly average 
number of headache days will be calculated based on data available in that analysis window 
and prorated to 28 days using formula A;

For patients who have <10 days of e-diary data in an analysis window, the monthly average 
number of headache days will be imputed using the mean monthly average of headache days 
in the same analysis window for patients assigned to the same treatment group and having 
≥10 days of e-diary data.
Note: the imputation is only for post-baseline data and applies to all efficacy endpoints related to 
the number of headache days.


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In addition, as a sensitivity analysis, the primary endpoint will be analyzed using a MMRM 
method. Detail is provided in Section 6.2.3.
6.2.
Primary Efficacy Endpoint and Analysis
6.2.1.
Definition
The primary efficacy endpoint is the mean change from baseline (baseline period) in the monthly 
average number of headache days of at least moderate severity during the 12-week period after 
the first dose of the IMP.
The primary efficacy endpoint for this study will be derived from PTH data (presence of 
headache [yes/no] and peak severity [mild/moderate/severe]) collected daily using an electronic 
headache diary application.
Headache days of at least moderate severity will be derived from the e-diary data as described in 
Section 6.1.1. The 12-week period is the period from administration of the first dose of IMP to 
the EODBT as defined in Section 4.4. The monthly average number of headache days of at least 
moderate severity will be calculated using formula A. Missing data handling method is provided 
in Section 6.1.4.
6.2.2.
Primary Efficacy Analysis
The hypothesis testing for the primary analysis is: 
2
1
2
1
:
:






a
o
H
vs
H
where 
1and 
2

are the estimates of mean change from baseline in the monthly average number 
of headache days of at least moderate severity for the fremanezumab treatment group and the 
placebo group, respectively. 
The primary endpoint will be analyzed using an ANCOVA method. The model will include 
treatment as fixed effect and the baseline monthly average number of headache days of at least 
moderate severity and the posttraumatic headache onset (<12 months and ≥12 months) as 
covariates. The least square (LS) mean and SE for each treatment group, LS means and 
corresponding 95% confidence intervals for the treatment differences (fremanezumab - placebo), 
and associated p-values will be presented.
The analysis will be performed on the FAS and PP analysis sets.
Example SAS code for ANCOVA
PROC MIXED DATA=<name>; 
     CLASS TRTP ONSET;
     MODEL CHG= BASE ONSET TRTP /S;
     LSMEANS TRTP /DIFF=CONTROL (“Placebo”) CL ALPHA=0.05; 
     ODS OUTPUT LSMEANS= <name>  DIFFS= < name> ;
RUN;


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Where TRTP denotes the planned treatment group; CHG denotes the change from baseline in the 
monthly average number of headache days of at least moderate severity; BASE denotes the 
baseline monthly average number of headache days of at least moderate severity; ONSET 
denotes the posttraumatic headache onset (<12 months and ≥12 months). In bold are the SAS key 
words.
6.2.3.
Sensitivity Analysis for the Primary Efficacy Endpoint
A sensitivity analysis will be conducted to explore the impact of missing data in the primary 
efficacy analysis.
MMRM analysis will be utilized to estimate the mean change from baseline (baseline period) in 
the monthly average number of headache days of at least moderate severity during the 12-week 
period after the first dose of IMP.
Postbaseline data will include data from 3 monthly analysis windows (Month 1, Month 2, and 
Month 3) derived using the algorithm described in Section 6.1.3.
The MMRM will include the posttraumatic headache onset (<12 months and ≥12 months), 
treatment, month (3 levels), and month-by-treatment interaction as fixed effects and baseline 
monthly average number of headache days of at least moderate severity as a covariate. The 
unstructured covariance structure (UN) will be used to model intra-subject correlation. LS mean 
and SE for each treatment group, LS means and corresponding 95% confidence intervals for the 
treatment differences (fremanezumab - placebo), and the associated p-values from the overall 
results for treatment comparisons on the average of months 1 to 3 will be presented to support 
the primary analysis. Notes: if UN dose not converge, the hierarchy uses the first-order 
autoregressive structure [AR-(1)] and the compound-symmetry structure (CS).
Example SAS codes for MMRM analysis:
PROC MIXED DATA=<name> METHOD=REML;
      CLASS USUBJID TRTP ONSET AVISIT; 
      MODEL CHG=BASE ONSET TRTP AVISIT TRTP*AVISIT/S;
      REPEATED AVISIT/ SUB=USUBJID TYPE=UN;
      LSMEANS TRTP TRTP*AVISIT/ DIFF CL ALPHA=0.05;
      ODS OUTPUT LSMEANS= <name> DIFFS= < name> ;
RUN;
Where TRTP denotes the planned treatment group; ONSET denotes the posttraumatic headache 
onset (<12 months and ≥12 months); AVISIT denotes the analysis window; BASE denotes the 
baseline monthly average number of headache days of at least moderate severity; CHG denotes 
the change from baseline.
The analysis will be performed on the FAS.


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6.3.
Secondary Efficacy Endpoints and Analyses
The key secondary efficacy endpoints are listed in Section 1.2. Analyses will be based on the 
FAS and PP analysis sets.
6.3.1.
Proportion of Patients Reaching at Least 50% Reduction From Baseline in the 
Monthly Average Number of Headache Days of at Least Moderate Severity 
During 12-Week Period of Treatment with the IMP
This secondary efficacy endpoint will be analyzed using Cochran-Mantel-Haenszel (CMH) test 
stratified by the posttraumatic headache onset (<12 months and ≥12 months). Descriptive 
statistics (count and percent) and p-value for Row Mean Scores difference will be presented.
The 12-week period is the period from the first dose of the IMP to the EODBT as defined in
Section 4.4. Headache during the 12-week period will be derived from the e-diary data as 
described in Section 6.1.1. The monthly average number of headache days of at least moderate
severity will be calculated using formula A. Missing data handling methods are provided 
in Section 6.1.4 .
The proportion of reduction for a patient will be calculated using formula B. Responders will be 
those with ≥50% reduction. 
Example SAS code for CMH:
PROC FREQ DATA=<name>;
     TABLES ONSET*TRTP*AVALC / CMH; 
     OUTPUT OUT=<name> CMH;
RUN;
Where TRTP denotes the planned treatment group; ONSET denotes posttraumatic headache 
onset (<12 months and ≥12 months); and AVALC denotes the responses with yes for responders 
(with ≥50% reduction) and no for non-responders (with <50% reduction).
6.3.2.
Proportion of Patients Reaching at Least 50% Reduction From Baseline in the 
Monthly Average Number of Headache Days of at Least Moderate Severity 
During First 4-Week, 5- to 8-Week, and 9- to 12-Week Periods of Treatment 
with the IMP
The following endpoints will be analyzed using CMH test in a manner analogous to the analysis 
described in Section 6.3.1, respectively.

proportion of patients reaching at least 50% reduction from baseline (baseline period) 
in the monthly average number of headache days of at least moderate severity during 
the first 4-week period after the first dose of the IMP

proportion of patients reaching at least 50% reduction from baseline (baseline period) 
in the monthly average number of headache days of at least moderate severity during 
the 5- to 8-week period after the first dose of the IMP


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
proportion of patients reaching at least 50% reduction from baseline (baseline period) 
in the monthly average number of headache days of at least moderate severity during 
the 9- to 12-week period after the first dose of the IMP
Postbaseline data will include data from 3 monthly analysis windows (Month 1/1- to 4-Week, 
Month 2/5- to 8-week, and Month 3/9- to 12 week) derived using the algorithm described in 
Section 6.1.3. Data in each analysis window will be prorated to 28 days using formula A. 
Headache of at least moderate severity within each analysis window will be derived from the 
e-diary data as described in Section 6.1.1. The proportion of reduction for a patient will be 
calculated using formula B for each analysis window. Responders will be those with ≥50% 
reduction. 
6.3.3.
Mean Change from Baseline in the Number of Headache Days of at Least 
Moderate Severity During the First 4-Week, 5- to 8-Week, and 9- to 12-Week
Periods after the First Dose of the IMP
The following endpoints will be analyzed using MMRM method in a manner analogous to the 
analysis described in Section 6.2.3.

mean change from baseline (baseline period) in the number of headache days of at 
least moderate severity during the first 4-week period after the first dose of the IMP

mean change from baseline (baseline period) in the number of headache days of at 
least moderate severity during the 5- to 8-week period after the first dose of the IMP

mean change from baseline (baseline period) in the number of headache days of at 
least moderate severity during the 9- to 12-week period after the first dose of the IMP
Postbaseline data will include data from 3 monthly analysis windows (Month 1/1- to 4-Week, 
Month 2/5- to 8-week, and Month 3/9- to 12 week) derived using the algorithm described in 
Section 6.1.3. Data in each analysis window will be prorated to 28 days using formula A. 
Headache of at least moderate severity within each analysis window will be derived from the e-
diary data as described in Section 6.1.1.
Results for each endpoint will be separated from PROC MIXED outputs. The results from the 
last analysis window will be presented.
6.3.4.
Mean Change From Baseline in Disability Score, as Measured by the 6-Item 
Headache Impact Test (HIT-6) at Week 12 After the First Dose of the IMP
The HIT-6 (Appendix B) is a tool used to measure the impact headaches have on a patient’s 
normal daily life and ability to function. The HIT-6 consists of 6 items, including pain, social 
functioning, role functioning, vitality, cognitive functioning, and psychological distress. Each 
item is answered on a 5-point Likert scale (6 = never, 8 = rarely, 10 = sometimes, 11 = very 
often, or 13 = always), which are summed to produce a total score that ranges from 36 to 78, 
with larger scores reflecting greater impact of headache on the daily life of the patient.
During the double-blind treatment period patients will complete the HIT-6 questionnaire at visit 
2 and visit 5/week 12 before the administration of the IMP or at ET visit.
The HIT-6 total score mean change from baseline at visit 5/week 12 will be analyzed using an 
ANCOVA method in a manner analogous to the analysis described in Section 6.2.2.


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Categorical and numerical responses for each of 6-item questions will be summarized using 
descriptive statistics by visit.
6.3.5.
Mean Change From Baseline in the Assessment of Patient Satisfaction, as 
Measured by the Patient Global Impression of Change Scale, at 4, 8, and 
12 Weeks after the First Dose of the IMP
The PGIC is a validated generic tool for the assessment of overall change in the severity of 
illness following treatment. 
During the double-blind treatment period patients will complete the HIT-6 questionnaire at visit 
2 and visit 5/week 12 before the administration of the IMP or at ET visit.
During the double-blind treatment period, at visit 2/week 0, visit 3/week 4, visit 4/week 8, visit 
5/week 12 before the administration of the IMP or at ET visit, patients will rate how they feel 
compared with how they felt before receiving IMP using the following 7-point scale:
1=No change (or condition has got worse)
2=Almost the same, hardly any change at all
3=A little better, but no noticeable change
4=Somewhat better, but the change has not made any real difference
5=Moderately better, and a slight but noticeable change
6=Better, and a definite improvement that has made a real and worthwhile difference
7=A great deal better, and a considerable improvement that has made all the Difference
For analysis purposes, a dichotomous scale of ‘Yes’ or ‘No’ will be derived. A favorable change 
is score of 5-7, which means there is significant improvement (Yes) with the treatment. If the 
response is 1-4, it is considered no significant improvement (No).
The percentage of patients’ dichotomous scale of ‘Yes’ or ‘No’ of PGIC assessments at baseline 
(week 0/visit 2), weeks 4, 8, and 12 (visits 3 to 5) will be analyzed using a CMH method in a 
manner analogous to the first secondary endpoint described in Section 6.3.1. Missing data will 
not be imputed.
Raw data for these visits will be summarized using descriptive statistics. Missing category will 
be presented if applicable.
6.4.
 


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.


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7.
MULTIPLE COMPARISONS AND MULTIPLICITY
A fixed-sequence (hierarchical) testing procedure will be implemented to control the type 1 error 
rate at 0.05. 
Testing of statistical significance at a 2-sided alpha of 0.05, fremanezumab 675-mg sc treatment 
group versus placebo group, will be performed for the primary endpoint. If the primary endpoint 
meets statistical significance, then each of the key secondary endpoints will be tested for 
significance in a pre-specified order at a 2-sided alpha of 0.05. If and when any p>0.05, no 
further comparisons will be interpreted inferentially. 
The sequence of comparisons will be as follows:
1. Primary endpoint (mean change from baseline (baseline period) in the monthly average 
number of headache days of at least moderate severity during the 12-week period after 
the first dose of the IMP)
2. 1st key secondary endpoint (proportion of patients reaching at least 50% reduction from 
baseline (baseline period) in the monthly average number of headache days of any 
severity during the 12-week period of treatment with the IMP)
3. 2nd key secondary endpoint (mean change from baseline (visit 2) in disability score, as 
measured by the 6-item Headache Impact Test (HIT-6) at week 12 after the first dose of 
the IMP)


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8.
SAFETY ANALYSIS
8.1.
General
For double-blind treatment period (up to visit 5), the safety analysis set will be used for all safety 
analyses. Summaries will be presented using descriptive statistics by treatment group as actually 
received unless otherwise stated and overall.
For open-label treatment period (visits 5 to 8/EOT/EOS/ET), OL-ITT analysis set will be used 
for safety analyses. Changes from baseline or change from visit 5 will be presented. Summaries 
will be presented using descriptive statistics overall. The data will be analyzed after the 
completion of the study.
8.2.
Duration of Exposure to Study Drug
8.2.1.
Double-Blind Treatment Period
During the double-blind treatment period patients will receive 3 sc injections of fremanezumab 
or placebo at visit 2, visit 3, and visit 4.
Duration of the double-blind treatment period (days) for a patient is defined as the number of 
days a patient is in the double-blind treatment period and calculated as the date of visit 5 - the
first date of the IMP + 1. For patients who do not complete double-blind treatment period, date 
of visit 5 will be estimated as the date of last IMP administration in double-blind treatment 
period + 27. Dosing visit interval (days) is defined as the number of days between dosing visit
(dose 1 and dose 2; dose 2 and dose 3) and calculated as date of next dosing - date of current 
dosing.
Duration of the double-blind treatment period (days), dosing visit interval (days), the number of 
doses received, and total number of injections received will be summarized using descriptive 
statistics. Summary will be presented by treatment group.
IMP administration and accountability data will be listed.
8.2.2.
Open-Label Treatment Period
During the open-label treatment period patients will receive 3 sc injections of fremanezumab at 
visit 5, visit 6, and visit 7.
Duration of the treatment (days) in the study (both in double-blind and open label) for a patient is 
defined as the number of days a patient is in the study and calculated as the date of visit 8 - the
first date of the IMP + 1. Duration of the treatment (days) in the open-label treatment period for a 
patient is defined as the number of days a patient is in the open-label treatment period and 
calculated as the date of visit 8 - the date of the IMP at visit 5 + 1. For patients who are do not 
complete open-label treatment, date of visit 8 will be estimated as the date of last IMP 
administration + 27.
Duration of the treatment (days) in the study and in the open-label period will be summarized 
using descriptive statistics.


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IMP administration and accountability data will be listed.
8.3.
Adverse Events
Adverse events will be recorded from time informed consent is obtained through the end of study 
participation.
The following are considered protocol-defined adverse events of special interest (PDAESI) to be 
sent to the sponsor’s Global Patient Safety and Pharmacovigilance Department for evaluation:
ophthalmic-related adverse events of at least moderate severity, events of possible drug-induced 
liver injury (AST or ALT ≥3× ULN, total bilirubin ≥2× ULN, or international normalized ratio 
>1.5), Hy’s Law events, or events of anaphylaxis and severe hypersensitivity. 
All adverse events will be coded using MedDRA. Each patient will be counted only once in each 
preferred term or SOC category for the analyses of safety. Summaries will be presented for all 
adverse events (overall and by severity), adverse events determined by the investigator to be 
related to test IMP (defined as related or with missing relationship) (overall, overall by severity,
serious AEs, PDAESI), serious adverse events, PDAESI, and adverse events causing withdrawal 
from the study. Adverse events with the missing flag indicating serious will be excluded from the 
summary of serious adverse events but included in the summary of non-serious adverse events.
Summaries for injection site adverse events will be presented (overall and by severity).
Listings for deaths, serious adverse events, adverse events leading to treatment withdrawn, 
adverse events leading to study discontinuation, adverse event requiring concomitant or 
additional treatment, injection site adverse events, PDAESI, and hypersensitivity and suspected 
anaphylaxis/hypersensitivity reactions related adverse events will be presented. In addition, 
listings for MedDRA dictionary terms for adverse event descriptions and adverse event preferred 
terms by patient number and treatment group will be presented.
Spontaneous abortion or an elective abortion due to developmental anomalies will be reported as 
a serious adverse event (protocol Section 7.2). These serious adverse events will be listed 
separately if applicable.
Summaries will include treatment-emergent adverse events which are defined as adverse events 
occurring at or after the first dose of the IMP. The listing will include all adverse events
recorded.
Adverse events for patients who did not meet screening criteria will be listed.
8.4.
Injection Site Assessments
Injection site assessments will be performed immediately (+10 minute) and 1 hour (±15 minutes) 
after receiving each dose of the IMP at visits 2, 3, and 4. The injection sites will be assessed for 
erythema, induration, and ecchymosis. More details are in Section 7.9 of the study protocol.
Injection-site reactions should be recorded as adverse events. Injection-site related adverse 
events will be summary as indicated in Section 8.3.


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8.5.
Hypersensitivity/Anaphylaxis 
Patients will be assessed for suspected anaphylaxis/hypersensitivity reactions during and after 
administration of the IMP at visits 2, 3, and 4. Data will be summarized using descriptive 
statistics.
The number of patients with suspected anaphylaxis/hypersensitivity reactions and number of 
suspected anaphylaxis/hypersensitivity reactions per patient will be summarized using 
descriptive statistics.
The relative time of suspected event will be calculated as date/time of suspected event -
date/time of most current IMP administration and summarized using descriptive statistics. If a 
patient has more than one suspected anaphylaxis reactions, the earliest time will be used for the 
calculation.
Data will be listed.
8.6.
Electronic Columbia Suicide Severity Rating Scale
The eC-SSRS ‘Baseline/Screening’ version will be completed at visit 1, and the eC-SSRS ‘Since 
Last Visit’ version will be completed at all other visits (visits 2, 3, 4, and 5), including 
unscheduled visits. Any positive findings on the eC-SSRS ‘Since Last Visit’ version require 
evaluation by a physician or doctoral-level psychologist.
Data for patients with positive findings (having suicidal ideation or suicidal behavior) will be 
listed.
8.7.
Deaths
If any patient dies during the study, all relevant information will be discussed in the patient 
narrative included in the clinical study report.
8.8.
Clinical Laboratory Tests
Clinical laboratory tests (serum chemistry, hematology, coagulation, and urinalysis; see protocol 
Appendix K for the list) will be performed at all study visits using the central laboratory. All 
clinical laboratory test results outside of the reference range will be judged by the investigator as 
belonging to one of the following categories:

abnormal and not clinically significant

abnormal and clinically significant
A laboratory test result that is judged by the investigator as clinically significant will be recorded 
on the source documentation and the CRF as an adverse event, and monitored as described in 
Section 7.1.2 of the protocol.
Laboratory test results will be presented in standard international (SI) units in summaries.
Laboratory values and changes from baseline to each visit in the double-blind treatment period 
and Last Assessment (see Section 4.4) will be summarized using descriptive statistics. Shifts 
(below [low], within [normal], and above [high] the normal range) from baseline to each visit in 
the double-blind treatment period and the Last Assessment will be summarized using patient 


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counts. Baseline is defined as the last observed data before the administration of the first dose of 
the IMP (also see Section 4.2).
The potentially clinically significant abnormal values will be derived using criteria specified in 
Table 2 based on all postbaseline values (including scheduled, unscheduled, and withdrawal
visits). The overall incidence of potentially clinically significant abnormal values will be 
summarized for laboratory variables using descriptive statistics by treatment group. Listings for 
patients who have potentially clinically significant abnormal laboratory data will be presented.
Table 2:
Criteria for Potentially Clinically Significant Laboratory Values
Test
Criterion value
Serum chemistry
ALT
3x ULN
AST
3x ULN
ALP
3x ULN
GGT
3x ULN
LDH
3x ULN
BUN
10.71 mmol/L
Creatinine
177 mol/L
Bilirubin (total)
34.2 mol/L
Hematology
Hematocrit
Men
<0.37 L/L
Women
<0.32 L/L
Hemoglobin
Men
115 g/L
Women
95 g/L
WBC counts
3 x 109/L 
20 x 109/L
Eosinophils
10%
ANC
1 x 109/L
Platelet counts
75 x 109/L 
700 x 109/L
Urinalysis
HGB
2 unit increase from baseline
Glucose
2 unit increase from baseline
Ketones
2 unit increase from baseline
Total protein
2 unit increase from baseline


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ALP=alkaline phosphatase; ALT=alanine aminotransferase; ANC=absolute neutrophil count AST=aspartate 
aminotransferase; BUN=blood urea nitrogen; GGT=gamma- glutamyl transpeptidase; HGB=hemoglobin; 
LDH=lactate dehydrogenase; RBC=red blood cell; ULN=upper limit of normal range; WBC=white blood cell
Pregnancy tests will be performed for all women of childbearing potential. Test results will be 
listed.
Current menstruating status (yes or no) will be collected at all female patients. The data will be 
listed.
8.8.1.
Laboratory Values Meeting Hy’s Law Criteria
All occurrences of possible drug-induced liver injury that meet Hy’s law criteria as defined in the
Section 7.1.5.1 of the study protocol will be included in serious adverse events reporting.
8.9.
Physical Examinations
Physical examinations will be performed at visits 1, 2, and 5. Any physical examination finding 
that is judged by the investigator as a clinically significant change (worsening) compared with a 
baseline value will be considered an adverse event, recorded on the CRF, and monitored as 
described in Section 7.1.2 of the study protocol.
Abnormal physical examination findings will be listed.
Weight and height will be summarized and listed with vital signs data.
8.10.
Vital Signs
Vital signs (pulse, systolic and diastolic blood pressure, and body temperature) will be measured 
visit 1 through visit 5. Weight will be measured at all study visits. Any vital sign value that is 
judged by the investigator as a clinically significant change (worsening) from a baseline value 
will be considered an adverse event, recorded on the source documentation and transcribed onto 
the CRF, and monitored as described in Section 7.1.2 of the protocol.
Vital signs (including weight) values and changes from baseline to each visit in the double-blind 
treatment period and the Last Assessment (see Section 4.4) will be summarized using descriptive 
statistics. The incidence of potentially clinically significant abnormal values will be summarized 
for selected vital signs using descriptive statistics. Baseline is defined as the last observed data 
before the administration of the first dose of the IMP (also see Section 4.2).
Table 3 specifies the criteria for identifying vital signs as potentially clinically significant 
abnormal values. Note that in order to qualify as potentially clinically significant abnormal, a 
value needs to meet both criteria below ie, have a value beyond the criterion value and a change 
of at least the magnitude specified in the change relative to baseline column. The potentially 
clinically significant abnormal vital signs values will include all postbaseline values (including 
scheduled, unscheduled, and early withdrawal visits) for the summaries.


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Table 3:
Criteria for Potentially Clinically Significant Vital Signs
Vital Sign
Criterion value
Change relative to baseline
Pulse
120 bpm
Increase of 15 bpm
50 bpm
Decrease of 15 bpm
Systolic blood pressure
180 mm Hg
Increase of 20 mm Hg
90 mm Hg
Decrease of 20 mm Hg
Diastolic blood pressure
105 mm Hg
Increase of 15 mm Hg
50 mm Hg
Decrease of 15 mm Hg
Temperature
≥38.3C
Change of 1.1C
bpm=beats per minute
Height will be measured at screening visit, and data will be listed in the vital sign listing.
8.11.
Electrocardiography
Triplicate 12-lead ECGs will be collected at study visits. Any ECG finding that is judged by the 
investigator as a potentially clinically significant change (worsening) compared with a baseline 
value will be considered an adverse event, recorded on the source documentation and in the 
CRF, and monitored as described in Section 7.1.2 of the protocol.
For ECG variables, the mean of recorded results from last three measurements at a visit will be 
calculated. The mean results and mean changes from baseline to each visit in the double-blind 
treatment period and Last Assessment (see Section 4.4) will be summarized using descriptive 
statistics. Baseline is determined based on the last set of observed data before the administration 
of the first dose of the IMP.
For ECG findings, the worst value of recorded from last three findings at a visit will be used for 
analysis. Baseline ECG findings and shifts (normal, abnormal not clinically significant, and 
abnormal clinically significant) from baseline to each visit in the double-blind treatment period,
overall (worst value for a patient), and the Last Assessment (worst value of recorded findings
from the last visit) will be summarized using patient counts.
8.12.
Concomitant Medications or Therapies 
Concomitant medications, treatments, or procedures will be recorded throughout the study.
All concomitant medications will be coded using the WHO Drug. The incidence of concomitant 
medications will be summarized using descriptive statistics by therapeutic class and preferred 
term. Patients are counted only once in each therapeutic class category, and only once in each 
preferred term category. The concomitant medications will include all medications taken after 
administration of the first IMP.
The subset of medications or therapies will be summarized by the indication categories as 
indicated in Section 5.5.


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9.
TOLERABILITY VARIABLES AND ANALYSIS
Injection site reaction adverse events will be listed and summarized descriptively. See
Section 8.3.


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10.
PHARMACOKINETIC ANALYSIS
Pharmacokinetic plasma concentration results for fremanezumab will be tabulated descriptively 
at each planned sampling time point. The summary will be based on the safety analysis set. At 
the open-label period, pharmacokinetic plasma concentration results will be tabulated 
descriptively at each planned sampling time point per treatment group. The plasma concentration 
will be listed by scheduled visits, time points and treatment. 


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11.
PHARMACOGENOMIC ANALYSIS
Pharmacogenomic analysis will be conducted to correlate clinical observations 
(pharmacokinetic, safety, efficacy, or other effects) with genotypes observed in the study. 
Pharmacogenomic analysis may be conducted at a later time and will be reported in a separate 
addendum report.


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12.
PHARMACOKINETIC/PHARMACODYNAMIC ANALYSIS
The pharmacokinetic/pharmacodynamic relationship analysis if performed will be reported 
separately.


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13.
BIOMARKER ANALYSIS
 
 


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14.
IMMUNOGENICITY ANALYSIS
A summary of immunogenicity results will be provided, and the incidence of immunogenicity 
will be calculated. The impact of immunogenicity on the pharmacokinetic profile, fremanezumab 
efficacy, and clinical safety will be evaluated.


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15.
PLANNED INTERIM ANALYSIS
There will be no formal interim analysis. However, a database lock from the double-blind period 
will occur following the completion of visit 5 by the last patient. Unblinding will occur after the 
database lock from the double-blind period.


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16.
STATISTICAL SOFTWARE
All data listings, summaries, and statistical analyses will be generated using SAS® version 9.4 or 
later.


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17.
CHANGES TO ANALYSES SPECIFIED IN THE STUDY 
PROTOCOL
None.


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18.
REFERENCES
Scoring Software (v5.0) Copyright© 2004, 2007, 2009, 2010, 2016 QualityMetric Incorporated 
24 Albion Road, Bldg 400. Lincoln, R.I. 02865, U.S.A.


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