Clinical trial NCT03107052
Conditions: Cluster Headache
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc.
Start date: 2017-04-27; Completion date: 2019-06-11
Enrollment: 275 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a 68-week study to evaluate the long-term safety and efficacy of fremanezumab in participants with cluster headache (CH). Participants who complete the pivotal studies TV48125-CNS-30056 (NCT02945046) and TV48125-CNS-30057 (NCT02964338) and enroll into the current study will visit the investigational center for investigational medicinal product (IMP) administration, safety and efficacy assessments, and blood and urine collections for pharmacokinetics, immunogenicity (anti-drug antibodies \[ADAs\]), and biomarker analyses. Participants will return to the investigational center for a follow-up visit to evaluate ADAs, fremanezumab concentrations, biomarkers, and safety (adverse events and concomitant medications) approximately 7.5 months after the last dose of IMP.

Detailed description:

Arms: arm 1: Participants with ECH or CCH who received fremanezumab at 900 mg intravenous (IV) infusion at Week 0 and fremanezumab at 225 mg subcutaneous (SC) injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30056 or TV48125-CNS-30057, and participants with CCH who received fremanezumab at 675 mg SC injection at Week 0 and placebo SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30057; will receive fremanezumab at 225 mg SC injection monthly (approximately every 4 weeks, administered as single SC injection of fremanezumab at 225 mg \[225 mg/1.5 milliliter {mL}\] at Week 0 and 36; and 2 placebo SC injections at Weeks 0, 12, 24, and 36 for blinding in participants rolled over from Study TV48125-CNS-30056; fremanezumab at 225 mg as a single SC injection (225 mg/1.5 mL) at Week 0, 12, 24, and 36; 2 SC injections of placebo at Week 0 for blinding in participants rolled over from Study TV48125-CNS-30057) through Week 36 in this study. arm 2: Participants with CCH who received placebo IV infusion and SC injection at Week 0 and placebo SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30057; will receive fremanezumab 675 mg SC injection as loading dose (administered as 3 SC injections of fremanezumab at 225 mg \[225 mg/1.5 mL\] at Week 0) followed by monthly (approximately every 4 weeks) fremanezumab at 225 mg SC injection (administered as single SC injection of fremanezumab at 225 mg \[225 mg/1.5 mL\] at Weeks 12, 24, and 36) through Week 36. arm 3: Participants with ECH who received fremanezumab at 675 mg SC injection at Week 0 and placebo SC injection at Weeks 4 and 8, respectively in the pivotal study; or placebo IV infusion and SC injection at Week 0 and placebo SC injection at Weeks 4 and 8, respectively in the pivotal study TV48125-CNS-30056; will receive fremanezumab at 675 mg SC injection quarterly (approximately every 12 weeks, administered as 3 SC injections of fremanezumab at 225 mg \[225 mg/1.5 mL\] at Weeks 0 an 36; and single placebo SC injections at Weeks 4, 8, 16, 20, 28, and 32 for blinding) through Week 36.
Interventions: intervention 1: Fremanezumab
Intervention descriptions: intervention 1: Fremanezumab

Protocol documents:
Prot_000.pdf: 
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Uncontrolled Study–Cluster Headache
Clinical Study Protocol with Amendment 04
Study TV48125-CNS-30058
1
 
Clinical Study Protocol with Amendment 04
Study Number TV48125-CNS-30058
A Multicenter, Double-Blind, Double-Dummy Study to Explore the Long-Term Safety and 
Efficacy of TEV-48125 for the Prevention of Cluster Headache
Safety and Efficacy Study (Phase 3)
IND number: 129606
EudraCT number: 2016-003172-43
EMA Decision number of Pediatric Investigation Plan: Not Applicable
Article 45 or 46 of 1901/2006 does not apply
Protocol with Amendment 04 Approval Date: 28 August 2018
Protocol Approval Date: 08 August 2016
Sponsor
Teva Branded Pharmaceutical 
Products R&D, Inc. 
41 Moores Road
Frazer, Pennsylvania 19355
United States of America
Information regarding clinical laboratories and other departments and institutions is 
found in Appendix A.
Confidentiality Statement
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).
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.
© 2018 Teva Branded Pharmaceutical Products R&D, Inc. All rights reserved.


Uncontrolled Study–Cluster Headache
Clinical Study Protocol with Amendment 04
Study TV48125-CNS-30058
2
AMENDMENT HISTORY
The protocol for Study TV48125-CNS-30058 (original protocol dated 08 August 2016) has been 
amended and reissued as follows:
Amendment 04
ROW-28 August 2018
Sweden 28 August 2018
Amendment 03
ROW-26 April 2018
Sweden 07 June 2018
Amendment 02
ROW-03 May 2017
Sweden-19 October 2017
No patients randomized/enrolled to date
Amendment 01
30 November 2016
No patients randomized/enrolled to date
Protocol approval
08 August 2016
Letter of Clarification-USM
ROW-04 April 2018
US-06 April 2018
Letter of Clarification 08
14 March 2018
Letter of Clarification 07 (Sweden 
Only)
18 October 2017
Letter of Clarification 06
27 August 2017
Letter of Clarification 05
10 May 2017
Letter of Clarification 04
13 December 2016
Letter of Clarification 03
03 November 2016
Letter of Clarification 02
10 October 2016
Letter of Clarification 01
09 September 2016
The Summary of Changes to the Protocol includes the corresponding reason/justification for 
each change and is provided in Section 16.


Uncontrolled Study–Cluster Headache
Clinical Study Protocol with Amendment 04
Study TV48125-CNS-30058
3
INVESTIGATOR AGREEMENT
Clinical Study Protocol with Amendment 04
Original Protocol Dated 08 August 2016
IND number: 129606; EudraCT number: 2016-003172-43
EMA Decision number of Pediatric Investigation Plan: Not Applicable
Article 45 or 46 of 1901/2006 does not apply
A Multicenter, Double-Blind, Double-Dummy Study to Explore the Long-Term Safety and Efficacy 
of TEV-48125 for the Prevention of Cluster Headache
Principal Investigator: 
Title:
Address of Investigational Center:
Tel:
I have read the protocol with Amendment 04 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
SPONSOR PROTOCOL APPROVAL


Uncontrolled Study–Cluster Headache
Clinical Study Protocol with Amendment 04
Study TV48125-CNS-30058
4
COORDINATING INVESTIGATOR AGREEMENT
Clinical Study Protocol with Amendment 04
Original Protocol Dated 08 August 2016
IND number: 129606; EudraCT number: 2016-003172-43
EMA Decision number of Pediatric Investigation Plan: Not Applicable
Article 45 or 46 of 1901/2006 does not apply
A Multicenter, Double-Blind, Double-Dummy Study to Explore the Long-Term Safety and 
Efficacy of TEV-48125 for the Prevention of Cluster Headache
I have read the protocol with Amendment 04 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 approval of this protocol and 
attachments, and provides assurance that this study will be conducted according to all 
stipulations of the protocol, including all statements regarding confidentiality, and according to 
national and local legal and regulatory requirements and applicable regulations and guidelines.
I will make available the protocol and all information on the investigational medicinal product 
(IMP) that were furnished to me by the sponsor to all physicians and other study personnel 
responsible to me who participate in this study and will discuss this material with them to ensure 
that they are fully informed regarding the IMP and the conduct of the study. I agree to keep 
records on all patient information, IMP shipment and return forms, and all other information 
collected during the study, in accordance with national and local Good Clinical Practice (GCP) 
regulations. In addition I will assume the responsibility of the coordinating investigator 
according to a separate contract.
Coordinating Investigator:
________________________________________
Title:
________________
Address of Investigational Center: _
_
________
 _______________________
Tel:
Coordinating Investigator
Signature
Date


Uncontrolled Study–Cluster Headache
Clinical Study Protocol with Amendment 04
Study TV48125-CNS-30058
5
CLINICAL STUDY PROTOCOL SYNOPSIS
with Amendment 04
Study TV48125-CNS-30058
Title of Study: A Multicenter, Double-Blind, Double-Dummy Study to Explore the Long-Term 
Safety and Efficacy of TEV-48125 for the Prevention of Cluster Headache
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc.
Investigational New Drug (IND) Number: 129606
EudraCT Number: 2016-003172-43
EMA Decision number of Pediatric Investigation Plan: Not applicable
Article 45 or 46 of 1901/2006 does not apply
Name of Test Investigational Medicinal Product (IMP): Fremanezumab (TEV-48125)
EudraVigilance (EV) code for the IMP, if applicable: SUB181665
Type of the Study: Safety and Efficacy Study (Phase 3)
Indication: Cluster headache (CH)
Is this study conducted to investigate the New Use of an approved, marketed product? No
Number of Investigational Centers Planned: Approximately 80
Countries Planned: Approximately 12
Planned Study Period: Approximately 42 months, Q1/2017 (first patient in) to Q2/2020 (last 
patient last visit)
Number of Patients Planned (total): Prior to 15 June 2018, up to 600 patients from the Phase 3 
pivotal efficacy studies (Studies TV48125-CNS-30056 and TV48125-CNS-30057) are expected 
to enroll in this study.
Prior to 15 June 2018, patients rolled over from the episodic TV48125-CNS-30056 and chronic 
TV48125-CNS-30057 cluster headache studies into the Long Term Safety study 
(TV48125-CNS-30058). 
As of 15 June 2018, the chronic cluster headache (CCH) Study TV48125-CNS-30057 was 
terminated based on the study meeting pre-specified stopping criteria (conditional power < 25%)
during a planned interim analysis. Thus, all CCH patients included in this study have been asked 
to discontinue treatment, and are encouraged to continue in the anti-drug antibody (ADA) and 
safety follow-up portion of this study. At the time of unblinding the treatment code in
Study TV48125-CNS-30057 (planned for Q4 2018), those CCH patients who were receiving 
placebo in Study TV48125-CNS-30057 (ie, never received any study drug) will not be required 
to complete additional safety follow-up visits, and will be discharged from the study.
As of 15 June 2018, only patients from the episodic cluster headache (ECH) Study 
TV48125-CNS-30056 will enroll in this study for active treatment.


Uncontrolled Study–Cluster Headache
Clinical Study Protocol with Amendment 04
Study TV48125-CNS-30058
6
Study Population: The study population will be composed of male and female patients, 18 to 
70 years of age, inclusive, with a history of CH (chronic and episodic forms), as defined by 
International Classification of Headache Disorders, third revision beta criteria (Headache 
Classification Committee of the International Headache Society 2013), who participated in the 
Phase 3 pivotal efficacy studies (Studies TV48125-CNS-30056 and TV48125-CNS-30057) prior 
to 15 June 2018. After 15 June 2018, only patients who participated in the ECH study 
(Study TV48125-CNS-30056) will be enrolled in this study for active treatment.
Primary and Secondary Objectives and Endpoints: 
As of 15 June 2018, only patients from the ECH study (Study TV48125-CNS-30056) will enroll 
in this study for active treatment. As of 15 June 2018, all CCH patients included in this study 
have been asked to discontinue treatment, and are encouraged to continue in the ADA and safety 
follow-up portion of this study. Data from CCH patients enrolled prior to 15 June 2018 will be 
evaluated per all objectives of this study.


Uncontrolled Study–Cluster Headache
Clinical Study Protocol with Amendment 04
Study TV48125-CNS-30058
7
Objectives
Endpoints
The primary objective of this 
study is to evaluate the 
long-term safety of 
fremanezumab in adult patients 
with CH.
Safety endpoints are as follows:
occurrence of adverse events throughout the study
changes from baseline (day 0 of the Phase 3 pivotal 
efficacy studies) in clinical laboratory (serum 
chemistry, hematology, coagulation, and urinalysis) 
test results
changes from baseline (day 0 of the Phase 3 pivotal 
efficacy studies) in vital signs (pulse, systolic and 
diastolic blood pressure, and oral temperature) 
measurements 
Note: Oxygen saturation will be measured in cases 
of suspected anaphylaxis and severe 
hypersensitivity. Respiratory rate will also be 
measured in these cases but not as a standard vital 
sign.
abnormal standard 12-lead electrocardiogram (ECG) 
findings
clinically significant changes in physical 
examination, including body weight
occurrence of injection site reactions (ie, erythema, 
induration, and ecchymosis) and injection site pain
occurrence of anaphylaxis and hypersensitivity 
reactions
use of concomitant medications during the study
suicidal ideation and behavior as measured by the 
electronic Columbia-Suicide Severity Rating Scale 
(eC-SSRS)
There are no secondary objectives and secondary endpoints in this study.
Immunogenicity Assessment Objectives and Endpoints:
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)


Uncontrolled Study–Cluster Headache
Clinical Study Protocol with Amendment 04
Study TV48125-CNS-30058
8
Exploratory Objectives and Endpoints:
Exploratory objectives are:

 



 

 
Exploratory endpoints are:

 

 

 

 
 


 
 

 
 
Wearable sensor substudy exploratory objectives are the following:

 

 

 


Uncontrolled Study–Cluster Headache
Clinical Study Protocol with Amendment 04
Study TV48125-CNS-30058
9

 

 

 

 

 


Wearable sensor substudy exploratory endpoints are the following:

 

 

 

 

 

 

 

 

 


Uncontrolled Study–Cluster Headache
Clinical Study Protocol with Amendment 04
Study TV48125-CNS-30058
10


 
 
General Design:
This is a 68-week extension study to evaluate the long-term safety and efficacy of fremanezumab
in adult patients with CH. During the course of any CH attack, patients will be allowed to use 
acute medications to treat acute headaches, as needed (PRN).
Upon completion of the final study assessments, early withdrawal from the study or 
discontinuation for any reason, patients will be offered the opportunity to enter a 32-week 
long-term safety study (as described in Study TV48125-CNS-30058) for safety and ADA 
evaluation without additional dosing. Patients who satisfactorily complete the study may be 
offered to enroll the long-term safety study TV 48125-CNS-30058 for 68 weeks (as described in 
this study protocol) to receive additional dosing and a final follow-up visit for safety and ADA 
evaluation. In any case, during the period of the long-term safety study, where patients are not 
receiving additional dosing (and are waiting for ADA evaluation), these patients should be 
treated with standard of care as appropriate. 
Prior to 15 June 2018, up to 360 eligible patients with ECH and CCH rolling over from the 
pivotal studies (Studies TV48125-CNS-30056 and TV48125-CNS-30057, respectively) will 
receive fremanezumab during this study as summarized in Table 1. After 15 June 2018, only 
patients who participated in the ECH study (Study TV48125-CNS-30056) will be enrolled in this 
study for active treatment. At the time of unblinding the treatment code in 
Study TV48125-CNS-30057 (planned for Q4 2018), those CCH patients who were receiving 
placebo in Study TV48125-CNS-30057 (ie, never received any study drug) will not be required 
to complete additional safety follow-up visits, and will be discharged from the study.


Uncontrolled Study–Cluster Headache
Clinical Study Protocol with Amendment 04
Study TV48125-CNS-30058
11
Table 1:
Summary of Treatments During Study TV48125-CNS-30058
Study number
Treatment group in pivotal 
study
Treatment in the long-term safety extension studya, b
Study 
TV48125-CNS-
30056 (ECH)
Fremanezumab 900-mg iv 
loading dose groupc
Fremanezumab at 225 mg sc monthly (approximately every 4 
weeks) through week 36
Fremanezumab 675-mg sc 
quarterly groupd
Fremanezumab at 675 mg sc quarterly (approximately every 12 
weeks) through week 36
Placebo groupe
Fremanezumab at 675 mg sc quarterly (approximately every 12 
weeks) through week 36
Study 
TV48125-CNS-
30057 
Prior to 
15 June 2018 
termination of 
CCH Study 
TV48125-CNS-
30057.
No additional 
CCH patients 
will be enrolled 
after 
15 June 2018 
for active 
treatment.
Fremanezumab 900-mg iv 
loading dose groupc
Fremanezumab at 225 mg sc monthly (approximately every 4 
weeks) through week 36
Fremanezumab 675-mg sc 
loading dose groupf
Fremanezumab at 225 mg sc monthly (approximately every 4 
weeks) through week 36
Placebo groupe
Fremanezumab 675-mg sc loading dose followed by monthly 
(approximately every 4 weeks) fremanezumab at 225 mg sc 
through week 36
a In order to maintain blinding throughout the study, the number of sc injections at each visit will be the same for all 
patients rolling over from Study TV48125-CNS-30056, regardless of their assigned treatment group. Thus, 
patients will receive 3 sc injections of test IMP (1.5 mL-injections each containing fremanezumab at a 
concentration of 150 mg/mL) or 1 injection of test IMP (1.5-mL injection containing fremanezumab at a 
concentration of 150 mg/mL) and 2 sc injections of placebo IMP (1.5-mL injections) at visits 1, 4, 7, and 10, and a 
single sc injection of test IMP or placebo IMP at visits 2, 3, 5, 6, 8, and 9.
b In order to maintain blinding throughout the study, the number of sc injections at each visit will be the same for all 
patients rolling over from Study TV48125-CNS-30057, regardless of their assigned treatment group. Thus, 
patients will receive 3 sc injections of either test IMP (1.5-mL injections each containing fremanezumab at a 
concentration of 150 mg/mL) or 1 sc injection of test IMP (1.5-mL injection containing fremanezumab at a 
concentration of 150 mg/mL) and 2 sc injections of placebo IMP (1.5-mL injections) at visit 1, and patients will 
receive a single sc injection of test IMP (1.5-mL injection containing fremanezumab at a concentration of 
150 mg/mL) at all other visits.
c Fremanezumab at 900 mg iv at visit 2 (week 0) of the pivotal study and fremanezumab at 225 mg sc at visits 3 and 
4 (weeks 4 and 8, respectively) of the pivotal study.
d Fremanezumab at 675 mg sc at visit 2 (week 0) of the pivotal study and placebo sc at visits 3 and 4 (weeks 4 and 
8, respectively) of the pivotal study.
e Placebo iv and sc at visit 2 (week 0) of the pivotal study and placebo sc at visits 3 and 4 (weeks 4 and 8, 
respectively) of the pivotal study.
f Fremanezumab at 675 mg sc at visit 2 (week 0) of the pivotal study and fremanezumab at 225 mg sc at visits 3 and 
4 (weeks 4 and 8, respectively) of the pivotal study.
CCH=chronic cluster headache; ECH=episodic cluster headache; IMP=investigational medicinal product; 
iv=intravenous; sc=subcutaneous.
Patients with a diagnosis of ECH who experience CH remission, defined as no CH attacks for 
12 successive weeks at any time after starting IMP (ie, administration of the first dose of IMP in 


Uncontrolled Study–Cluster Headache
Clinical Study Protocol with Amendment 04
Study TV48125-CNS-30058
12
the pivotal study), will be offered the possibility to stop treatment and continue to attend the 
subsequent scheduled visits. If treatment is stopped and CH attacks resume within 12 weeks after 
stopping treatment, patients will restart treatment at their previous dose regimen through 
week 36. If treatment is stopped and CH attacks resume after more than 12 weeks after stopping 
treatment, patients will restart fremanezumab treatment at 675 mg subcutaneous (sc) quarterly 
through week 36.
Patients with a diagnosis of CCH who experience CH remission, defined as no CH attacks for 
24 successive weeks at any time after starting IMP (ie, administration of the first dose of IMP in 
the pivotal study), will be offered the possibility to stop treatment and continue to attend the 
subsequent scheduled visits. If treatment is stopped and CH attacks resume within 12 weeks after 
stopping treatment, patients will restart fremanezumab treatment at 225 mg sc monthly through 
week 36. If treatment is stopped and CH attacks resume after more than 12 weeks after stopping 
treatment, patients will restart fremanezumab treatment with a 675-mg sc loading dose followed 
by 225-mg sc monthly through week 36. After 15 June 2018, only patients who participated in 
the ECH study (Study TV48125-CNS-30056) will be enrolled for active treatment. All CCH 
patients included in this study have been asked to discontinue treatment and are encouraged to 
continue in the ADA and safety follow-up portion of this study.
All patients will return to the study center approximately every 4 weeks after administration of 
the first dose of the IMP (visit 1 [week 0]) through the end-of-treatment (EOT) visit (visit 11 
[week 40]), which will occur approximately 4 weeks after administration of the last dose of the 
IMP (week 36). Patients will return for a follow-up visit (visit 12) to evaluate ADAs, biomarkers, 
and safety (adverse events and concomitant medications) approximately 7.5 months after the last 
dose of the IMP. Patients who withdraw from the study before completing the 40-week treatment 
period will have EOT visit procedures and assessments performed on the last day the patients 
received the IMP or as soon as possible thereafter, and they will be asked to return for a 
follow-up visit approximately 7.5 months after their last dose of the IMP.
Patients who enter the long-term safety follow-up study for safety follow-up only will not follow 
the same visit schedule as that for patients receiving treatment. The procedures and assessments 
for the patients participating in the safety follow-up are described in Table 5. 
CH attack information will be captured daily throughout the treatment period (ie, visit 1 [week 0] 
through visit 11 [week 40]) using an electronic diary device. Assessments of change in quality of 
life, satisfaction with treatment, and health status (using the Hospital Anxiety and Depression 
Scale, EuroQol-5 Dimension questionnaire, 12-Item Short-Form Health Survey, Impact on 
Partner and Family questionnaire, and Work Productivity and Activity Impairment 
questionnaire); satisfaction with treatment (using the Patient Perceived Satisfactory Improvement 
and Patient Global Impression of Change scale); safety evaluations; blood collection for 
pharmacokinetic, immunogenicity, and biomarker analyses; and urine sampling for biomarker 
analysis will be performed at pre-specified time points.
The long-term safety of fremanezumab in patients with CH will be evaluated through adverse 
event and concomitant medication inquiries, ECGs, vital signs measurements, clinical laboratory 
tests, physical examinations, injection site assessments, assessments for anaphylaxis and 
hypersensitivity, and administration of the eC-SSRS.


Uncontrolled Study–Cluster Headache
Clinical Study Protocol with Amendment 04
Study TV48125-CNS-30058
13
Wearable Sensor Substudy: Patients rolling over from the Phase 3 pivotal efficacy studies who 
also enrolled in the wearable sensor substudy will be allowed to continue in this substudy during 
this long-term safety extension study provided they consent to continuing their participation. 
These patients will return to the investigational center for up to 2 additional visits after any dose 
of the IMP for blood sampling for pharmacokinetics analysis, triplicate 12-lead ECGs, and 
inquiries about adverse events and concomitant medications. After 15 June 2018, only patients 
who participated in the ECH study (Study TV48125-CNS-30056) will be enrolled for active 
treatment. All CCH patients included in this study have been asked to discontinue treatment and 
are encouraged to continue in the ADA and safety follow-up portion of this study.
Brief Summary of Study Design for the Trial Registry(s):
This is a 68-week extension study to evaluate the long-term safety and efficacy of fremanezumab 
in adult patients with CH. Patients who complete the pivotal studies and enroll into the current 
study (at visit 1 [week 0]) will visit the investigational center approximately every 4 weeks for 
36 weeks for IMP administration (fremanezumab at 675 mg sc quarterly, 225 mg sc monthly, or 
a loading dose of 675 mg sc followed by 225 mg sc monthly), safety assessments, and blood and 
urine collections for pharmacokinetics, immunogenicity (ADAs), and biomarker analyses. An 
EOT visit will occur approximately 4 weeks after administration of the last dose of IMP. Patients 
will return to the investigational center for a follow-up visit to evaluate ADAs, biomarkers, and 
safety (adverse events and concomitant medications) approximately 7.5 months after the last 
dose of IMP.
The long-term safety of fremanezumab in patients with CH will be evaluated through adverse 
event and concomitant medication inquiries, ECGs, vital signs measurements, clinical laboratory 
tests, physical examinations, injection site assessments, assessments for anaphylaxis and 
hypersensitivity, and administration of the eC-SSRS. Efficacy will be evaluated using CH attack 
data entered daily throughout the treatment period in an electronic diary and administration of 
questionnaires to evaluate change in quality of life, satisfaction with treatment, and health status. 
In addition, blood will be collected for pharmacokinetics, immunogenicity, and biomarkers, 
(blood for pharmacogenomics is collected during the pivotal studies), and urine will be collected 
for biomarker analysis.
Method of Randomization and Blinding:
This is a double-blind study; blinding will be retained from the pivotal studies and throughout 
this long-term safety extension study. Patients will be assigned to treatments as described in 
Table 1 based on their randomization in the pivotal studies (Studies TV48125-CNS-30056 and 
TV48125-CNS-30057). Refer to the protocols for the pivotal studies 
(Studies TV48125-CNS-30056 and TV48125-CNS-30057) for details regarding randomization 
of patients in this study. After 15 June 2018, only patients who participated in the ECH study 
(Study TV48125-CNS-30056) will be enrolled for active treatment.
Packaging vendor(s) will package test IMP and placebo IMP into single-visit kits according to 
Good Manufacturing Practice procedures. Kits will be identical in appearance. Adequate kit 
supply for upcoming study visits will be managed by interactive response technology (IRT) and 
kept (refrigerated at 2°C to 8°C) at the investigational centers.


Uncontrolled Study–Cluster Headache
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Study TV48125-CNS-30058
14
At visits 1 through 10, the IRT will be queried, and investigational center personnel will retrieve 
and administer each prefilled syringe contained in the appropriately numbered kit(s). Kit 
numbers will be entered into the case report form.
In the event that the IRT system is not functioning for emergency unblinding, the next course of 
action is to contact via phone the IRT on-call customer support helpline for manual emergency 
unblinding.
Investigational Medicinal Products: Dose, Pharmaceutical Form, Route of Administration, 
and Administration Rate:
IMPs are defined as the test IMP and placebo IMP (Table 2).
Table 2:
Investigational Medicinal Products Used in the Study
IMP name
Test IMP
Placebo IMP
Trade name and INN, if 
applicable, or 
company-assigned 
number
Fremanezumab (TEV-48125 [formerly 
LBR-101, PF-04427429, or RN307])
n/a
Formulation
Solution for injection
Solution for injection
Unit dose strength(s)
dosage level(s)
225 mg/1.5 mL
675 mg sc quarterly, 225 mg sc 
monthly, or 675 mg sc loading dose 
followed by 225 mg monthly
n/a
Route of administration
Fremanezumab will be administered as 
sc injections (1.5 mL per injection) by 
qualified study personnel at the study 
center.
Placebo will be administered as sc 
injections (1.5 mL per injection) by 
qualified study personnel at the study 
center.
Packaging
Fremanezumab will be provided in 
prefilled syringes contained in 
uniquely numbered kits and stored 
(refrigerated at 2°C to 8°C) at the 
investigational centers. Prefilled 
syringes (1.5 mL) will contain 
fremanezumab at a concentration of 
150 mg/mL. 
Placebo will be provided in prefilled 
syringes contained in uniquely numbered 
kits and stored (refrigerated at 2°C to 8°C) 
at the investigational centers. Prefilled 
syringes (1.5 mL) will contain the same 
vehicle and excipients as those for active 
infusion and injection.
Manufacturer
Teva Branded Pharmaceutical 
Products R&D, Inc.
Teva Branded Pharmaceutical Products 
R&D, Inc.
IMP=investigational medicinal product; INN=International Nonproprietary Name; n/a=not applicable; 
sc=subcutaneous.
Patients who received fremanezumab during the pivotal studies at 225 mg sc monthly after a 
loading dose of 900-mg intravenously or 675 mg sc or fremanezumab at 675 mg sc quarterly 
during the pivotal studies will continue receiving the same dose (ie, 225 mg sc monthly or 
675 mg sc quarterly depending upon their diagnosis and randomization in the pivotal studies) 
during this long-term safety extension study. These dose regimens are expected to maintain
steady state at a blood concentration level that will provide clinical efficacy. The doses and 


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dosing regimens also account for the natural history of the 2 forms of CH; patients with ECH are 
likely to remit after initial treatment whereas CCH patients are continuously inflicted by pain. 
Patients who received placebo during the pivotal studies will be assigned to receive either 
fremanezumab 675 mg sc quarterly (patients with ECH from Study TV48125-CNS-30056) or a 
loading dose 675 mg sc followed by monthly fremanezumab at 225 mg sc monthly (patients with 
CCH from Study TV48125-CNS-30057). This will provide these patients with the opportunity to 
receive potential benefit from therapeutic doses including the loading dose of 675 mg sc. After 
15 June 2018, only patients who participated in the ECH study (Study TV48125-CNS-30056) 
will be enrolled for active treatment. All CCH patients included in this study have been asked to 
discontinue treatment and are encouraged to continue in the ADA and safety follow-up portion 
of this study. At the time of unblinding the treatment code in Study TV48125-CNS-30057 
(planned for Q4 2018), those CCH patients who were receiving placebo in 
Study TV48125-CNS-30057 (ie, never received any study drug) will not be required to complete
further safety follow-up visits and will be discharged from the study.
When the cluster cycle is almost over in ECH, the number of headache attacks per day start to 
decrease with associated mild to moderate intensity. Patients often look for preventive options in 
the very early part of the headache cycle in an attempt to reduce its duration. Equally, when 
complete remission is achieved patients with ECH consider stopping their medication and thus 
withdraw from treatment when the cluster period is over (May 2005). Accordingly, continuous 
long-term treatment in ECH might not be needed as these patients may have long remission 
periods between the cluster episodes. Patients with CCH may face a different situation, where the 
remission period is very short (less than a month). These patients might be more inclined to 
continue with long-term preventive treatment. Thus, the current study will evaluate the concept 
of intermittent treatment in both ECH and CCH; IMP administration may be discontinued in 
patients with CH remission (defined in ECH as patients with at least 12 successive weeks of no 
CH attacks at any time after starting IMP and in CCH as patients with at least 24 successive 
weeks of no CH attacks at any time after starting IMP).
Differentiating between remission periods lasting 12 weeks or less and remission period lasting 
more than 12 weeks after treatment has been stopped, dictates the need for the administration of 
a loading dose of fremanezumab at 675 mg sc when remission lasted for more than 12 weeks (as 
most of the drug is eliminated after 12 weeks). Thereafter, the doses and dosing regimens are 
identical to those in the pivotal studies for each CH form (ie, 225 mg sc monthly for CCH and 
675 mg sc quarterly for ECH). If treatment is stopped and headache attacks restart within 
12 weeks of stopping the treatment, patients will proceed with their previous dose, which is 
expected to re-establish efficacy and which maintains the differentiation between the 2 CH 
forms. After 15 June 2018, only patients who participated in the ECH study 
(Study TV48125-CNS-30056) will be enrolled for active treatment.
Test IMP: Fremanezumab
Reference IMP: None
Placebo IMP: Same vehicle and excipients as those for fremanezumab
Duration of Patient Participation and Maximal Exposure to IMP: Participation of patients 
who enroll in this study for the purpose of evaluating the long-term safety and efficacy of 


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fremanezumab will last for approximately 68 weeks (not including participation in the Phase 3 
pivotal efficacy studies). 
Study Duration: Approximately 42 months from Q1/2017 to Q2/2020
End of Study: End of study is defined as the date the last patient attends the follow-up visit.
Plans for Treatment or Care after the Patient Has Ended Participation in the Study: Not 
applicable
Inclusion Criteria: Patients may be included in the treatment portion of the study only if they 
meet all of the following criteria: 
a.
The patient is a male or female and 18 to 70 years of age, inclusive, at the start of the 
pivotal study.
b. The patient signs and dates the informed consent document.
c.
The patient completes either the Phase 3 pivotal study for ECH 
(Study TV48125-CNS-30056) or the Phase 3 pivotal study for CCH 
(Study TV48125-CNS-30057) without important protocol deviations related to 
patient safety and patient compliance and at least 75% diary data completion during 
the pivotal study. Prior to 15 June 2018, patients from the ECH study and the CCH 
study were enrolled. After 15 June 2018, only patients who participated in the ECH 
study (Study TV48125-CNS-30056) will be enrolled for active treatment.

In addition, patients who do not complete the pivotal efficacy studies, and patients 
who complete the pivotal efficacy studies but will not continue treatment during 
this long-term safety study, will be offered to enroll in this study for the purpose 
of evaluating ADAs and safety (adverse events and concomitant medications) 
approximately 7.5 months after administration of the last dose of the IMP.
d. Women may be included only if they have a negative beta-human chorionic 
gonadotropin test at visit 1; are sterile or postmenopausal; and are not lactating (not 
applicable for patients participating in safety follow-up only). Definitions of sterile 
and postmenopausal are given in Appendix E.
e.
Women of childbearing potential (WOCBP) whose male partners are potentially 
fertile (ie, no vasectomy) must use highly effective birth control methods (see
Appendix E) for the duration of the study and for 7.5 months after discontinuation of 
IMP. 
Men must be sterile or, if they are potentially fertile/reproductively competent (not 
surgically [eg, vasectomy] or congenitally sterile), and their female partners are of 
childbearing potential, must agree to use, together with their female partners, 
acceptable birth control methods for the duration of the study and for 7.5 months after 
administration of IMP. 
Definitions of women of non-childbearing potential, sterile and postmenopausal 
women; male contraception; and highly effective and acceptable birth control 
methods, including examples, are given in Appendix E.


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f.
The patient must be willing to stop concomitant medications used in clinical practice 
for the prevention of CH (ie, verapamil, topiramate, valproate, lithium, or 
methysergide) for the duration of this study. Patients must begin tapering these 
preventive medications as soon as they begin this study. The period of time needed to 
taper off these medications will be based on the investigator’s medical judgment but 
should not exceed 1 month from the beginning of participation in this study 
(Appendix H) (not applicable for patients participating in safety follow-up only).
g. The patient is in good health in the opinion of the investigator as determined by a 
medical and psychiatric history; medical examination; 12-lead ECG; and serum 
chemistry, hematology, coagulation, and urinalysis (not applicable for patients 
participating in safety follow-up only). 
h. The patient must be willing and able to comply with study restrictions to remain at 
the clinic for the required duration during the study period and to return to the clinic 
for the follow-up evaluations, as specified in this protocol.
Exclusion Criteria: Patients will be excluded from participating in this study if they meet any of 
the following criteria 
a.
The patient has a history of any suicide attempt in the past or current active suicidal 
ideation, as measured by the eC-SSRS.
b. Any finding in the 12-lead ECG performed as part of the EOT visit (visit 5) 
procedures for the pivotal studies considered clinically significant in the judgment of 
the investigator 
c.
Any finding that, in the judgment of the investigator, is a clinically significant 
abnormality, including serum chemistry, hematology, coagulation, and urinalysis test 
values (abnormal tests may be repeated for confirmation)
d. Hepatic enzymes (alanine aminotransferase and aspartate aminotransferase) 
>1.5 × the upper limit of the normal range (ULN) after confirmation in a repeat test or 
suspected hepatocellular damage that fulfills criteria for Hy’s law
e.
Serum creatinine >1.5 × the ULN or evidence of clinically significant renal disease in 
the judgment of the investigator
Patients rolling over only for safety follow-up and ADA, who are not receiving study 
medication, are not required to fulfil all inclusion exclusion criteria.


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Statistical Considerations:
Sample Size Rationale: Up to 600 patients from the Phase 3 pivotal efficacy studies 
(Studies TV48125-CNS-30056 and TV48125-CNS-30057) are expected to enroll in this study. 
The sample size for each of the pivotal studies TV48125-CNS-30056 for ECH and 
TV48125-CNS-30057 for CCH is approximately 300 patients. All of the 600 patients 
participating in the pivotal studies will roll over to the long-term safety study. Approximately 
360 patients (out of the completers from the pivotal studies) will be offered to receive treatment 
during 40 weeks and these patients will return for a follow-up visit approximately 7.5 months 
after the last dose of the IMP. Approximately 240 patients (including early termination patients 
in the pivotal studies) will be offered to continue in a long-term safety evaluation collecting AEs, 
SAEs, and for ADA evaluation approximately 7.5 months after administration of the last dose of 
the IMP. 
Prior to 15 June 2018, patients from ECH TV48125-CNS-30056 and CCH 
TV48125-CNS-30057 studies were enrolled. After 15 June 2018, only patients who participated 
in the ECH study (Study TV48125-CNS-30056) will be enrolled for active treatment.
Analysis of Primary Endpoint: The primary endpoints for this study are related to safety. Refer 
to the safety analysis section below for details.
Analysis of Secondary Endpoints: Not applicable
Primary Efficacy Analysis: Not applicable
Sensitivity Analysis: Not applicable
Secondary Efficacy Analysis: Not applicable
Multiple Comparisons and Multiplicity: Not applicable
Exploratory Efficacy Analysis:
 
 
 


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All efficacy variables will be summarized descriptively overall, by indication (ECH or CCH), 
and by treatment group. For continuous variables, descriptive statistics (number of patients [n], 
mean, standard deviation [SD], and standard error of mean, median, minimum, and maximum) 
will be provided for actual values and changes from baseline to each visit. For categorical 
variables, frequency and percentage will be provided.
Baseline is defined as the baseline in the pivotal efficacy studies.
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) (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.
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 IMP.
Changes in laboratory, ECG, and vital signs measurements data will be summarized 
descriptively. All values will be compared with pre-specified boundaries to identify potentially 
clinically significant changes or values, and such values will be listed.
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 also be provided.
Suicidal ideation and behavior will be measured using the eC-SSRS. Data for patients with 
positive findings will be listed.
If any patient dies during the study, a listing of deaths will be provided, and all relevant 
information will be discussed in the patient narrative included in the clinical study report.
Tolerability Analysis: Tolerability was not specifically defined.
Pharmacokinetics Analysis: Pharmacokinetic plasma concentration results (fremanezumab) 
will be tabulated descriptively at each planned sampling time point by diagnosis (ECH or CCH) 
and by treatment.
In addition, the most appropriate population pharmacokinetic model will be developed, and 
covariates that may affect it will be tested for inclusion in the model. This analysis will be 
reported separately.
Pharmacodynamics Analysis: Not applicable


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Pharmacokinetics/Pharmacodynamics Analysis: The pharmacokinetics/pharmacodynamics 
parameters may be estimated by compartmental techniques. The pharmacokinetics parameters 
will be based on fremanezumab measurements. The pharmacodynamics parameters will be the 
efficacy/safety response(s). 
The pharmacokinetics/pharmacodynamics relationship may be estimated using the most 
appropriate model after comparing different candidate models for their quality of fit. Covariates 
that may affect the pharmacokinetics/pharmacodynamics parameters will be tested for inclusion 
in the model. If performed, this analysis will be reported separately.
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, IMP efficacy, and clinical safety will be evaluated. This ADA-impact 
analysis will be reported separately.
Exploratory Biomarker Analysis: Exploratory biomarker measurements will be made using 
appropriately validated assays. Results, if generated, will typically be expressed as % change 
from baseline and reported in a separate addendum report.
Pharmacogenomic Analysis: Pharmacogenomic analysis results will be summarized for each 
gene tested. An attempt will be made to correlate clinical observations (pharmacokinetics, safety, 
efficacy, or other effects) with the genotypes observed. Additional pharmacogenomic analysis 
may be conducted at a later time and will be reported in a separate addendum report. 
Ancillary Study Analysis: Analysis will include summary statistics and multimodal algorithms 
to monitor physiological activity, sleep/wake activity, and treatment responses. Results will be 
reported separately.
Planned Interim Analysis: Not applicable


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TABLE OF CONTENTS
TITLE PAGE...................................................................................................................................1
AMENDMENT HISTORY .............................................................................................................2
INVESTIGATOR AGREEMENT...................................................................................................3
COORDINATING INVESTIGATOR AGREEMENT...................................................................4
CLINICAL STUDY PROTOCOL SYNOPSIS...............................................................................5
LIST OF ABBREVIATIONS........................................................................................................29
1.
INTRODUCTION AND BACKGROUND INFORMATION ..................................31
1.1.
Introduction.................................................................................................................31
1.1.1.
Cluster Headache........................................................................................................31
1.1.2.
Rationale for Fremanezumab Development as a Preventive Treatment for 
Cluster Headache........................................................................................................32
1.1.3.
Study Purpose.............................................................................................................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 ..........................................................................36
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) ..................................................................................................37
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...............................................................................39
2.2.
Exploratory Objectives and Endpoints.......................................................................39
2.2.1.
Exploratory Objectives and Endpoints.......................................................................39
2.2.2.
Wearable Sensor Substudy Exploratory Objectives and Endpoints...........................40
3.
STUDY DESIGN .......................................................................................................42
3.1.
General Design and Study Schematic Diagram..........................................................42
3.2.
Planned Number of Patients and Countries................................................................48
3.3.
Justification for Study Design and Selection of Population.......................................48
3.4.
Stopping Rules for the Study......................................................................................49


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3.5.
Schedule of Study Procedures and Assessments........................................................49
4.
SELECTION AND WITHDRAWAL OF PATIENTS..............................................55
4.1.
Patient Inclusion Criteria ............................................................................................55
4.2.
Patient Exclusion Criteria...........................................................................................56
4.3.
Withdrawal Criteria and Procedures for the Patient...................................................56
4.4.
Replacement of Patients .............................................................................................58
4.5.
Rescreening.................................................................................................................58
4.6.
Screening Failure........................................................................................................58
5.
TREATMENTS..........................................................................................................59
5.1.
Investigational Medicinal Products Used in the Study...............................................59
5.1.1.
Test Investigational Medicinal Product......................................................................60
5.1.1.1.
Starting Dose and Dose Levels...................................................................................60
5.1.2.
Placebo Investigational Medicinal Product ................................................................61
5.2.
Preparation, Handling, Labeling, Storage, and Accountability for 
Investigational Medicinal Products ............................................................................61
5.3.
Justification for Investigational Medicinal Products..................................................61
5.3.1.
Justification for Dose of Test Investigational Medicinal Product ..............................61
5.4.
Restrictions .................................................................................................................62
5.4.1.
Activity .......................................................................................................................62
5.4.2.
Blood Donation...........................................................................................................62
5.4.3.
Pregnancy ...................................................................................................................62
5.5.
Prior and Concomitant Medication or Therapy..........................................................62
5.6.
Procedures for Monitoring Patient Compliance .........................................................63
5.7.
Temporary Discontinuation of Investigational Medicinal Product ............................63
5.8.
Randomization and Blinding......................................................................................63
5.9.
Maintenance of Randomization and Blinding............................................................64
5.9.1.
Maintenance of Randomization..................................................................................64
5.9.2.
Blinding and Unblinding ............................................................................................64
5.9.3.
Data Monitoring Committee.......................................................................................65
5.10.
Total Blood Volume ...................................................................................................65
6.
ASSESSMENT OF EFFICACY ................................................................................66
6.1.
Assessments of Efficacy.............................................................................................66
6.2.
Electronic Diary Device .............................................................................................66


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6.3.
Hospital Anxiety and Depression Scale .....................................................................66
6.4.
EuroQol-5 Dimension Questionnaire .........................................................................67
6.5.
Twelve-Item Short-Form Health Survey....................................................................67
6.6.
Work Productivity and Activity Impairment Questionnaire ......................................67
6.7.
Impact on Partner and Family Questionnaire .............................................................67
6.8.
Patient-Perceived Satisfactory Improvement .............................................................68
6.9.
Patient Global Impression of Change Scale ...............................................................68
7.
ASSESSMENT OF SAFETY.....................................................................................69
7.1.
Adverse Events ...........................................................................................................69
7.1.1.
Definition of an Adverse Event..................................................................................69
7.1.2.
Recording and Reporting of Adverse Events .............................................................70
7.1.3.
Severity of an Adverse Event .....................................................................................70
7.1.4.
Relationship of an Adverse Event to the Test Investigational Medicinal 
Product........................................................................................................................71
7.1.5.
Serious Adverse Events..............................................................................................71
7.1.5.1.
Definition of a Serious Adverse Event .......................................................................72
7.1.5.2.
Expectedness...............................................................................................................73
7.1.5.3.
Reporting a Serious Adverse Event............................................................................73
7.1.6.
Protocol-Defined Adverse Events not for Expedited Reporting ................................75
7.1.7.
Protocol-Defined Adverse Events of Special Interest ................................................75
7.1.8.
Protocol Deviations Because of an Adverse Event ....................................................75
7.2.
Pregnancy ...................................................................................................................75
7.3.
Medication Error and Special Situations Related to the Investigational 
Medicinal Products .....................................................................................................76
7.4.
Clinical Laboratory Tests ...........................................................................................77
7.4.1.
Serum Chemistry, Hematology, and Urinalysis .........................................................77
7.4.1.1.
Human Chorionic Gonadotropin Tests.......................................................................77
7.5.
Physical Examinations................................................................................................78
7.6.
Vital Signs ..................................................................................................................78
7.7.
Electrocardiography....................................................................................................78
7.8.
Immunogenicity..........................................................................................................79
7.9.
Assessment of Suicidality...........................................................................................79
7.10.
Concomitant Therapy or Medication..........................................................................80


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7.11.
Injection Site Assessments .........................................................................................80
8.
ASSESSMENT OF PHARMACOKINETICS/BIOMARKERS/ 
IMMUNOGENICITY/ANCILLARY STUDIES.......................................................82
8.1.
Pharmacokinetics Assessment....................................................................................82
8.2.
Pharmacodynamics Assessment.................................................................................82
8.3.
Immunogenicity Testing.............................................................................................82
8.4.
Assessment of Exploratory Biomarkers .....................................................................82
8.5.
Pharmacogenomics.....................................................................................................83
8.6.
Ancillary Study – Wearable Sensor Substudy............................................................83
9.
STATISTICS ..............................................................................................................85
9.1.
Sample Size and Power Considerations .....................................................................85
9.2.
Analysis Sets...............................................................................................................85
9.2.1.
Intent-to-Treat Analysis Set........................................................................................85
9.2.2.
Safety Analysis Set.....................................................................................................85
9.2.3.
Full Analyses Set ........................................................................................................85
9.2.4.
Per-Protocol Analysis Set...........................................................................................85
9.3.
Data Handling Conventions........................................................................................86
9.3.1.
Definition of Baseline.................................................................................................86
9.3.2.
Handling Withdrawals and Missing Data...................................................................86
9.4.
Study Population.........................................................................................................86
9.4.1.
Patient Disposition......................................................................................................86
9.4.2.
Demographic and Baseline Characteristics ................................................................86
9.5.
Efficacy Analysis........................................................................................................86
9.5.1.
Primary Endpoint........................................................................................................87
9.5.2.
Secondary Endpoints ..................................................................................................87
9.5.3.
Exploratory Endpoints................................................................................................87
9.5.4.
Planned Method of Analysis.......................................................................................88
9.5.4.1.
Primary Efficacy Analysis..........................................................................................88
9.5.4.2.
Sensitivity Analysis ....................................................................................................88
9.5.4.3.
Secondary Efficacy Analysis......................................................................................88
9.5.4.4.
Exploratory Efficacy Analysis....................................................................................89
9.6.
Multiple Comparisons and Multiplicity......................................................................89
9.7.
Safety Analysis ...........................................................................................................89


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9.8.
Tolerability Analysis ..................................................................................................89
9.9.
Pharmacokinetic Analysis ..........................................................................................90
9.10.
Pharmacokinetics/Pharmacodynamics Analysis ........................................................90
9.11.
Pharmacogenomic Analysis........................................................................................90
9.12.
Biomarker Analysis ....................................................................................................90
9.13.
Immunogenicity Analysis...........................................................................................90
9.14.
Ancillary Study Analysis............................................................................................90
9.15.
Planned Interim Analysis............................................................................................90
9.16.
Reporting Deviations from the Statistical Plan ..........................................................91
10.
QUALITY CONTROL AND QUALITY ASSURANCE .........................................92
11.
COMPLIANCE STATEMENT..................................................................................93
12.
DATA MANAGEMENT AND RECORD KEEPING ..............................................94
13.
FINANCING AND INSURANCE.............................................................................95
14.
PUBLICATION POLICY ..........................................................................................96
15.
REFERENCES ...........................................................................................................97
16.
SUMMARY OF CHANGES TO THE PROTOCOL ................................................99
16.1.
Amendment 04 Dated 28 August 2018 ......................................................................99
16.1.1.
Letter of Clarification 05 Dated 10 May 2017 .........................................................115
16.1.2.
Letter of Clarification 06 Dated 27 August 2017 to Correct a Typographical 
Error in Sweden Protocol Amendment 02................................................................118
16.1.3.
Letter of Clarification 07 Dated 18 October 2017....................................................121
16.1.4.
Letter of Clarification 08 Dated 14 March 2018 ......................................................124
16.1.5.
Letter of Clarification USM Dated 06 April 2016....................................................126
16.2.
Amendment 03 Dated 26 April 2018........................................................................127
16.3.
Amendment 02 Dated 03 May 2017.........................................................................134
16.4.
Amendment 01 Dated 30 November 2016 ...............................................................150
16.5.
Letter of Clarification 04 Dated 13 December 2016 ................................................162
APPENDIX A.
CLINICAL LABORATORIES AND OTHER DEPARTMENTS AND 
INSTITUTIONS.......................................................................................................165
APPENDIX B.
STUDY PROCEDURES AND ASSESSMENTS BY VISIT.........................169
Patients Enrolling in the Study from the Pivotal Studies.............................................................169
Patients Enrolling in This Study for Evaluation of Antidrug Antibodies and Safety 
(Adverse Events and Concomitant Medications) .....................................................180


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APPENDIX C.
QUALITY CONTROL AND QUALITY ASSURANCE ..............................182
APPENDIX D.
ETHICS ...........................................................................................................184
APPENDIX E.
WOMEN OF CHILDBEARING POTENTIAL AND BIRTH 
CONTROL METHODS ...........................................................................................185
APPENDIX F.
LOST TO FOLLOW-UP .................................................................................187
APPENDIX G.
HANDLING, LABELING, STORAGE, AND ACCOUNTABILITY 
FOR INVESTIGATIONAL MEDICINAL PRODUCT(S) .....................................188
APPENDIX H.
PREVENTIVE CLUSTER HEADACHE MEDICATIONS AND 
DISALLOWED MEDICATIONS............................................................................190
APPENDIX I.
ICHD-3 BETA DIAGNOSTIC CRITERIA .....................................................191
APPENDIX J.
GUIDANCE ON SAFETY MONITORING....................................................193
APPENDIX K.
CLINICAL CRITERIA FOR DIAGNOSING ANAPHYLAXIS...................196
APPENDIX L.
TOTAL BLOOD VOLUME............................................................................197
APPENDIX M.
CLINICAL LABORATORY TESTS.............................................................198
APPENDIX N.
PHARMACOKINETICS SAMPLES .............................................................199
APPENDIX O.
IMMUNOGENICITY SAMPLES ..................................................................200
APPENDIX P.
EXPLORATORY BIOMARKERS SAMPLES ..............................................201
APPENDIX Q.
PHARMACOGENOMIC ASSESSMENTS...................................................202
APPENDIX R.
PRODUCT COMPLAINTS ............................................................................203
APPENDIX S.
DATA MANAGEMENT AND RECORD KEEPING....................................205
APPENDIX T.
PUBLICATION POLICY................................................................................208
APPENDIX U.
NATIONAL INSTITUTES OF HEALTH PATIENT EDUCATION 
GUIDELINES OF SEPTEMBER 2015 ...................................................................209


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LIST OF TABLES
Table 1:
Summary of Treatments During Study TV48125-CNS-30058..................................11
Table 2:
Investigational Medicinal Products Used in the Study...............................................14
Table 3:
Summary of Treatments During Study TV48125-CNS-30058..................................43
Table 4:
Study Procedures and Assessments for Treated Patients ...........................................50
Table 5:
Study Procedures and Assessments for Patients Rolling Over from the 
Pivotal Efficacy Studies for Evaluation of Antidrug Antibodies and Safety 
(Adverse Events and Concomitant Medications) Only ..............................................54
Table 6:
Investigational Medicinal Products Used in the Study...............................................59
Table 7:
The Relationship of an Adverse Event to the Test Investigational Medicinal 
Product........................................................................................................................71
Table 8:
Severity of Pain Scale for Injection Site Assessments ...............................................80


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LIST OF FIGURES
Figure 1:
Overall Study Schematic Diagram .............................................................................46


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LIST OF ABBREVIATIONS
Abbreviation
Term
ADA
antidrug antibody
ALT
alanine aminotransferase
ALP
alkaline phosphatase
AST
aspartate aminotransferase
AUC
area under the plasma concentration-time curve
AUC0-∞
area under the plasma concentration-time curve from time 0 to infinity
β-HCG
beta-human chorionic gonadotropin
CBC
complete blood cell
CCH
chronic cluster headache
CDMS
clinical data management system
CFR
Code of Federal Regulations (USA)
CGRP
calcitonin gene-related peptide
CH
cluster headache
CIOMS
Council for International Organizations of Medical Sciences
CL
Clearance
CL/F
apparent total plasma clearance 
Cmax
maximum observed concentration
CRF
case report form (refers to any media used to collect study data [ie, paper or electronic])
CRO
contract research organization
eC-SSRS
electronic Columbia-Suicide Severity Rating Scale
CYP
cytochrome P450
ECG
Electrocardiogram
ECH
episodic cluster headache
EFD
embryo/fetal developmental toxicity
EOT
end-of-treatment
EQ-5D
EuroQol-5 Dimension
FAS
full analysis set
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GGT
gamma glutamyl transpeptidase
GLP
Good Laboratory Practice
HADS
Hospital Anxiety and Depression Scale
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
ICHD
International Classification of Headache Disorders-third edition beta


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Abbreviation
Term
IEC
Independent Ethics Committee
Ig
Immunoglobulin
IHS
International Headache Society
IMP
investigational medicinal product
INR
international normalized ratio
IRB
Institutional Review Board
IRT
interactive response technology
ITT
intent-to-treat
iv
intravenous(ly)
LSO
local safety officer
n
number of patients
PEF
peak expiratory flow
PGIC
Patient Global Impression of Change
PPSI
Patient-Perceived Satisfactory Improvement
RSI
reference safety information
RTSM
Randomization and Trial Supply Management 
sc
subcutaneous(ly)
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
time to maximum observed concentration
ULN
upper limit of the normal range
VIP
vasoactive intestinal peptide
Vss
volume of distribution at steady state
Vz/F
apparent total volume of distribution during the terminal phase
WOCBP
women of childbearing potential
WPAI
Work Productivity and Activity Impairment


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1.
INTRODUCTION AND BACKGROUND INFORMATION
1.1.
Introduction
1.1.1.
Cluster Headache
Cluster headache (CH) is a primary headache disorder characterized by repetitive attacks of 
excruciating unilateral head pain and associated with cranial autonomic features (such as 
lacrimation, conjunctival injection, nasal congestion, nasal rhinorrhea, and partial Horner’s 
syndrome) (Rozen 2005). CH attacks last up to 180 minutes and occur from once every other day 
to 8 times a day. Cluster periods usually last a few months (typically 3 months) followed by 
remission periods of months to years (Headache Classification Committee of the International 
Headache Society [IHS] 2013). A unique feature of CH is the circadian and circannual 
periodicity nature of the headache attacks. Peak time periods for daily CH onset are 0100 to 
0200, 1300 to 1500, and after 2100, with night awakening attacks being more severe than those 
occurring during the day (Rozen 2005). Some patients tend to have seasonal attacks related to the 
duration of the photoperiod, with the highest incidence of attacks occurring in January or July 
with possible relation to solstices or equinoxes (Kudrow 1987). 
There are 2 forms of CH: episodic cluster headache (ECH), which is the most common form, 
where distinct pain-free periods lasting at least 1 month are evident, and chronic cluster headache 
(CCH) occurring for more than 1 year without remission or with remission periods lasting less 
than 1 month. About 10% to 15% of patients with CH have the CCH form (Headache 
Classification Committee of the IHS 2013). 
The pathophysiology of CH is complex and not fully understood. Current theories implicate 
mechanisms such as vascular dilation, trigeminal nerve stimulation, and circadian effects. 
Histamine release, an increase in mast cells, genetic factors, and autonomic nervous system 
activation may also contribute (Weaver-Agostoni 2013). However, 3 major features of CH are 
the main focus for understanding its pathophysiological model: trigeminal distribution of the 
pain (including association with neuropeptide level changes), ipsilateral cranial autonomic 
features, and (circadian) episodic pattern of attacks (May 2005).
The excruciatingly severe unilateral pain is likely to be mediated by activation of the first 
(ophthalmic) division of the trigeminal nerve, whereas the autonomic symptoms such as 
lacrimation are due to activation of the cranial parasympathetic outflow from the seventh cranial 
nerve (Goadsby 2002). When the trigeminal system becomes highly activated, the excitation 
spreads to the superior salivary nucleus, resulting in excitation from the sphenopalatine ganglion 
to parasympathetic nerves of intracranial large blood vessels, lacrimal glands, and nasal mucosa. 
As a result, ipsilateral autonomic symptoms such as Horner’s sign, lacrimation, nasal congestion, 
and rhinorrhea are manifested (Goadsby 2002, Japanese Headache Society 2013). Stimulation of 
the superior sagittal sinus activates the trigeminovascular pathway, and this also results in the 
release of neuropeptides such as calcitonin gene-related peptide (CGRP) and vasoactive 
intestinal peptide (VIP) in the external jugular vein. During attacks, the levels of CGRP and VIP 
are raised in cranial venous blood in all patients.


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1.1.2.
Rationale for Fremanezumab Development as a Preventive Treatment for 
Cluster Headache
Worldwide, there are currently no approved medications for the preventive treatment of CH, and 
medications used off-label in clinical practice for this indication lack meaningful evidence to 
support their use. Among the medications used for ECH and CCH are short-course 
corticosteroids for transitional prophylaxis and verapamil (the most common first-line 
treatment), anti-seizure drugs (valproic acid, topiramate), ergotamine, melatonin, and capsaicin 
for maintenance prophylaxis. Lithium and deep-brain stimulation have also been used as 
preventive treatments for CCH (Weaver-Agostoni 2013). Each of these treatment options is 
suboptimal due to limited evidence of efficacy, troublesome side effects, and/or an unfavorable 
risk to benefit ratio (Rozen 2005, Weaver-Agostoni 2013).
Teva is developing fremanezumab (TEV-48125) for the preventive treatment of CH (chronic and 
episodic forms). Fremanezumab is a potent, selective CGRP binder and blocks both CGRP 
isoforms (α- and β-CGRP) from binding to the CGRP receptor. Fremanezumab is highly specific 
for CGRP and does not bind to closely related family members amylin, calcitonin, and 
intermedin. It demonstrates a very weak binding interaction with adrenomedullin 
 
. Two mutations were introduced into the constant region of 
the fremanezumab heavy chain to limit antibody effector functions. This loss of function 
prevents fremanezumab from stimulating antibody-dependent cell-mediated cytotoxicity and 
triggering complement-mediated lysis; these activities can lead to unwanted consequences such 
as cell lysis, opsonization, and cytokine release and inflammation (Armour et al 1999, Zeller et al 
2008).
Similar to migraine, the trigeminal system plays a pivotal role in the pathophysiology of CH. 
During CH attacks, activation of the trigeminal system causes neurovascular inflammation 
mediated by CGRP and other neuropeptides (Fanciullacci et al 1995, Fanciullacci et al 1997, 
Goadsby and Edvinsson 1994). In CH, the generator appears to be in the posterior grey matter of 
the hypothalamus (third neuron) (May et al 1999). Blocking CGRP in the peripheral ganglia of 
the trigeminal system should result in desensitization of the first and second neurons of the 
trigeminal system. Fremanezumab does not cross the blood brain barrier, but its demonstrated 
safety profile (briefly summarized in Section 1.2) provides an opportunity to block the peripheral 
CGRP released in the trigeminal system, leading to a further desensitization of the third-order 
neuron in the hypothalamus. Thus, fremanezumab could potentially normalize the system and 
prevent further attacks without having central nervous system secondary effects. 
Few, if any, medical disorders are more painful than CH. Treatments that provide quick and 
lasting relief (ie, for the duration of the cluster period) and that prevent CH attacks are therefore 
a priority for this patient population. Results from the Phase 2b studies of fremanezumab 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) suggest that fremanezumab may fulfil these treatment needs for patients with CH.
1.1.3.
Study Purpose
The purpose of the current study is to evaluate the long-term safety and efficacy of 
fremanezumab administered subcutaneously (sc) to adult patients with CH.


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Prior to 15 June 2018, patients rolled over from the episodic TV48125-CNS-30056 and chronic 
TV48125-CNS-30057 cluster headache studies into the Long Term Safety study 
(TV48125-CNS-30058). 
As of 15 June 2018, CCH Study TV48125-CNS-30057 was terminated based on the study 
meeting pre-specified stopping criteria (conditional power < 25%) during a planned interim 
analysis. The planned interim analysis was for futility evaluation based on 50% of patients (ie, 
the first 150 patients who had completed the study or withdrawn from the study early). An 
independent unblinded statistician from a third party performed the analysis. The futility 
evaluation was assessed using conditional power. The sponsor was notified that the conditional 
power was less than 25% for both comparisons (fremanezumab 900 mg iv loading dose group 
versus placebo or fremanezumab 675 mg sc loading dose group versus placebo). Thus, all CCH 
patients included in this study have been asked to discontinue treatment and are encouraged to 
continue in the ADA and safety follow-up portion of this study.
At the time of unblinding the treatment code in Study TV48125-CNS-30057 (planned for 
Q4 2018), those CCH patients who were receiving placebo in Study TV48125-CNS-30057 (ie,
never received any study drug) will not be required to complete additional safety follow-up 
visits, and will be discharged from the study.
As of 15 June 2018, only patients from the ECH study (Study TV48125-CNS-30056) will enroll 
in this study for active treatment.
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).
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 


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monkeys, and no toxicological concerns were identified following chronic dosing to 
experimental animals at dose levels up to 300 mg/kg/week. 
 
 
 
 
 
 
 
 
 
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 (NOAEL), is at least 54-fold 
higher 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.
 
In a GLP embryo/fetal developmental toxicity (EFD) 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 EFD 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 zero 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 in this package support the safe, 
repeated (monthly) administration of fremanezumab in human subjects for the duration of the 
Phase 3 pivotal trials (3 months) and the long-term safety extension (1 year).
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 


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(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 5 ongoing clinical 
studies of fremanezumab: 2 pivotal efficacy studies in patients with migraine (1 study each for 
patients with chronic migraine and patients with episodic migraine 
[Studies TV48125-CNS-30049 and TV48125-CNS-30050]); a long-term safety study in patients 
with migraine (Study TV48125-CNS-30051); a pharmacokinetic, safety, and tolerability Phase 1 
study in healthy Japanese and Caucasian subjects (Study TV48125-PK-10078); and a Phase 1 
study (Study TV48125-BE-10114) comparing the pharmacokinetics of fremanezumab 
administered sc using a device referenced to a prefilled syringe configuration. 
Further details may be found in the current IB.
1.2.2.1.
Clinical Pharmacology Studies
The clinical pharmacology development (Phase 1) program for fremanezumab in migraine 
includes 8 completed studies. A total of 318 healthy subjects were enrolled, of which 
256 subjects received at least 1 dose of fremanezumab. 
 
 
. A description of the objectives of these 6 Phase 1 studies is as follows:

Studies B0141001 and B0141002 were iv single-dose escalation PK and PD studies 
in healthy men.

Study B0141006 was a 2-cohort, placebo-controlled crossover study to examine the 
acute effects of iv administration of fremanezumab on capsaicin flare response in 
healthy men.

Study B0141007 was a parallel-group, repeat-dose PK and PD study of iv 
administration of fremanezumab in healthy men and women.

Study LBR-101-008 was a single-dose study examining the safety, tolerability, PK, 
and PD of doses up to 2000 mg of fremanezumab administered iv to healthy women.

Study LBR-101-011 was a randomized, placebo-controlled, double-blind, 
parallel-group study examining the safety, tolerability, absolute bioavailability (BA), 
and PK of 2 different single doses of fremanezumab administered iv or sc to healthy 
men and women.
Two additional Phase 1 studies, Studies TV48125-PK-10078 and TV48125-BE-10114, were 
conducted using the current validated bioanalytical method. A description of the objectives of 
these 2 Phase 1 Studies is as follows:

Study TV48125-PK-10078 was a randomized, double-blind, placebo-controlled study 
to assess the PK, safety, and tolerability of single-dose sc administration of 
fremanezumab (single ascending doses and single doses up to 900 mg) in Japanese 
and Caucasian healthy subjects.


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
Study TV48125-BE-10114 was an open-label, single-dose, randomized, parallel, 
bioequivalence study to compare the PK of fremanezumab administered sc using an 
auto-injector or a pre-filled syringe in healthy adult men and women.
Additional ongoing bioequivalence study (TV48125-BE-10145) is another open-label, 
single-dose, randomized, parallel, bioequivalence study to compare the PK of fremanezumab 
administered sc using an auto-injector or a pre-filled syringe in healthy adult men and women.
The pharmacokinetics (non-compartmental analysis; Study TV48125-PK-10078) of 
fremanezumab demonstrated an increase in Cmax and AUC values slightly greater than the dose 
proportionality over the sc dose range of 225 to 900 mg. Median time to maximum observed 
concentration (tmax) values was generally 5 to 7 days post sc doses. Mean values for apparent 
total volume of distribution during the terminal phase (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 plasma 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 were similar 
for healthy Japanese and Caucasian subjects. 
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 
ongoing Phase 1 study (Study TV48125-PK-10078), and no serious adverse events considered 
related to the investigational medicinal product (IMP) have been reported for the ongoing pivotal 
efficacy studies (Studies TV48125-CNS-30049 and TV48125-CNS-30050, 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.


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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/exploratory 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 swelling, injection site pain, injection site pruritus, injection site dermatitis, injection site 
rash, injection site edema, 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, injection site rash, injection site induration, and injection site pruritus. 
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 
diphenhydramine and methylprednisolone. Neither of these identified risks are considered 
important risks.
Potential risks for fremanezumab include perivascular inflammation; development of antidrug 
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. 
The benefit and risk assessment for fremanezumab has been re-assessed for patients with CCH. 
As of 15 June 2018, the CCH study (Study TV48125-CNS-30057) was terminated based on the 
study meeting pre-specified stopping criteria (conditional power < 25%) during a planned 
interim analysis. Thus, all CCH patients included in this study have been asked to discontinue 
treatment and are encouraged to continue in the ADA and safety follow-up portion of this study.


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2.
STUDY OBJECTIVES AND ENDPOINTS
2.1.
Primary and Secondary Study Objectives and Endpoints
As of 15 June 2018, only patients from the ECH study (Study TV48125-CNS-30056) will enroll 
in this study for active treatment. As of 15 June 2018, all CCH patients included in this study 
have been asked to discontinue treatment and are encouraged to continue in the ADA and safety 
follow-up portion of this study. Data from CCH patients enrolled prior to 15 June 2018 will be 
evaluated per all objectives of this study.
The primary and secondary study objectives and endpoints are:
Objectives
Endpoints
The primary objective of this 
study is to evaluate the 
long-term safety of 
fremanezumab in adult patients 
with cluster headache (CH).
Safety endpoints are as follows:

occurrence of adverse events throughout the study 

changes from baseline (day 0 of the Phase 3 pivotal 
efficacy studies) in clinical laboratory (serum chemistry, 
hematology, coagulation, and urinalysis) test results

changes from baseline (day 0 of the Phase 3 pivotal 
efficacy studies) in vital signs (pulse, systolic and diastolic 
blood pressure, and oral temperature) measurements

Note: Oxygen saturation will be measured in cases of 
suspected anaphylaxis and severe hypersensitivity. 
Respiratory rate will also be measured in these cases but 
not as a standard vital sign.

abnormal standard 12-lead electrocardiogram (ECG) 
findings

clinically significant changes in physical examination, 
including body weight

occurrence of injection site reactions (ie, erythema, 
induration, and ecchymosis) and/or injection site pain

occurrence of anaphylaxis and hypersensitivity reactions

use of concomitant medications during the study

suicidal ideation and behavior as measured by the 
electronic Columbia Suicide Severity Rating Scale 
(eC-SSRS)
There are no secondary objectives and secondary endpoints in this study.


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Objectives
Endpoints
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)
2.1.1.
Justification of Primary Endpoint
The primary endpoints are standard safety endpoints for clinical studies to evaluate the long-term 
safety of a drug. Endpoints related to injection site reactions/injection site pain and 
anaphylaxis/hypersensitivity reactions are included based on identified risks of fremanezumab
(see Section 1.3.1). 
2.2.
Exploratory Objectives and Endpoints
2.2.1.
Exploratory Objectives and Endpoints
Exploratory objective are:
 
 
 
 
Exploratory endpoints are:
 
 
 
 
 


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2.2.2.
Wearable Sensor Substudy Exploratory Objectives and Endpoints
Wearable sensor substudy exploratory objectives are the following: 
 
 
 
 
 
 
 
 
Wearable sensor substudy exploratory endpoints are the following:
 
 


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
 
 
 


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3.
STUDY DESIGN
3.1.
General Design and Study Schematic Diagram
This is a 68-week extension study to evaluate the long-term safety and efficacy of fremanezumab
in adult patients with CH. During the course of any CH attack, patients will be allowed to use 
acute medications to treat acute headaches, as needed (PRN).
Upon completion of the final study assessments, early withdrawal from the study, or 
discontinuation for any reason, patients will be offered the opportunity to enter a 32-week 
long-term safety study (as described in this study protocol) for safety and ADA evaluation 
without additional dosing. Patients who satisfactorily complete the study may be offered to enroll 
the long-term safety study TV48125-CNS-30058 for 68 weeks (as described in this study 
protocol) to receive additional dosing and a final follow-up visit for safety and ADA evaluation. 
In any case, during the period of the long-term safety study, where patients are not receiving 
additional dosing (and are waiting for ADA evaluation), these patients should be treated with 
standard of care as appropriate.
Prior to 15 June 2018, up to 360 eligible patients with ECH and CCH rolling over from the 
pivotal studies (Studies TV48125-CNS-30056 and TV48125-CNS-30057, respectively) will 
receive fremanezumab during this study, as summarized in Table 3. After 15 June 2018, only 
patients who participated in the ECH study (Study TV48125-CNS-30056) will be enrolled in this 
study for active treatment. At the time of unblinding the treatment code in
Study TV48125-CNS-30057 (planned for Q4 2018), those CCH patients who were receiving 
placebo in Study TV48125-CNS-30057 (ie, never received any study drug) will not be required 
to complete additional safety follow-up visits, and will be discharged from the study.


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Table 3:
Summary of Treatments During Study TV48125-CNS-30058
Study number
Treatment group 
in pivotal study
Treatment in the long-term safety extension studya, b
Study TV48125-CNS-30056 
(ECH)
Fremanezumab 
900-mg iv 
loading dose 
groupc
Fremanezumab at 225 mg sc monthly (approximately every 
4 weeks) through week 36
Fremanezumab 
675-mg sc 
quarterly groupd
Fremanezumab at 675 mg sc quarterly (approximately every 
12 weeks) through week 36
Placebo groupe
Fremanezumab at 675 mg sc quarterly (approximately every 
12 weeks) through week 36
Study TV48125-CNS-30057 
(CCH)
Prior to 15 June 2018 
termination of CCH 
Study TV48125-CNS-30057.
No additional CCH patients 
will be enrolled after 
15 June 2018 for active 
treatment.
Fremanezumab
900-mg iv 
loading dose 
groupc
Fremanezumab at 225 mg sc monthly (approximately every 
4 weeks) through week 36
Fremanezumab
675-mg sc 
loading dose 
groupf
Fremanezumab at 225 mg sc monthly (approximately every 
4 weeks) through week 36
Placebo groupe
Fremanezumab 675-mg sc loading dose followed by monthly 
(approximately every 4 weeks) fremanezumab at 225 mg sc 
through week 36
a In order to maintain blinding throughout the study, the number of sc injections at each visit will be the same for all 
patients rolling over from Study TV48125-CNS-30056, regardless of their assigned treatment group. Thus, 
patients will receive 3 sc injections of test IMP (1.5-mL injections each containing fremanezumab at a 
concentration of 150 mg/mL) or 1 sc injection of test IMP (1.5-mL injection containing fremanezumab at a 
concentration of 150 mg/mL) and 2 sc injections of placebo IMP (1.5-mL injections) at visits 1, 4, 7, and 10, and a 
single sc injection of test IMP or placebo IMP at visits 2, 3, 5, 6, 8, and 9.
b In order to maintain blinding throughout the study, the number of sc injections at each visit will be the same for all 
patients rolling over from Study TV48125-CNS-30057, regardless of their assigned treatment group. Thus, 
patients will receive 3 sc injections of either test IMP (1.5-mL injections each containing fremanezumab at a 
concentration of 150 mg/mL) or 1 sc injection of test IMP (1.5-mL injection containing fremanezumab at a 
concentration of 150 mg/mL) and 2 sc injections of placebo IMP (1.5-mL injections) at visit 1, and patients will 
receive a single sc injection of test IMP (1.5-mL injection containing fremanezumab at a concentration of 
150 mg/mL) at all other visits.
c Fremanezumab at 900 mg iv at visit 2 (week 0) of the pivotal study and fremanezumab at 225 mg sc at visits 3 and 
4 (weeks 4 and 8, respectively) of the pivotal study.
d Fremanezumab at 675 mg sc at visit 2 (week 0) of the pivotal study and placebo sc at visits 3 and 4 (weeks 4 and 
8, respectively) of the pivotal study.
e Placebo iv and sc at visit 2 (week 0) of the pivotal study and placebo sc at visits 3 and 4 (weeks 4 and 8, 
respectively) of the pivotal study.
f Fremanezumab at 675 mg sc at visit 2 (week 0) of the pivotal study and fremanezumab at 225 mg sc at visits 3 and 
4 (weeks 4 and 8, respectively) of the pivotal study.
CCH=chronic cluster headache; ECH=episodic cluster headache; IMP=investigational medicinal product; 
iv=intravenous; sc=subcutaneous.
Patients with a diagnosis of ECH who experience CH remission, defined as no CH attacks for 
12 successive weeks at any time after starting IMP (ie, administration of the first dose of IMP in 
the pivotal study), will be offered the possibility to stop treatment and continue to attend the 


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subsequent scheduled visits. If treatment is stopped and CH attacks resume within 12 weeks after 
stopping treatment, patients will restart treatment at their previous dose regimen through 
week 36. If treatment is stopped and CH attacks resume after more than 12 weeks after stopping 
treatment, patients will restart fremanezumab treatment at 675 mg sc quarterly through week 36.
Patients with a diagnosis of CCH who experience CH remission, defined as no CH attacks for 
24 successive weeks at any time after starting IMP (ie, administration of the first dose of IMP in 
the pivotal study), will be offered the possibility to stop treatment and continue to attend the 
subsequent scheduled visits. If treatment is stopped and CH attacks resume within 12 weeks after 
stopping treatment, patients will restart fremanezumab treatment at 225 mg sc monthly through 
week 36. If treatment is stopped and CH attacks resume after more than 12 weeks after stopping 
treatment, patients will restart fremanezumab treatment with a 675-mg sc loading dose followed 
by 225-mg sc monthly through week 36. After 15 June 2018, only patients who participated in 
the ECH study (Study TV48125-CNS-30056) will be enrolled for active treatment. All CCH 
patients included in this study have been asked to discontinue treatment and are encouraged to 
continue in the ADA and safety follow-up portion of this study.
All patients will return to the investigational center approximately every 4 weeks after 
administration of the first dose of the IMP (visit 1 [week 0]) through the end-of-treatment (EOT) 
visit (visit 11 [week 40]), which will occur approximately 4 weeks after administration of the last 
dose of the IMP (week 36). Patients will return for a follow-up visit (visit 12) to evaluate ADAs, 
biomarkers, and safety (adverse events and concomitant medications) approximately 7.5 months 
after the last dose of the IMP. Patients who withdraw from the study before completing the 
40-week treatment period will have EOT visit procedures and assessments performed on the last 
day the patients received the IMP or as soon as possible thereafter, and they will be asked to 
return for a follow-up visit approximately 7.5 weeks after their last dose of IMP.
Patients who enter the long-term safety follow-up study for safety follow-up only will not follow 
the same visit schedule as that for patients receiving treatment. The procedures and assessments 
for the patients participating in the safety follow-up are described in Table 5.
CH attack information will be captured daily throughout the treatment period (ie, visit 1 [week 0] 
through visit 11 [week 40]) using an electronic diary device. Assessments of change in quality of 
life and health status (using the Hospital Anxiety and Depression Scale [HADS], EuroQol-5 
Dimension [EQ-5D] questionnaire, 12-Item Short-Form Health Survey [SF-12], Impact on 
Partner and Family questionnaire, and Work Productivity and Activity Impairment [WPAI] 
questionnaire); satisfaction with treatment (using the Patient-Perceived Satisfactory 
Improvement [PPSI] and the Patient Global Impression of Change [PGIC] scale); safety 
evaluations; blood collection for pharmacokinetic, immunogenicity, and biomarker analyses; and 
urine sampling for biomarker analysis will be performed at pre-specified time points (Table 4). 
The long-term safety of fremanezumab in patients with CH will be evaluated through adverse 
event and concomitant medication inquiries, ECGs, vital signs measurements, clinical laboratory 
tests, physical examinations, injection site assessments, assessments for anaphylaxis and 
hypersensitivity, and administration of the electronic Columbia-Suicide Severity Rating Scale 
(eC-SSRS).
The end of study is defined as the date the last patient attends the follow-up visit.
The study duration will be for approximately 42 months, from Q1/2017 to Q2/2020.


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The study schematic diagram for patients enrolling in this study for the purpose of evaluating the 
long-term safety and efficacy of fremanezumab is presented in Figure 1. 


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Figure 1:
Overall Study Schematic Diagram


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a As of 15 June 2018, only patients from the ECH study (Study TV48125-CNS-30056) will enroll in this study. As of 15 June 2018, all CCH patients included in 
this study have been asked to discontinue treatment, and are encouraged to continue in the ADA and safety follow-up portion of this study. At the time of 
unblinding the treatment code in Study TV48125-CNS-30057 (planned for Q4 2018), those CCH patients who were receiving placebo in Study 
TV48125-CNS-30057 (ie, never received any study drug) will not be required to complete additional safety follow-up visits, and will be discharged from the 
study.
b The run-in period for patients with ECH lasted at least 7 days (+3 days), and the run-in period for patients with CCH lasted at least 28 days (+3 days).
c Screening will occur at visit 1 of the Phase 3 pivotal efficacy studies. After 15 June 2018, only patients who participated in the ECH study
(Study TV48125-CNS-30056) will be enrolled for active treatment. 
d Visit 1 of this study corresponds to the EOT visit (visit 5) of the pivotal efficacy studies. The EOT visit procedures/assessments for the pivotal efficacy study 
must be completed before beginning visit 1 procedures/assessments. EOT visit procedures/assessments will not be repeated at visit 1 of this study. The EOT 
visit procedures/assessments are detailed in the protocols for Studies TV48125-CNS-30056 and TV48125-CNS-30057.
e Visit 11 corresponds to Visit 1 for the ADA and Safety follow-up portion of this study. 
ADA=anti-drug antibody; CCH=chronic cluster headache; ECH=episodic cluster headache; EOT=end-of-treatment; iv=intravenous; pts=patients; 
sc= subcutaneous; V=visit; W=week.
Note: Up to 600 patients from the Phase 3 pivotal efficacy studies (Studies TV48125-CNS-30056 and TV48125-CNS-30057) are expected to enroll in this study.


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Wearable Sensor Substudy: This substudy is being conducted to understand the utility of 
physiological biomarker measures captured through wearable digital sensor devices as tools to 
monitor response to treatment and disease symptoms (eg, activity/sleep disruption). Patients 
rolling over from the Phase 3 pivotal efficacy studies who also enrolled in the wearable sensor 
substudy will be allowed to continue in this substudy during this long-term safety extension 
study.
 
 
 
After 15 June 2018, only patients who participated in the ECH study
(Study TV48125-CNS-30056) will be enrolled for active treatment. All CCH patients included in 
this study have been asked to discontinue treatment and are encouraged to continue in the ADA 
and safety follow-up portion of this study.
3.2.
Planned Number of Patients and Countries
Prior to 15 June 2018, up to 600 patients from the Phase 3 pivotal efficacy studies (Studies 
TV48125-CNS-30056 and TV48125-CNS-30057) are expected to enroll in this study. After 
15 June 2018, only patients who participated in the ECH study (Study TV48125-CNS-30056)
will be enrolled in this study for active treatment.
The study is planned to be conducted in approximately 12 countries in approximately 
80 investigational centers. The study is expected to start in Q1/2017 (first patient in) and last 
until approximately Q2/2020 (last patient last visit).
3.3.
Justification for Study Design and Selection of Population
It is very important to recognize the significant difficulty of asking patients with CH to continue 
in a double-blind, placebo-controlled study beyond 3 months. Hence, in the current study, all 
patients will receive fremanezumab so that all patients have the opportunity to receive potential 
benefit from therapeutic doses including the loading dose of 675 mg sc. The dosing regimens 
planned for this study are consistent with dosing regimens in the pivotal studies. Refer to 
Section 5.3 for additional details regarding the rationale for the doses and dose regimens.
This study is double-blind to ensure impartiality in evaluating the long-term safety and efficacy 
of different dose regimens of fremanezumab and to avoid unblinding the pivotal studies before 
they are completed. The blind will be maintained according to standard blinding procedures (see 
Section 5.9.2) and through the use of dummy injections to ensure that number of injections is the 
same at each visit for patients with ECH and patients with CCH (see Section 5.1.1.1). After 
15 June 2018, only patients who participated in the ECH study (Study TV48125-CNS-30056)
will be enrolled for active treatment.
The study population will be composed of male and female patients, aged 18 to 70 years, 
inclusive, with a history of CCH or ECH (as defined by International Classification of Headache 
Disorders-third edition beta [ICHD-3 beta] criteria [Headache Classification Committee of the 
IHS 2013]) for at least 12 months prior to screening. Concomitant medications that are 
commonly prescribed for the preventive treatment of CH (listed in Appendix H) are prohibited 
throughout this study so that effects of the test IMP can be distinguished from effects of these 
concomitant preventive medications. Thus, patients who were taking concomitant preventive 


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medications during the pivotal studies will be required to taper off these medications during the 
first month of treatment in this study.
CH is an intensely painful primary headache disorder, and there is a significant unmet medical 
need for preventive treatments for CH.
3.4.
Stopping Rules for the Study
There are no formal rules for early termination of this study. During the conduct of the study, 
serious adverse events will be reviewed (see Section 7.1.5) as they are reported from the 
investigational centers to identify safety concerns.
The study may be terminated by the sponsor for any reason at any time. For example, the 
sponsor should terminate the study in the event that:

new toxicological or pharmacological findings or safety issues invalidate the earlier 
positive benefit-risk assessment

discontinuation of the development of the IMP
A patient may discontinue participation in the study at any time for any reason (eg, lack of 
efficacy, consent withdrawn, or adverse event). The investigator and/or sponsor can withdraw a 
patient from the study at any time for any reason (eg, lack of efficacy, protocol deviation as 
defined in Appendix C, noncompliance, or adverse event). In addition, patients with positive 
eC-SSRS findings or abnormal hepatic laboratory values (eg, alanine aminotransferase [ALT], 
aspartate aminotransferase [AST], alkaline phosphatase [ALP], gamma-glutamyl transpeptidase 
[GGT], bilirubin [total, direct, or indirect], or international normalized ratio [INR]) may meet 
criteria for discontinuation from the IMP as summarized in Appendix J.
3.5.
Schedule of Study Procedures and Assessments
Study procedures and assessments with their time points for patients enrolling in this study from 
the pivotal efficacy studies for treatment are presented in Table 4. Assessments and procedures 
for patients rolling over from the pivotal efficacy studies for the purpose of evaluating ADAs and 
safety (adverse events and concomitant medications) only is presented in Table 5. 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 B.


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Table 4:
Study Procedures and Assessments for Treated Patients
Double-blind treatment perioda
Follow-up 
period
Visit number
V1b
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12
Procedures and assessments 
(completed before dosing, 
when applicable, unless 
otherwise noted)
Week 0
(day 0) 
Week 4
(±3 days)
Week 8 
(±3 days)
Week 12 
(±3 days)
Week 16 
(±3 days)
Week 20 
(±3 days)
Week 24 
(±3 days)
Week 28 
(±3 days)
Week 32 
(±3 days)
Week 36 
(±3 days)
EOT/early 
withdrawal
week 40 
(±3 days)
Follow-up
week 68 
(±1 week)c
Informed consent
Xd,e
Inclusion and exclusion 
criteria
X
Taper current preventive 
medicationf
X
Full physical examination, 
including weight
X
X
X
X
X
X
X
X
Triplicate 12-lead ECGg,h
X
X
X
X
Vital signs measurementg
X
X
X
X
X
X
X
X
X
X
X
Adverse eventsi
Xj
X
X
X
X
X
X
X
X
X
X
X
Concomitant medication 
inquiry
X
X
X
X
X
X
X
X
X
Xk
X
Clinical laboratory testsl,m
X
X
X
X
Serum β-HCG testn
X
Urine β-HCG testn
X
X
X
X
X
X
X
X
X
X
eC-SSRSo,p
X
X
X
X
X
X
X
X
X
X
X
Enter cluster headache attack 
information in the electronic 
diary deviceq
X
X
Review electronic diary data
X
X
X
X
X
X
X
X
X
X


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Table 4:
Study Procedures and Assessments for Treated Patients (Continued)
Double-blind treatment perioda
Follow-up 
period
Visit number
V1b
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12
Procedures and assessments 
(completed before dosing, 
when applicable, unless 
otherwise noted)
Week 0
(day 0) 
Week 4
(±3 days)
Week 8 
(±3 days)
Week 12 
(±3 days)
Week 16 
(±3 days)
Week 20 
(±3 days)
Week 24 
(±3 days)
Week 28 
(±3 days)
Week 32 
(±3 days)
Week 36 
(±3 days)
EOT/early 
withdrawal
week 40 
(±3 days)
Follow-up
week 68 
(±1 week)c
Return electronic diary 
device
X
Blood sample for 
pharmacokinetics analysisr
X
X
X
X
X
X
X
X
X
X
Blood sample for serum 
ADA analysiss
X
X
X
X
X
Blood collection for serum, 
plasma, and RNA biomarker 
analysist
X
X
X
X
X
Urine collection for 
biomarker analysis
X
X
X
X
X
HADSp
X
X
X
X
EQ-5D questionnairep
X
X
X
X
SF-12p
X
X
X
X
WPAI questionnairep
X
X
X
X
X
Impact on Partners and 
Family questionnairep,u
X
X
X
X
X
PPSIv
X
X
X
X
X
X
PGIC scalev
X
X
X
X
X
X
Wearable sensor substudy 
data capturew
X
X


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Table 4:
Study Procedures and Assessments for Treated Patients (Continued)
Double-blind treatment perioda
Follow-up 
period
Visit number
V1b
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12
Procedures and assessments 
(completed before dosing, 
when applicable, unless 
otherwise noted)
Week 0
(day 0) 
Week 4
(±3 days)
Week 8 
(±3 days)
Week 12 
(±3 days)
Week 16 
(±3 days)
Week 20 
(±3 days)
Week 24 
(±3 days)
Week 28 
(±3 days)
Week 32 
(±3 days)
Week 36 
(±3 days)
EOT/early 
withdrawal
week 40 
(±3 days)
Follow-up
week 68 
(±1 week)c
Wearable sensor check and 
compliance check 
X
X
X
X
X
X
X
X
X
X
Return wearable sensor
X
Study IMP administrationx
X
X
X
X
X
X
X
X
X
X
Injection site reaction/pain 
assessmenty
X
X
X
X
X
X
X
X
X
X
Anaphylaxis and 
hypersensitivity reaction 
assessmentz
X
X
X
X
X
X
X
X
X
X
a 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.
b Visit 1 of the current study corresponds with the EOT visit (visit 5) of the pivotal efficacy studies. EOT visit procedures/assessments must be completed before 
the patient begins participation in this study, and the EOT procedures/assessments will not be repeated at visit 1 of this study. The EOT visit 
procedures/assessments are detailed in the protocols for Studies TV48125-CNS-30056 and TV48125-CNS-30057. 
c For patients who discontinue the study early and patients who achieve CH remission (ie, meaning they stop and may restart treatment depending upon whether 
or not CH attacks recur), the follow-up visit will be approximately 7.5 months after the last dose of IMP.
d In addition to the patient, the partner or family member who will complete the Impact on Partner and Family questionnaire, if applicable, will also provide 
written informed consent. 
e Patients participating in the wearable sensor substudy will be asked to provide consent to continue participating in the substudy during this long-term safety 
study.
f Current preventive medication should be tapered over 1 month from the beginning of participation in this study.
g Procedure/assessment will be performed before blood draws and administration of questionnaires.
h Electrocardiograms will be performed in triplicate, with approximately 1 to 5 minutes between recordings.
i Adverse events will be recorded from the time informed consent for this study is obtained through the end of study participation. Inquiries about adverse events 
will be made at every visit. At visits 1 through 10 inquiries about adverse events will be made before and after dosing of the IMP.


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j The predose adverse event inquiry will be completed as part of EOT visit (visit 5) procedures for the pivotal studies.
k As appropriate, patients should be treated with standard of care following completion of the EOT/early withdrawal visit.
l Serum chemistry, hematology, coagulation, and urinalysis.
m Currently menstruating (yes, no, n/a) information will be collected from each female patient prior to blood and urine collection for clinical laboratory tests.
n WOCBP only.
o The eC-SSRS Since Last Visit version will be completed at every visit including unscheduled visits.
p Responses will be entered in the site tablet. 
q Patients will enter CH attack information (ie, occurrence and number of CH attacks) duration of CH attack[s], severity of CH attack[s], and acute CH-specific 
medication and oxygen use) daily into the electronic diary device through visit 11 (week 40). 
r Blood samples for pharmacokinetic analysis will be collected prior to dosing, where applicable. Patients who signed consent for the wearable sensor substudy 
(at the pivotal studies) only will return to the investigational center for up to 2 additional visits after any dose of the IMP for blood sampling for 
pharmacokinetics analysis, triplicate12-lead ECGs, and inquiries about adverse events and concomitant medications. These visits should occur during the 
following time periods relative to any dose of the IMP: 3 to 10 days or 15 to 20 days after IMP.
s Blood samples for serum ADA assessment (
) will also be collected upon observation of any severe hypersensitivity reaction and anaphylaxis.
t Blood for further biomarkers analyses will be collected after blood collection for pharmacokinetic and immunogenicity analyses as follows: 8.5 mL for serum, 
6 mL for plasma, and 2.5 mL for PAXgene RNA.
u Partners/family members will be asked to attend the study visit with the patient or to return to the investigational center within ±3 days of the patient’s visit if 
unable to appear at the same time.
v In addition to the time points presented in this table, patients will also complete this procedure/assessment at week 1. Patients will record responses at week 1 in 
the electronic diary, and responses at all other time points will be recorded in the site tablet.
w Patients rolling over from the Phase 3 pivotal efficacy studies who also enrolled in the wearable sensor substudy will be allowed to continue in the substudy 
during this long-term safety study provided they consent to continuing their participation at visit 1. Patients will be required to wear the digital wearable device 
on the wrist continuously throughout the treatment period of this study.
x Doses/dosing regimens will be assigned based on randomization in the pivotal studies, and dummy placebo sc injections will be administered to maintain 
blinding. Refer to Table 3 and Section 5.1.1.1 for additional details.
y Injection sites will be assessed for erythema, induration, ecchymosis, and pain immediately (+10 minutes) and 1 hour (±15 minutes) after IMP administration. 
If a patient has severe injection site induration, erythema, ecchymosis, or pain at 1 hour after completion of IMP administration, the patient will be reassessed 
3 hours (±15 minutes) after IMP administration and hourly (±15 minutes) thereafter until the reaction is of moderate or less severity.
z Patients will be assessed for hypersensitivity reaction and anaphylaxis during and after receiving the IMP (through 1 hour postdose).
ADA=antidrug antibody; β-HCG=beta-human chorionic gonadotropin; CCH=chronic cluster headache; CH=cluster headache; CRF = case report form; 
ECG=electrocardiogram; ECH=episodic cluster headache; eC-SSRS=electronic Columbia-Suicide Severity Rating Scale; EOT=end-of-treatment; 
EQ-5D=EuroQol-5 Dimension; HADS=Hospital Anxiety and Depression Scale; IMP=investigational medicinal product; n/a=not applicable; PGIC=Patient 
Global Impression of Change; PPSI=Patient-Perceived Satisfactory Improvement; sc=subcutaneous; SF-12=12-Item Short-Form Health Survey; V=visit; 
WOCBP=women of childbearing potential; WPAI=Work Productivity and Activity Impairment. 


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Table 5:
Study Procedures and Assessments for Patients Rolling Over from the Pivotal Efficacy Studies for Evaluation of 
Antidrug Antibodies and Safety (Adverse Events and Concomitant Medications) Only
Procedures and assessments
Enrollment visit
Follow-up visit
Visit 1a
Visit 12
Day 0
Approximately 7.5 months (approximately 5 half-lives of the IMP) after the 
last dose of the IMP during the pivotal efficacy study
Informed consent
X
Adverse eventsb
X
X
Concomitant medication inquiry
X
X
Blood sample for ADA analysis
X
a Visit 1 of the current study corresponds with the EOT visit/early withdrawal visit of the pivotal efficacy studies. EOT visit procedures/assessments must be 
completed before the patient begins participation in this study. The EOT visit procedures/assessments are detailed in the protocols for Studies TV48125-CNS-
30056 and TV48125-CNS-30057. 
b Patients will return for unscheduled visits in the event of any safety concern.
ADA=antidrug antibody; EOT=end-of-treatment; IMP=investigational medicinal product. 


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4.
SELECTION AND WITHDRAWAL OF PATIENTS
Prospective waivers (exceptions) from study inclusion and exclusion criteria to allow patients to 
be enrolled are not granted by Teva (Appendix C). Any deviation from the eligibility criteria will 
result in study drug discontinuation in the event that a patient has not been dosed.
4.1.
Patient Inclusion Criteria
Patients may be included in the treatment portion of the study only if they meet all of the 
following criteria:
a.
The patient is a male or female and 18 to 70 years of age, inclusive, at the start of the 
pivotal study.
b. The patient signs and dates the informed consent document.
c.
The patient completes either the Phase 3 pivotal study for ECH 
(Study TV48125-CNS-30056) or the Phase 3 pivotal study for CCH 
(Study TV48125-CNS-30057) without important protocol deviations related to 
patient safety and patient compliance and at least 75% diary data completion during 
the pivotal study. Prior to 15 June 2018, patients from the ECH study and the CCH 
study were enrolled. After 15 June 2018, only patients who participated in the ECH 
study (Study TV48125-CNS-30056) will be enrolled for active treatment.

In addition, patients who do not complete the pivotal efficacy studies, and patients 
who complete the pivotal efficacy studies but do not wish to continue treatment 
during this long-term safety study, will be offered to enroll in this study for the 
purpose of evaluating ADAs and safety (adverse events and concomitant 
medications) approximately 7.5 months after administration of the last dose of the 
IMP.
d. Women may be included only if they have a negative beta-human chorionic 
gonadotropin (β-HCG) test at visit 1, are sterile or postmenopausal, and are not 
lactating (not applicable for patients participating in safety follow-up only). 
Definitions of sterile and postmenopausal are given in Appendix E.
e.
Women of childbearing potential (WOCBP) whose male partners are potentially 
fertile (ie, no vasectomy) must use highly effective birth control methods 
(see Appendix E) for the duration of the study and for 7.5 months after 
discontinuation of IMP.
Men must be sterile or, if they are potentially fertile/reproductively competent (not 
surgically [eg, vasectomy] or congenitally sterile), and their female partners are of 
childbearing potential, must agree to use, together with their female partners, 
acceptable birth control methods for the duration of the study and for 7.5 months after 
administration of IMP. 
Definitions of women of non-childbearing potential, sterile and postmenopausal 
women; male contraception; and highly effective and acceptable birth control 
methods, including examples, are given in Appendix E.


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f.
The patient must be willing to stop concomitant medications used in clinical practice 
for the prevention of CH (ie, verapamil, topiramate, valproate, lithium, or 
methysergide) for the duration of this study. Patients must begin tapering these 
preventive medications as soon as they begin this study. The period of time needed to 
taper off these medications will be based on the investigator’s medical judgment but 
should not exceed 1 month from the beginning of participation in this study 
(Appendix H) (not applicable for patients participating in safety follow-up only).
g. The patient is in good health in the opinion of the investigator, as determined by a 
medical and psychiatric history; medical examination; 12-lead ECG; and serum 
chemistry, hematology, coagulation, and urinalysis (not applicable for patients 
participating in safety follow-up only).
h. The patient must be willing and able to comply with study restrictions to remain at 
the clinic for the required duration during the study period and to return to the clinic 
for the follow-up evaluations, as specified in this protocol.
4.2.
Patient Exclusion Criteria
Patients will be excluded from participating in the treatment portion of this study if they meet 
any of the following criteria:
a.
The patient has a history of any suicide attempt in the past or current active suicidal 
ideation, as measured by the eC-SSRS.
b. Any finding in the 12-lead ECG performed as part of the EOT visit (visit 5) 
procedures for the pivotal studies considered clinically significant in the judgment of 
the investigator.
c.
Any finding that, in the judgment of the investigator, is a clinically significant 
abnormality, including serum chemistry, hematology, coagulation, and urinalysis test 
values (abnormal tests may be repeated for confirmation).
d. Hepatic enzymes (ALT and AST) >1.5 × the upper limit of the normal range (ULN) 
after confirmation in a repeat test or suspected hepatocellular damage that fulfills 
criteria for Hy’s law.
e.
Serum creatinine >1.5 × the ULN or evidence of clinically significant renal disease in 
the judgment of the investigator.
Patients rolling over only for safety follow-up and ADA who are not receiving study medication 
are not required to fulfil all inclusion exclusion criteria.
4.3.
Withdrawal Criteria and Procedures for the Patient
Each patient is free to withdraw from this study at any time, without prejudice to their continued 
care. Patients must be withdrawn from this study if any of the following events occur:
1. Patient withdraws consent or requests discontinuation from this study for any reason.
2. Patient develops an illness that would interfere with his/her continued participation.


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3. Patient is noncompliant with the study procedures and assessments or administration of 
IMPs (including noncompliance with wearable sensor substudy, if applicable) 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 result.
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. The investigator and/or sponsor may withdraw an individual patient from the study at any 
time for any reason (eg, lack of efficacy, protocol deviation as defined in Section 10, 
noncompliance, or adverse event). In addition, patients with positive eC-SSRS findings 
or abnormal hepatic laboratory values (eg, ALT, AST, ALP, GGT, bilirubin [total, direct, 
or indirect], or INR) may meet criteria for discontinuation from the IMP as summarized 
in Appendix J.
In the event that a patient was incorrectly enrolled and has already started taking the study drug, 
a risk/benefit evaluation should take place between the investigator and sponsor, and a strong 
clinical justification must be provided if the patient is not withdrawn from study drug.
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 or 
discontinuation. Results of any evaluations and observations, together with a narrative describing 
the reason(s) for withdrawal, must be recorded in the source documents. The case report form 
(CRF) must document the primary reason for withdrawal or discontinuation.
See Appendix F for information regarding how the study will define and address lost to 
follow-up patients to help limit the amount and impact of missing data.
If a patient is withdrawn from the study for multiple reasons that include also 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” and 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 why the patient is withdrawing or being 
withdrawn from the study.
The reason for and date of withdrawal from the study must be recorded on the source 
documentation and transcribed to the CRF. If a patient withdraws consent, every attempt will be 
made to determine the reason. 


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All protocol-specified procedures/assessments should be performed at the early withdrawal visit 
(see Table 4). Patients who withdraw from the study will not be replaced. 
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 via 2 different methods (phone, 
text, e-mail, certified letter, etc). In the case of patients lost to follow-up, attempts to contact the 
patient must be made and documented in the patient’s medical records and transcribed to the 
CRF.
4.4.
Replacement of Patients
A patient who is enrolled but does not complete the treatment period will not be replaced.
4.5.
Rescreening
A patient who is screened and does not meet study inclusion and exclusion criteria will not be 
considered for screening again.
4.6.
Screening Failure
Screening failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomized/enrolled in the study. Minimal information includes but is not 
limited to demography, screening failure details, eligibility criteria, and any adverse events or 
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5.
TREATMENTS
5.1.
Investigational Medicinal Products Used in the Study
IMP is defined as the test IMP and placebo IMP. Details of the test and placebo IMPs are 
presented in Table 6.
Table 6:
Investigational Medicinal Products Used in the Study
IMP name
Test IMP
Placebo IMP
Trade name and INN, 
if applicable, or 
company-assigned 
number
Fremanezumab (formerly LBR-101, PF-
04427429, or RN 307)
n/a
Formulation
Solution for injection
Solution for injection
Unit dose strength(s)
dosage level(s)
225 mg/1.5 mL
675 mg sc quarterly, 225 mg sc monthly, or 
675 mg sc loading dose followed by 225 mg 
monthly
n/a
Route of 
administration
Fremanezumab will be administered as sc 
injections (1.5 mL per injection) by 
qualified study personnel at the 
investigational center.
Placebo will be administered as sc 
injections (1.5 mL per injection) by 
qualified study personnel at the 
investigational center.
Packaging
Fremanezumab will be provided in prefilled 
syringes contained in uniquely numbered 
kits and stored (refrigerated at 2°C to 8°C) 
at the investigational centers. Prefilled 
syringes (1.5 mL) will contain 
fremanezumab at a concentration of 
150 mg/mL. 
Placebo will be provided in prefilled 
syringes contained in uniquely numbered 
kits and stored (refrigerated at 2°C to 8°C) 
at the investigational centers. Prefilled 
syringes (1.5 mL) will contain the same 
vehicle and excipients as those for active 
infusion and injection.
Manufacturer
Teva Branded Pharmaceutical Products 
R&D, Inc.
Teva Branded Pharmaceutical Products 
R&D, Inc.
IMP=investigational medicinal product; INN= International Nonproprietary Names; n/a=not applicable; 
sc=subcutaneous.
The recommended sc injection sites follow the National Institutes of Health Patient Education 
Guidelines of September 2015, which are available in Appendix U of this document and at the 
following website: http://www.cc.nih.gov/ccc/patient_education/pepubs/subq.pdf. The suggested 
sites of injection are back of upper arms, lower abdomen/belly/waistline, and front of thighs. At 
each visit, the injections should be given in a different location (eg, not in precisely the same 
place), and study staff member(s) responsible for administration of injections should inspect 
previous injection sites to ensure that they are free of bruising and tenderness and that proper 
rotation of sites is performed. The total number of sc injections and their locations will be 
recorded for each dosing visit (visits 1 through 10). A 1.5-mL volume from each prefilled 
syringe must be injected sc for dosing to be considered complete.


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5.1.1.
Test Investigational Medicinal Product
Fremanezumab is a fully humanized IgG2a/kappa monoclonal antibody derived from a murine 
precursor. Additional details may be found in Table 6 and in the IB for fremanezumab. 
5.1.1.1.
Starting Dose and Dose Levels
Patients rolling over from Study TV48125-CNS-30056 with ECH:

Patients who were in the fremanezumab 900-mg iv loading dose group will receive 
fremanezumab at 225 mg sc as a single injection at visit 1 and every 4 weeks 
thereafter through week 36 (visit 10). For blinding, these patients will also receive 
2 placebo sc injections at visits 1, 4, 7, and 10.

Patients who were in the placebo group and the fremanezumab 675-mg sc quarterly 
group will receive fremanezumab at 675 mg sc as 3 injections (225 mg/1.5 mL) at 
visit 1 and every 12 weeks thereafter through week 36 (visit 10). For blinding, 
patients will receive 1 single placebo sc injections at visits 2, 3, 5, 6, 8, and 9.
 
 
 
 
 
 
After 15 June 2018, only patients who participated in the ECH study
(Study TV48125-CNS-30056) will be enrolled for active treatment. Patients with CCH will be 
rolled over from Study TV48125-CNS-30057 until 15 June 2018 as follows (after 15 June 2018 
no additional CCH patients will be enrolled):

Patients who were in the fremanezumab 900-mg iv loading dose group and the 
fremanezumab 675-mg sc loading dose group will receive fremanezumab at 225 mg 
as a single sc injection (225 mg/1.5 mL) at visit 1 and every 4 weeks thereafter 
through week 36 (visit 10). For blinding, these patients will also receive 2 sc placebo 
injections at visit 1. 

Patients who were in the placebo group will receive a loading dose of fremanezumab 
at 675 mg as 3 sc injections (225 mg/1.5 mL) at visit 1 and fremanezumab at 225 mg 
administered as a single sc injection every 4 weeks thereafter through week 36 
(visit 10). 
 
 
 
 
 
 After 15 June 2018, only patients who participated in 


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the ECH study (Study TV48125-CNS-30056) will be enrolled for active treatment. All CCH 
patients included in this study have been asked to discontinue treatment and are encouraged to 
continue in the ADA and safety follow-up portion of this study. At the time of unblinding the 
treatment code in Study TV48125-CNS-30057 (planned for Q4 2018), those CCH patients who 
were receiving placebo in Study TV48125-CNS-30057 (ie, never received any study drug) will 
not be required to complete additional safety follow-up visits, and will be discharged from the 
study.
Of note, blinding of the pivotal studies and the initial treatments during this long-term safety 
extension study will be maintained throughout study participation.
5.1.2.
Placebo Investigational Medicinal Product
The placebo will be the same vehicle and excipients as those for fremanezumab. See Table 6 for 
additional details. 
5.2.
Preparation, Handling, Labeling, Storage, and Accountability for 
Investigational Medicinal Products
Information pertaining to the preparation, handling, labeling, storage, and accountability for the 
IMP used in this study can be found in Appendix G.
5.3.
Justification for Investigational Medicinal Products
5.3.1.
Justification for Dose of Test Investigational Medicinal Product
As noted in Section 5.1.1.1, as of June 15 2015, CCH patients are no longer enrolling in this
study.
Patients who received fremanezumab at 225 mg sc monthly after a loading dose of 900-mg iv or 
675 mg sc or fremanezumab at 675 mg sc quarterly during the pivotal studies will continue 
receiving the same dose (ie, 225 mg sc monthly or 675 mg sc quarterly depending upon their 
diagnosis and randomization in the pivotal studies) during this long-term safety extension study. 
These dose regimens are expected to maintain steady state at a blood concentration level that will 
provide clinical efficacy. The doses and dosing regimens also account for the usual course of the 
2 forms of CH; patients with ECH are likely to remit after initial treatment whereas CCH patients 
are continuously inflicted by pain. 
Patients who received placebo during the pivotal studies will be assigned to receive either 
fremanezumab 675 mg sc quarterly (patients with ECH from Study TV48125-CNS-30056) or a 
loading dose 675 mg sc followed by monthly fremanezumab at 225 mg sc monthly (patients with 
CCH from Study TV48125-CNS-30057). This will provide these patients with the opportunity to 
receive potential benefit from therapeutic doses including the loading dose of 675 mg sc.
In addition to evaluating maintenance of efficacy in this long-term safety extension study, the 
planned treatments account for the need to adjust treatment duration, which is of particular 
relevance for ECH. When the cluster cycle is almost over in ECH, the number of headache 
attacks per day start to decrease with associated mild to moderate intensity. Patients often look 
for preventive options in the very early part of the headache cycle in an attempt to reduce its 
duration. Equally, when complete remission is achieved, patients with ECH consider stopping 


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their medication and thus withdraw from treatment when the cluster period is over (May 2005). 
Accordingly, continuous long-term treatment in ECH might not be needed as these patients may 
have long remission periods between the cluster episodes.
 
 
 
 
 
 
 
 
 
 
 
. 
5.4.
Restrictions
Patients will be required to comply with the following restrictions:
5.4.1.
Activity
Patients must remain at the investigational center for safety observation for at least 60 minutes 
after IMP administration. Patients may be asked to remain at the investigational center longer if 
it is judged to be medically necessary. 
5.4.2.
Blood Donation
Patients may not donate blood while taking the IMP and for 5 half-lives (7.5 months) after the 
last dose of the IMP.
5.4.3.
Pregnancy
Restrictions in regard to pregnancy are provided in the inclusion criteria (Section 4.1). 
Restrictions in regard to sexual activity are also detailed in the inclusion and exclusion criteria 
(Section 4.1), and contraception methods are reviewed in Appendix E.
In addition, male patients may not donate sperm for the duration of the study and for 7.5 months 
(approximately 5 half-lives of the active IMP) after administration of the last dose of the IMP.
5.5.
Prior and Concomitant Medication or Therapy
Any concomitant medication, treatment, or procedure from the time of consent up to the end of 
the study, including follow-up, will be recorded on the CRF. Trade name and International 
Nonproprietary Names (if available), indication, dose, and start and end dates of the administered 


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medication will be recorded. The sponsor will encode all medication and treatment according to 
the World Health Organization drug dictionary.
Patients taking concomitant preventive medications (ie, verapamil, topiramate, valproate, 
lithium, or methysergide) during the pivotal studies must begin tapering as soon as they begin 
participation in this study, and they must be off these medications within 1 month from the 
beginning of participation in this study (not applicable for patients participating in safety follow-
up only). See Appendix H for details. 
For daily prescribed medications, patients must be on a stable dose and regimen for at least 
2 weeks prior to screening and throughout the study.
All concomitant medications taken during the study must be recorded with indication, daily dose, 
and start and stop dates of administration. All patients will be questioned about concomitant 
medication at each visit.
5.6.
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.
5.7.
Temporary Discontinuation of Investigational Medicinal Product
Patients who experience CH remission, defined as no CH attacks for 12 successive weeks and 
24 successive weeks for patients with ECH and CCH, respectively, at any time after starting IMP 
(ie, administration of the first dose of IMP in the pivotal study) will be offered the possibility to 
stop treatment. Patients will restart fremanezumab treatment if treatment is stopped and CH 
attacks resume during the 36-week double blind treatment period. Refer to Section 5.1.1.1 for 
additional details regarding treatment of these patients. After 15 June 2018, only patients who 
participated in the ECH study (Study TV48125-CNS-30056) will be enrolled for active 
treatment.
5.8.
Randomization and Blinding
This is a double-blind study; blinding will be retained from the pivotal studies and throughout 
this long-term safety extension study. Patients will be assigned to treatments as described in 
Table 3 and Section 5.1.1.1 based on their randomization in the pivotal studies 
(Studies TV48125-CNS-30056 and TV48125-CNS-30057).


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5.9.
Maintenance of Randomization and Blinding
5.9.1.
Maintenance of Randomization
Refer to the protocols for the pivotal studies (Studies TV48125-CNS-30056 and 
TV48125-CNS-30057) for details regarding randomization of patients in this study. 
Packaging vendor(s) will package test IMP and placebo IMP into single-visit kits according to 
Good Manufacturing Practice (GMP) procedures. Kits will be identical in appearance. Adequate 
kit supply for upcoming study visits will be managed by interactive response technology (IRT) 
and kept (refrigerated at 2°C to 8°C) at the investigational centers. 
At visits 1 through 10, the IRT will be queried, and investigational center personnel will retrieve 
and administer each prefilled syringe contained in the appropriately numbered kit(s). Kit 
numbers will be entered into the CRF. 
5.9.2.
Blinding and Unblinding
Blinding will be retained from the pivotal studies and throughout this long-term safety extension 
study.
Blinded pharmacokinetics data may be assessed during the study. Personnel responsible for 
bioanalysis (pharmacokinetics and immunogenicity) will be provided with the randomization 
code to facilitate the analysis. However, the personnel responsible for bioanalysis and 
pharmacokinetics 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 of the 
pivotal efficacy protocols. These individuals will not be involved in conduct of any study 
procedures or assessment of any adverse events.
In the event of an emergency, it will be possible to determine which treatment group and dose 
the patient has been allocated to by accessing the Randomization and Trial Supply Management 
(RTSM) system. All investigational centers will be provided with details of who can access the 
system for code breaking at the start of the study. The Medical Monitor or equivalent should be 
notified following unblinding. Any unblinding of the IMP performed by the investigator must be 
recorded in the source documents.
In case of a serious adverse event, pregnancy, or in cases when knowledge of the IMP 
assignment is needed to make treatment decisions, the investigator may unblind the patient’s 
IMP assignment as deemed necessary, mainly in emergency situations, through specialized 
access in the RTSM system. Breaking of the treatment code can always be performed by the 
investigator without prior approval of the sponsor; however, the sponsor should be notified that 
the code was broken, but the patient’s IMP assignment should not be revealed to the sponsor. In 
the event that the RTSM system is not functioning for emergency unblinding, the next course of 
action is to contact via phone the RTSM on-call customer support helpline for manual 
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When a blind is broken, the patient will be withdrawn from the study and the event will be 
recorded onto the CRF. The circumstances leading to the breaking of the code should be fully 
documented in the investigator’s study files and in the patient’s source documentation. 
Treatment assignment should not be recorded in any study documents or source document.
In 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 may independently request that the treatment code be broken (on a 
case-by-case basis) to comply with regulatory requirements. The report will be provided in an 
unblinded manner for regulatory submission. If this occurs, blinding will be maintained for the 
investigator and for other personnel involved in the conduct of the study, and analysis and 
reporting of the data.
5.9.3.
Data Monitoring Committee
There will be no Data Monitoring Committee in this study.
5.10.
Total Blood Volume
The total blood volume to be collected for each patient enrolling in this study for treatment with 
fremanezumab is approximately 205.5 mL for scheduled tests. An additional 30 mL of blood 
may be collected in the event of follow-up for liver enzymes as detailed in Appendix J.
The total blood volume to be collected for each patient enrolling in this for evaluation of ADAs, 
fremanezumab concentrations, and safety (adverse events and concomitant medications) is 
approximately 9 mL.
Details are provided in Appendix L.


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6.
ASSESSMENT OF EFFICACY
6.1.
Assessments of Efficacy
There is no primary efficacy measure.
6.2.
Electronic Diary Device
Efficacy endpoints related to CH attacks will be derived from data collected daily using an 
electronic diary device. Eligible patients will receive comprehensive training at screening from 
the investigational site personnel on the use of the electronic diary device. Investigational site 
personnel will also instruct patients on the requirement for timely and daily completion of the 
electronic diary.
Patients will complete electronic headache diary entries with questions about the previous day, 
starting from the day after the screening visit through the end of treatment (EOT)/early 
withdrawal visit. The electronic headache diary device will allow entry of headache information 
for up to 2 days after a given day.
Patients who report a CH attack will answer questions about the attack (ie, occurrence and 
number of CH attacks, duration of CH attack[s], severity of CH attack[s], and acute CH-specific 
medication and oxygen use). 
Patients will be asked about their performance at work or at school on CH attack-free days. 
Additional details can be found in the electronic diary device training manual.
If a patient fails to complete the diary for the preceding day, the patient will be prompted to enter 
the missed day’s information the next time he/she accesses the electronic diary provided no more 
than 2 days have elapsed since completion of that day. If more than 2 days have elapsed since 
completion of a diary day, the patient will not be allowed to enter diary information for that day, 
and it will be considered a missed day.
If a CH is reported, then CH intensity will be subjectively rated by the patient as follows:

Mild

Moderate

Severe

Very severe
6.3.
Hospital Anxiety and Depression Scale 
The HADS is a validated and reliable, 14-item scale developed by Zigmond and Snaith (1983) to 
measure anxiety (7-items) and depression (7-items). Each item is scored on a 4-point scale from 
0 to 3. Scores for depression and anxiety range from 0 to 21; a score of 0 to 7 is normal, 8 to 10 
is borderline abnormal, and 11 to 21 is abnormal.
Patients will complete the HADS at the time points detailed in Table 4. Responses will be 
recorded in the site tablet.


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6.4.
EuroQol-5 Dimension Questionnaire
The 5-level EQ-5D (EQ-5D-5L) is a standardized questionnaire that assesses overall state of 
health. The EQ-5D-5L consists of 2 parts. In part 1, patients rate their health state in 5 domains: 
mobility, self-care, usual activities, pain/discomfort, and mood using a scale of 1 to 5, where 
1 = no problems, 2 = slight problems, 3 = moderate problems, 4 = severe problems, and 
5 = extreme problems. In part 2, patients rate their health state on a 100 mm visual analog scale; 
a rating of 0 represents the worst imaginable health state, and a rating of 100 represents the best 
imaginable health state.
Patients will complete the EQ-5D-5L at the time points detailed in Table 4. Responses will be 
recorded in the site tablet.
6.5.
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 (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 at the time points detailed in Table 4. Responses will be 
recorded in the site tablet.
6.6.
Work Productivity and Activity Impairment Questionnaire
The generic version of the WPAI questionnaire measures the overall effect of health on 
productivity at work and daily activities. The specific health problems version of the WPAI 
questionnaire allows investigators to attribute productivity and activity impairment issues to 
specific health conditions. After the employment status of a respondent is identified, 
3 open-ended questions are asked concerning (1) hours absent from work due to health problems 
(or specific condition), (2) hours absent from work due to other reasons, and (3) hours actually 
worked. Two additional questions are included that ask about the impact of health on 
productivity, 1 concerning productivity at work and the other concerning daily activities outside 
of work. The response format of each item of the WPAI questionnaire consists of an 11-point 
scale ranging from 0 (no impairment) to 10 (complete impairment) (Reilly et al 1993). 
Patients will complete the WPAI questionnaire at the time points detailed in Table 4. Responses 
will be recorded in the site tablet.
6.7.
Impact on Partner and Family Questionnaire
The partners/family members of patients participating in the study, if applicable, will complete 
an Impact on Partner and Family questionnaire at the time points detailed in Table 4. Responses 
will be recorded in the site tablet. The questionnaire will include questions about the impact of 
CH on the patient’s ability to do chores, the number of days that the patient missed a family or 
social activity since the last assessment due to CH, and the frequency with which the patient 
avoids making plans for family/social activities due to CH. Partners/family members will be 


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asked to attend the study visit with the patient or to return to the investigational center within 
±3 days of the patient’s visit if unable to appear at the same time. 
6.8.
Patient-Perceived Satisfactory Improvement
The PPSI was developed by ten Klooster et al (2006) for pain intensity and was adjusted for CH 
symptoms improvement. Patients will mark the level of CH-associated pain and indicate if pain 
is “much worse,” “moderately worse,” “slightly worse,” “unchanged,” “slightly improved,” 
“moderately improved,” or “much improved” compared with 4 weeks ago. PPSI will be defined 
as the change in pain that corresponds with a minimal rating of “slightly improved.”
The PPSI will be completed at time points detailed in Table 4. Responses at week 1 will be 
entered into the electronic diary device, and responses at all other time points will be entered into 
the site tablet.
6.9.
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 the change in their overall health and wellbeing 
compared with how they felt at the start of the study (the time after the patient received the first 
IMP dose as “much worse,” “moderately worse,” “slightly worse,” “stayed the same,” “a little 
better,” “moderately better,” or “much better.”
The PGIC scale will be completed at the time points detailed in Table 4. Responses at week 1 
will be entered into the electronic diary device, and responses at all other time points will be 
entered into the site tablet.


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7.
ASSESSMENT OF SAFETY
In this study, safety will be assessed by qualified study personnel by evaluating reported adverse 
events, reported anaphylaxis/hypersensitivity reactions, clinical laboratory test results, vital signs 
measurements, ECG findings, physical examination findings (including body weight 
measurements), injection site assessment results, eC-SSRS responses, 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 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 1st 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 for this study is defined as the time period from 
signature of the informed consent form (ICF) through the follow-up visit. 
All adverse events that occur during the defined study period must be recorded on the source 
documentation and transcribed to the CRF, regardless of the severity of the event or judged 
relationship to the IMP. For serious adverse events and protocol-defined adverse events of 
special interest (see Section 7.1.7), the serious adverse event form must be completed and the 
serious adverse event or adverse event of special interest must be reported immediately (see 
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 
in a patient after the defined study period should be reported to the sponsor if the investigator 
becomes aware of them, following the procedures described in Section 7.1.5.3.1.
At each contact with the patient, the investigator or designee must question the patient about 
adverse events by asking an open-ended question such as, “Have you had any unusual symptoms 
or medical problems since the last visit? If yes, please describe”. All reported or observed signs 
and symptoms will be recorded individually, except when considered manifestations of a 
medical condition or disease state. A precise diagnosis will be recorded whenever possible. 
When such a diagnosis is made, all related signs, symptoms, and any test findings will be 
recorded collectively as a single diagnosis on the CRF and, if it is a serious adverse event, on the 
serious adverse event form.
The clinical course of each adverse event will be monitored at suitable intervals until resolved, 
stabilized, or returned to baseline; or until the patient is referred for continued care to a health 
care professional; or until a determination of a cause unrelated to the IMP or study procedure is 
made.
The onset and end dates, duration (in case of adverse event duration of less than 24 hours), action 
taken regarding IMP, treatment administered, and outcome for each adverse event must be 
recorded on the source documentation and transcribed to the CRF.
The relationship of each adverse event to IMP and study procedures, and the severity and 
seriousness of each adverse event, as judged by the investigator, must be recorded as described 
below.
Further details are given in the Safety Monitoring Plan.
7.1.3.
Severity of an Adverse Event
The severity of each adverse event must be recorded as 1 of the following:
Mild:
No limitation of usual activities
Moderate: Some limitation of usual activities
Severe:
Inability to carry out usual activities
For severity grading of local tolerability (injection site erythema, induration, ecchymosis, and 
pain), refer to Section 7.11.


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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 7):
Table 7:
The Relationship of an Adverse Event to the Test Investigational Medicinal 
Product
Term
Definition
Clarification
No reasonable 
possibility
(not related)
This category applies to adverse 
events that, after careful 
consideration, are clearly due to 
extraneous causes (disease, 
environment, etc) or to adverse 
events that, after careful medical 
consideration at the time they are 
evaluated, are judged to be unrelated 
to the IMP.
The relationship of an adverse event may be considered 
“no reasonable possibility” if it is clearly due to 
extraneous causes or if at least 2 of the following apply:

It does not follow a reasonable temporal sequence 
from the administration of the IMP.

It could readily have been produced by the patient’s 
clinical state, environmental or toxic factors, or other 
modes of therapy administered to the patient.

It does not follow a known pattern of response to the 
IMP.

It does not reappear or worsen when the IMP is 
re-administered.
Reasonable 
possibility
(related)
This category applies to adverse 
events for which, after careful 
medical consideration at the time 
they are evaluated, a connection with 
the administration of IMP cannot be 
ruled out with certainty.
The relationship of an adverse event may be considered 
“reasonable possibility” if at least 2 of the following 
apply:

It follows a reasonable temporal sequence from 
administration of the IMP.

It cannot be reasonably explained by the known 
characteristics of the patient’s clinical state, 
environmental or toxic factors, or other modes of 
therapy administered to the patient.

It disappears or decreases on cessation or reduction in 
dose. There are important exceptions when an 
adverse event does not disappear after 
discontinuation of the IMP, yet an IMP relationship 
clearly exists.

It follows a known pattern of response to the IMP.
IMP=investigational medicinal product.
7.1.5.
Serious Adverse Events
For recording of serious adverse events, the study period is defined for each patient as that time 
period from signature of the ICF to the end of the follow-up period. Serious adverse events 
occurring in a patient after the end of the follow-up period should be reported to the sponsor if 
the investigator becomes aware of them, following the procedures described in Section 7.1.5.3.1.


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7.1.5.1.
Definition of a Serious Adverse Event
A serious adverse event is an adverse event occurring at any dose that results in any of the 
following outcomes or actions:

results in death

is life-threatening adverse event (ie, the patient was at risk of death at the time of the 
event); it does not refer to an event which hypothetically might have caused death if it 
were more severe

requires inpatient hospitalization or prolongation of existing hospitalization, which 
means that hospital inpatient admission or prolongation of hospital stay were required 
for treatment of an adverse event, or that they occurred as a consequence of the event
Hospitalizations scheduled before the patient signed the ICF will not be considered 
serious adverse events, unless there was worsening of the 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:

ALT or AST increase of ≥3 × the ULN

total bilirubin increase of ≥2 × ULN

absence of initial findings of cholestasis (ie, no substantial increase of ALP)

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.


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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 Global Patient Safety and Pharmacovigilance 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.
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 should be reported to the sponsor if the investigator becomes aware of them.
The serious adverse event form should be sent to the local safety officer (LSO) or designee (a 
contract research organization [CRO] in a country without a sponsor LSO) (contact information 
is in the Clinical Study Personnel Contact Information section); the LSO will forward the report 
to the sponsor’s Global Patient Safety and Pharmacovigilance.
The following information should be provided to record the event accurately and completely:

study number

investigator and investigational center identification

patient number

onset date and detailed description of adverse event

investigator’s assessment of the relationship of the adverse event to the 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


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
severity

explanation of assessment of relatedness

concomitant medication (including doses, routes of administration, and regimens) and 
treatment of the event

pertinent laboratory or other diagnostic test data

medical history

results of dechallenge/rechallenge, if known

for an adverse event resulting in death

cause of death (whether or not the death was related to IMP)

autopsy findings (if available)
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.
For all countries, the sponsor’s Global Patient Safety and Pharmacovigilance will distribute the 
Council for International Organizations of Medical Sciences (CIOMS) form/Extensible Markup 
Language (XML) file to the LSO/CRO for submission to the competent authorities, Independent 
Ethics Committee/Institutional Review Boards (IEC/IRBs), and investigators, according to 
regulations. The investigator must ensure that the IEC/IRB is also informed of the event, in 
accordance with national and local regulations.
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 
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 
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
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
7.1.7.
Protocol-Defined Adverse Events of Special Interest
The following are considered protocol-defined adverse events of special interest to be sent to the 
sponsor’s Global Patient Safety and Pharmacovigilance Department for evaluation: ophthalmic 
adverse events of at least moderate severity, events of possible IMP-induced liver injury (AST or 
ALT ≥3 × the ULN, total bilirubin ≥2 × the ULN, or INR >1.5), Hy’s Law events, or events of 
anaphylaxis and severe hypersensitivity reactions. Refer to Appendix J for guidance regarding 
monitoring of patients with elevated liver function tests. Anaphylaxis and severe hypersensitivity 
reactions will be monitored using the diagnostic criteria for anaphylaxis as outlined by the 2006 
Joint National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis 
Network Second Symposium on Anaphylaxis (Sampson et al 2006) (also see Appendix K). In 
the event of suspected anaphylaxis, vital signs, including oxygen saturation and respiration rate, 
will be measured. Other assessments will be performed at the discretion of the investigator. As a 
precaution, each investigational center should have a resuscitation cart nearby.
The process for reporting a protocol-defined adverse event of special interest is the same as that 
for reporting a serious adverse event (see Section 7.1.5.3). These events 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 warranted 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. The same reporting 
process as for all other protocol deviations will apply. A noncompliant patient may continue 
taking the study treatment only if this does not jeopardize the patient’s safety. The sponsor will 
assess each protocol deviation and decide whether any of these noncompliances should be 
reported to the Regulatory Authority as a serious breach of Good Clinical Practice (GCP) and the 
protocol.
7.2.
Pregnancy
Any female subject becoming pregnant during the study will discontinue IMP.
All pregnancies of women participating in the study and female partners of men participating in 
the study that occur during the study or within at least 7.5 months after administration 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).


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The investigator is not required to report female subjects who are found to be pregnant between 
screening and baseline, provided no protocol-related procedures were applied.
All female subjects or female partners of men participating in the study who become pregnant 
will be monitored for the outcome of the pregnancy (including spontaneous, elective, or 
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 
that the investigator becomes aware of after withdrawal from the study will be reported as an 
adverse event or serious adverse event, as appropriate.
If the pregnancy in the woman participating in the study and/or the female partners of men 
participating in the study does not continue to term, 1 of the following actions will be taken:

For a spontaneous abortion, report as a serious adverse event.

For an elective abortion due to developmental anomalies, report as a serious adverse 
event.

For an elective abortion not due to developmental anomalies, report on the pregnancy 
form; do not report as an adverse event.
7.3.
Medication Error and Special Situations Related to the 
Investigational Medicinal Products
Any administration of IMP that is not in accordance with the study protocol should be reported 
as an important deviation, if it meets the important deviation criteria specified in the protocol 
(Appendix C), or as a deviation, in the patient’s source documents, regardless of whether or not 
an adverse event occurs as a result. When meeting important protocol deviation criteria, all 
instances of incorrect IMP administration should be reported in the clinical trial management 
system. A non-compliant patient may continue taking the study treatment only if this does not 
jeopardize the patient’s safety.
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 
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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 which occur in infants following exposure to 
a medicinal product from breast milk.
7.4.
Clinical Laboratory Tests
All clinical laboratory test results outside of the reference range will be judged by the 
investigator as belonging to one of the following categories:

abnormal and not clinically significant

abnormal and clinically significant
A laboratory test result that is judged by the investigator as clinically significant will be recorded 
on the source documentation, transcribed to the CRF as an adverse event, and monitored as 
described in Section 7.1.2. An event may include a laboratory or diagnostic test abnormality 
(once confirmed by repeated testing) that results in the withdrawal of the patient from the study, 
the temporary or permanent cessation of treatment with IMP or medical treatment, or further 
diagnostic workup. (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 urinalysis) will be performed at the 
time points detailed in Table 4. Clinical laboratory tests will be performed using the central 
laboratory. However, if other specific urgent tests are required, a local retest can be authorized 
by the sponsor or designee on a case-by-case basis. Specific laboratory tests to be performed are 
provided in Appendix M.
7.4.1.1.
Human Chorionic Gonadotropin Tests
Serum and urine β-HCG tests will be performed for all WOCBP at time points specified in 
Table 4. Any female patient who becomes pregnant during the study will be withdrawn. 
Procedures for reporting the pregnancy are provided in Section 7.2.


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7.5.
Physical Examinations
Physical examinations, including weight, will be performed at the time points detailed in
Table 4. A complete physical examination will include the following organ systems: general 
appearance; head, eyes, ears, nose, and throat; chest and lungs; heart; abdomen; musculoskeletal; 
skin; lymph nodes; and neurological. Any physical examination finding that is judged by the 
investigator as a potentially clinically significant change (worsening) compared with a baseline 
value will be considered an adverse event, recorded on the CRF, and monitored as described in
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 4. All vital signs results outside of the reference ranges will be judged by 
the investigator as belonging to one of the following categories:

abnormal and not clinically significant

abnormal and clinically significant
Before pulse and blood pressure are measured, the patient must be in a supine or 
semi-erect/seated position and resting for at least 5 minutes. The same position and arm should 
be used each time vital signs are measured for a given patient. For any abnormal vital sign 
finding, the measurement should be repeated as soon as possible. Any vital sign value that is 
judged by the investigator as a clinically significant change (worsening) from a baseline value 
will be considered an adverse event, recorded on the source documentation and transcribed onto 
the CRF, and monitored as described in Section 7.1.2.
In addition, potentially clinically significant values may be predefined by the sponsor for 
selected vital signs (see Section 7.6) and, if so, will be documented in the statistical analysis plan 
or other relevant documents (eg, medical monitoring plan).
7.7.
Electrocardiography
Twelve-lead ECGs will be conducted before other assessments (eg, blood draws and 
administration of questionnaires) at the time points detailed in Table 4. The ECGs should be 
performed after the patient has been supine for at least 5 minutes. The ECGs will be performed 
in triplicate, with approximately 1 to 5 minutes between recordings.
A qualified physician at a central diagnostic center will be responsible for interpreting the ECG. 
Electrocardiograms should be performed and transmitted according to the central ECG reading 
instructions provided in the ECG user manual. Electrocardiogram equipment will be provided to 
all investigational centers. 
Although the ECG interpretation will be performed centrally, the clinical evaluation remains the 
investigator’s responsibility.
The ECG will be evaluated by the investigator at the time of recording (signed and dated), and 
the printout should be kept in the source documentation file. When potentially clinically 
significant findings are detected by the investigator, a cardiologist should be consulted for a 


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definitive interpretation. All communications and diagnoses should be filed in the source 
documentation file. The investigator's interpretation will be recorded in the CRF regardless of 
the central reading interpretation. Any abnormal findings assessed by the investigator as 
clinically significant should be recorded in the relevant CRF modules (eg, adverse event, medical 
history).
Objective alerts are predefined as described in the central ECG reading manual. In these cases, 
the investigational center and the sponsor will be informed immediately. 
Any unscheduled ECGs must also be submitted for central ECG reading.
All ECG results outside of the reference ranges will be judged by the investigator as belonging to 
one of the following categories:

abnormal and not clinically significant 

abnormal and clinically significant
Any ECG finding that is judged by the investigator as clinically significant (except at the 
screening visit) will be considered an adverse event, recorded on the source documentation and 
in the CRF, and monitored as described in Section 7.1.2.
7.8.
Immunogenicity
Blood samples for serum ADA assessment will be collected at the time points detailed in Table 4
(patients enrolling in this study from the pivotal efficacy studies) and Table 5 (patients rolling 
over from the pivotal efficacy studies for evaluation of ADAs and safety [adverse events and 
concomitant medications] only). Blood samples for ADA assessment will also be collected upon 
observation of any severe hypersensitivity reaction and anaphylaxis. Bioanalytical personnel 
should be made aware of anaphylaxis occurrence as soon as possible in case an anti-
fremanezumab IgE assay is needed. After 15 June 2018, only patients who participated in the 
ECH study (Study TV48125-CNS-30056) will be enrolled for active treatment. All CCH patients 
included in this study have been asked to discontinue treatment, and are encouraged to continue 
in the ADA and safety follow-up portion of this study. At the time of unblinding the treatment 
code in Study TV48125-CNS-30057 (planned for Q4 2018), those CCH patients who were 
receiving placebo in Study TV48125-CNS-30057 (ie, never received any study drug) will not be 
required to complete additional safety follow-up visits, and will be discharged from the study.
7.9.
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 
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The eC-SSRS will be used to assess the patient’s suicidal ideation (severity and intensity) and 
behavior (Posner et al 2011). The eC-SSRS Since Last Visit version will be completed by the 
patient at every visit, including unscheduled visits. Any positive findings on the eC-SSRS Since 
Last Visit version requires evaluation by a physician or doctoral-level psychologist.
A positive finding will be defined as a current suicide ideation with some intent to act and no 
plan. The investigator, based on his medical judgment, will determine if the patient should be 
seen by a mental health specialist and if he/she should continue participating in the study. If a 
patient reports current suicide ideation with a specific plan and intent, then the patient should be 
immediately discontinued from the study and seen by a mental health specialist. 
Any patient should be excluded if any suicidal behaviors are reported.
Any patient with lifetime behaviors (actual, interrupted, and aborted attempts and preparatory 
actions) should be excluded and/or discontinued from the study.
7.10.
Concomitant Therapy or Medication
Concomitant therapy or medication usage will be monitored throughout the study. Details of 
prohibited medications are found in Section 5.5. 
7.11.
Injection Site Assessments
Injection site assessments will be performed immediately (+10 minutes) and 1 hour 
(±15 minutes) after administration of each dose of the IMP (see Table 4). 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 mm 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. 

For spontaneous report of local pain after the injection, it will be measured as 
summarized in Table 8.
Table 8:
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 induration, erythema, 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.


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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.


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8.
ASSESSMENT OF PHARMACOKINETICS/BIOMARKERS/ 
IMMUNOGENICITY/ANCILLARY STUDIES
8.1.
Pharmacokinetics Assessment
Sampling for pharmacokinetics will be sparse. Thus, the fremanezumab pharmacokinetics 
samples will be analyzed using a population pharmacokinetic approach and will be reported 
separately from the clinical study report.
Blood samples 
 will be collected via venipuncture/indwelling catheter at the time points 
detailed in Table 4 (patients enrolling in this study from the pivotal efficacy studies). The dates 
and times of IMP administration and the date and time of each pharmacokinetics sample will be 
recorded on the source documentation and transcribed onto the CRF.
Samples from all patients will be analyzed for concentration of fremanezumab using a validated 
method. Details on sample handling, storage, shipment, and analysis are given in Appendix G. 
8.2.
Pharmacodynamics Assessment
Pharmacodynamics parameters are not evaluated in this study.
8.3.
Immunogenicity Testing
Blood samples 
 will be collected via venipuncture or indwelling catheter at the time points 
detailed in Table 4 (patients enrolling in this study from the pivotal efficacy studies) and Table 5
(patients rolling over from the pivotal efficacy studies for evaluation of ADAs and safety 
[adverse events and concomitant medications] only) for immunogenicity testing. 
Samples from all patients will be analyzed. Details on sample handling, storage, shipment, and 
analysis are provided in Appendix O.
8.4.
Assessment of Exploratory Biomarkers
Biomarkers are defined as biological substances that monitor physiological effects, assess drug 
activity, and predict clinical outcome, safety, and response to therapy. Details on sample 
handling, storage, shipment, and analysis are provided in Appendix P.
CGRP-containing nerve fibers are prevalent in bone tissue and have been hypothesized to be 
important in the regulation of bone metabolism, response to bone injury, and the perception of 
bone pain. In vitro, CGRP is anabolic to osteoblasts and can inhibit maturation to osteoclasts. 
Preclinical studies suggest CGRP antagonism may have benefit in osteoarthritis (Benschop et al 
2014) and bone-related pain. 
 
 
In preclinical models, CGRP can promote angiogenesis in ischemia, capsaicin-induced synovitis, 
and neovascularization of tumors.
 


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CGRP is known to act directly on macrophage and dendritic cells by inhibiting them from 
producing inflammatory cytokines and presenting antigens to T cells. It has been hypothesized 
that CGRP may act as a regulator of the innate immune response.
 
 
Based on the known biology of CGRP’s mechanism of action, biomarker assessment will 
potentially include markers of bone remodeling, inflammation, and angiogenesis. The Validated 
multiplex immunoassay panels will be applied to measure changes in urine, serum, plasma, and 
RNA biomarkers.
The planned biomarker analysis will be detailed in a separate document, which may be updated 
at a later stage before the analysis to allow updating with new scientific information.
8.5.
Pharmacogenomics
For information regarding pharmacogenomics assessments, see Appendix Q. Multiple genetic 
loci have been identified that could affect the binding affinity of the CGRP-receptor-ligand 
complex, while other genetic loci have been identified as having roles in migraine and/or 
headache onset (Anttila et al 2013). To explore the potential impact of normal variations in these 
loci on parameters in this study, a blood sample will be collected from each patient (unless the 
patient declines testing or local regulations prohibit testing) for pharmacogenomic assessment 
during the pivotal efficacy study. Pharmacogenomic assessment potentially includes the 
association analysis of both known and unknown DNA and RNA genetic variations.
8.6.
Ancillary Study – Wearable Sensor Substudy
At selected sites, a subset of patients (n=90, approximately 45 from each Phase 3 pivotal study) 
will be asked to wear a sensor monitoring system (digital wearable device) on the wrist to track 
sleep patterns and activity patterns. 
 
 
 
 
 
 After 15 June 2018, only patients 
who participated in the ECH study (Study TV48125-CNS-30056) will be enrolled for active 
treatment. 
 
 
 
 
 
 
 
 
 


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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 clinical study report.
9.1.
Sample Size and Power Considerations
There are no statistical considerations for the sample size. Up to 600 patients from the Phase 3 
pivotal efficacy studies (Studies TV48125-CNS-30056 and TV48125-CNS-30057) are expected 
to enroll in this study
The sample size for each of the pivotal studies TV48125-CNS-30056 for ECH and 
TV48125-CNS-30057 for CCH is 300 patients. All of the 600 patients participating in the pivotal 
studies will roll over to the long-term safety study. Approximately 360 patients (out of the 
completers from the pivotal studies) will be offered to receive treatment during 40 weeks, and 
these patients will return for a follow-up visit approximately 7.5 months after the last dose of the 
IMP. Approximately 240 patients (including early termination patients in the pivotal studies) will 
be offered to continue in a long-term safety evaluation collecting AEs, SAEs, and for ADA 
evaluation approximately 7.5 months after administration of the last dose of the IMP.
Prior to 15 June 2018, patients from the ECH study and the CCH study were enrolled. After 
15 June 2018, only patients who participated in the ECH study (Study TV48125-CNS-30056) 
will be enrolled for active treatment. At the time of unblinding the treatment code in 
Study TV48125-CNS-30057 (planned for Q4 2018), those CCH patients who were receiving 
placebo in StudyTV48125-CNS-30057 (ie, never received any study drug) will not be required to 
complete additional safety follow-up visits, and will be discharged from the study.
9.2.
Analysis Sets
9.2.1.
Intent-to-Treat Analysis Set
The intent-to-treat (ITT) analysis set will include all patients who are enrolled in this study for 
long-term safety evaluation, regardless if they receive study treatment or not. 
9.2.2.
Safety Analysis Set
The safety analysis set will include all patients who receive any dose of IMP. 
9.2.3.
Full Analyses Set
 
9.2.4.
Per-Protocol Analysis Set
Not applicable


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9.3.
Data Handling Conventions
9.3.1.
Definition of Baseline
Baseline refers to the run-in period of the pivotal efficacy studies for CH variables and visit 2 
(day 0) of the pivotal efficacy studies for all other study variables.
9.3.2.
Handling Withdrawals and Missing Data
Missing data will be handled in the same way as in the double-blinded pivotal study. Details will 
be provided in the statistical analysis plan.
9.4.
Study Population
The ITT analysis set (see Section 9.2.1) will be used for all study population summaries unless 
otherwise specified. Summaries will be presented overall and by diagnosis (ECH or CCH 
headache) and treatment group.
9.4.1.
Patient Disposition
Data from patients screened, patients screened but not enrolled and the reason for not being 
enrolled; patients who are enrolled; patients enrolled but not treated; patients in the ITT, safety, 
and FASs; 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 ECG findings) will be summarized using descriptive statistics. For continuous variables, 
descriptive statistics (number of patients [n], mean, standard deviation [SD], median, minimum, 
and maximum) will be provided. For categorical variables, patient counts and percentages will 
be provided. Categories for missing data will be presented if necessary.
9.5.
Efficacy Analysis
 
 


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9.5.1.
Primary Endpoint
The primary endpoints for this study are related to safety (Section 2.1). Refer to Section 9.7 for a 
summary of the safety analyses.
9.5.2.
Secondary Endpoints
Not applicable
9.5.3.
Exploratory Endpoints
Exploratory efficacy endpoints are as follows:
 
 
 
 
 
 
 
 
 
 
 
 
Wearable sensor substudy exploratory endpoints are the following:
 
 


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9.5.4.
Planned Method of Analysis
The FAS (see Section 9.3) will be used for all efficacy analyses. Summaries will be presented 
overall and by diagnosis (CCH or ECH) group.
9.5.4.1.
Primary Efficacy Analysis
Not applicable
9.5.4.2.
Sensitivity Analysis
Not applicable
9.5.4.3.
Secondary Efficacy Analysis
Not applicable


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9.5.4.4.
Exploratory Efficacy Analysis
 
9.6.
Multiple Comparisons and Multiplicity
Not applicable
9.7.
Safety Analysis
Safety analyses will be performed on the safety analysis set (Section 9.2.2).
Safety assessments and time points are provided in Table 4 (patients enrolling in this study from 
the pivotal efficacy studies) and Table 5 (patients rolling over from the pivotal efficacy studies 
for evaluation of ADAs, adverse events, and concomitant medications only).
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.
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 IMP.
Changes in laboratory, ECG, and vital signs measurement data will be summarized descriptively. 
All values will be compared with pre-specified boundaries to identify potential clinically 
significant changes or values, and such values will be listed.
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 also be provided.
Suicidal ideation and behavior will be measured using the eC-SSRS. Data for patients with 
positive findings will be listed.
If any patient dies during the study, a listing of deaths will be provided, and all relevant 
information will be discussed in the patient narrative included in the clinical study report.
9.8.
Tolerability Analysis
Tolerability was not specifically defined.


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9.9.
Pharmacokinetic Analysis
Pharmacokinetic plasma concentration results (fremanezumab) will be tabulated descriptively at 
each planned sampling time point by diagnosis (ECH or CCH) and by treatment group.
In addition, the most appropriate population pharmacokinetic model will be developed, and 
covariates that may affect it will be tested for inclusion in the model. This analysis will be 
reported separately. 
9.10.
Pharmacokinetics/Pharmacodynamics Analysis
The pharmacokinetics/pharmacodynamics parameters may be estimated by compartmental 
techniques. The pharmacokinetics parameters will be based on fremanezumab measurements. 
The pharmacodynamics parameters will be the efficacy/safety response(s). 
The pharmacokinetics/pharmacodynamics relationship may be estimated using the most 
appropriate model after comparing different candidate models for their quality of fit. Covariates 
that may affect the pharmacokinetics/pharmacodynamics parameters will be tested for inclusion 
in the model. If performed, this analysis will be reported separately.
9.11.
Pharmacogenomic Analysis
Pharmacogenomic analysis results will be summarized for each gene tested. An attempt will be 
made to correlate clinical observations (pharmacokinetics, safety, efficacy, or other effects) with 
the genotypes observed. Additional pharmacogenomic analysis may be conducted at a later time 
and will be reported in a separate addendum report
9.12.
Biomarker Analysis
Biomarker analysis will include logistic regression, receiver operating characteristic curves, and 
summary statistics. This analysis will be reported separately. Measurements will be made using 
validated assays.
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, IMP efficacy, 
and clinical safety will be evaluated. This ADA impact analysis will be reported separately.
9.14.
Ancillary Study Analysis
Analysis will include summary statistics and multimodal algorithms 
 
. Results will be reported separately.
9.15.
Planned Interim Analysis
Not applicable


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9.16.
Reporting Deviations from the Statistical Plan
Deviations from the statistical plan, along with the reasons for the deviations, will be described 
in protocol amendments, the statistical analysis plan, the clinical study report, or any 
combination of these, as appropriate, and in accordance with applicable national, local, and 
regional requirements and regulations.


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10.
QUALITY CONTROL AND QUALITY ASSURANCE
Refer to Appendix C for information regarding quality control and quality assurance. This 
includes information about protocol amendments, deviations, responsibilities of the investigator 
to study personnel, study monitoring, and audit and inspection.
Refer to Appendix R 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 International Council on Harmonization 
(ICH) Harmonised Tripartite Guideline for GCP E6 and any applicable national and local laws 
and regulations (eg, Title 21 Code of Federal Regulations [CFR] Parts 11, 50, 54, 56, 312, 
and 314, Directive 2001/20/EC of the European Parliament and of the Council on the 
approximation of the laws, regulations and administrative provisions of the Member States 
relating to the implementation of GCP in the conduct of clinical trials on medicinal products for 
human use). Any episode of noncompliance will be documented.
The investigator is responsible for performing the clinical study in accordance with this protocol 
and the applicable GCP guidelines referenced above for collecting, recording, and reporting the 
data accurately and properly. Agreement of the investigator to conduct and administer this 
clinical study in accordance with the protocol will be documented in separate clinical study 
agreements with the sponsor and other forms as required by national competent authorities in the 
country where each investigational center is located.
The investigator is responsible for ensuring the privacy, health, and welfare of the patients during 
and after the clinical study; and must ensure that trained personnel are immediately available in 
the event of a medical emergency. The investigator and the involved clinical study personnel 
must be familiar with the background and requirements of the study and with the properties of 
the IMPs as described in the IB or prescribing information.
The principal investigator at each investigational center has the overall responsibility for the 
conduct and administration of the clinical study at that investigational center and for contacts 
with study management, with the IEC/IRB, and with competent authorities.
See Appendix D for the ethics expectations of informed consent, competent authorities and IEC 
and IRB, confidentiality regarding study patients, and requirements for registration of the clinical 
study.


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12.
DATA MANAGEMENT AND RECORD KEEPING
See Appendix S 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 T for information regarding the publication policy.


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15.
REFERENCES
Armour KL, Clark MR, Hadley AG, Williamson LM. Recombinant human IgG molecules 
lacking Fcgamma receptor I binding and monocyte triggering activities. Eur J Immunol 
1999;29(8):2613–24.
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.
Barloese MC. Neurobiology and sleep disorders in cluster headache. J Headache Pain 
2015;16:562.
Barloese MC, Jennum P, Knudsen S, Jensen R. Cluster headache and sleep, is there a 
connection? A review. Cephalalgia 2012;32(6):481-91.
Benschop RJ, Collins EC, Darling RJ, Allan BW, Leung D, Conner EM, et al. Development of a 
novel antibody to calcitonin gene-related peptide for the treatment of osteoarthritis-related pain. 
Osteoarthritis Cartilage. 2014;22(4):578-85.
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.
Fanciullacci M, Alessandri M, Figini M, Geppetti P, Michelacci S. Increase in plasma calcitonin 
gene-related peptide from the extracerebral circulation during nitroglycerin-induced cluster 
headache attack. Pain 1995;60(2):119-23.
Fanciullacci M, Alessandri M, Sicuteri R, Marabini S. Responsiveness of the trigeminovascular 
system to nitroglycerine in cluster headache patients. Brain 1997;120(Pt 2):283-8.
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.
Goadsby PJ. Pathophysiology of cluster headache: a trigeminal autonomic cephalgia. Lancet 
Neurol. 2002;1(4):251-7.
Goadsby PJ, Edvinsson L. Human in vivo evidence for trigenimovascular activation in cluster 
headache: neuropeptide changes and effects of acute attacks therapies. Brain 1994;117(Pt 3):427-
34.
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. 


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International Committee of Medical Journal Editors (ICMJE). Recommendations for the 
Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical Journals. Available 
at: http://www.icmje.org/recommendations/.
Japanese Headache Society. Clinical practice guideline for chronic headache 2013. Available at: 
www.neurology-jp.org/guidelinem/ch/documents/guideline2013.pdf.
Kudrow L. The cyclic relationship of natural illumination to cluster period frequency. 
Cephalalgia. 1987;7(Suppl6):76-8.
May A. Cluster headache: pathogenesis, diagnosis, and management. Lancet. 
2005;366(9488):843-55.
May A, Ashburner J, Büchel C, McGonigle DJ, Friston KJ, Frackowiak RS, et al. Correlation 
between structural and functional changes in brain in an idiopathic headache syndrome. Nat Med 
1999;5(7):836-8. 
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 3 multisite 
studies with adolescents and adults. Am J Psychiatry. 2011;168(12):1266-77.
Reilly MC, Zbrozek AS, Dukes EM. The validity and reproducibility of a work productivity and 
activity impairment instrument. Pharmacoeconomics. 1993;4(5):353-65.
Rozen TD. Cluster headache: diagnosis and treatment. Curr Pain Headache Rep. 
2005;9(2):135-40.
Rozen TD, Fishman RS. Cluster headache in the United States of America: demographics, 
clinical characteristics, triggers, suicidality, and personal burden. Headache 2012;52(1):99-113.
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.
ten Klooster PM, Drossaers-Bakker KW, Taal E, van de Laar MAFJ. Patient-Perceived 
Satisfactory Improvement (PPSI): Interpreting meaningful change in pain from the patient’s 
perspective. Pain. 2006;121:151-7.
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.
Weaver-Agostoni J. Cluster headache. Am Fam Physician. 2013;l88(2):122-8.
Zeller J, Poulsen KT, Sutton JE, Abdiche YN, Collier S, Chopra R, et al. CGRP 
function-blocking antibodies inhibit neurogenic vasodilatation without affecting heart rate or 
arterial blood pressure in the rat. Br J Pharmacol 2008;155(7):1093–103.
Zigmond AS, Snaith RP. The Hospital Anxiety and Depression Scale. Acta Psychiatr Scand. 
1983:67(6):361-70. 


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16.
SUMMARY OF CHANGES TO THE PROTOCOL
16.1.
Amendment 04 Dated 28 August 2018
The primary reason for this amendment is to describe the way in which patients who participated 
in the double-blind study for CCH TV48125-CNS-30057 will continue to participate in this 
Long Term Safety study (Study TV48125-CNS-30058), since the CCH study has been 
terminated. 
Prior to 15 June 2018, patients rolled over from the episodic TV48125-CNS-30056 and chronic 
TV48125-CNS-30057 cluster headache studies into the Long Term Safety study 
(TV48125-CNS-30058).
As of 15 June 2018, the CCH Study TV48125-CNS-30057 was terminated based on the study 
meeting pre-specified stopping criteria (conditional power < 25%) during a planned interim 
analysis. Thus, all CCH patients included in this study have been asked to discontinue treatment 
and are encouraged to continue in the ADA and safety follow-up portion of this study.
After 15 June 2018, only patients who participated in the ECH study
(Study TV48125-CNS-30056) will be enrolled for active treatment. At the time of unblinding the 
treatment code in Study TV48125-CNS-30057 (planned for Q4 2018), those CCH patients who 
were receiving placebo in Study TV48125-CNS-30057 (ie, never received any study drug) will 
not be required to complete additional safety follow-up visits, and will be discharged from the 
study.
The Amendment History table has been updated to correct some inadvertent errors.
Updated standardized text has been added to Section 5.9.2.
Additional changes to the protocol are presented below.
Letters of Clarification 05, 06, and 08 and the USM Letter of Clarification have been included. 
They were inadvertently omitted from being attached to previous protocol amendments. 
However, all changes to the protocol based on these letters were made at the applicable time 
points and are noted in the correct amendments. The letters are presented at the end of this 
amendment.
Letter of Clarification 07 was inadvertently noted and was applicable only to other studies in 
Sweden (Studies TV48125-CNS-30056 and TV48125-CNS-30057).
Appropriate areas of the protocol have been updated as outlined in the table below.


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Original text with changes shown
New wording
Reason/justification for change
Amendment History
Amendment 03 
058 ROW-26 April 2018
186 patients enrolled to date
058 Sweden 19 October 2017 07 June 2018
229 patients randomized to date
ROW-26 April 2018
Sweden 07 June 2018
To correct amendment dates.
Amendment 02
ROW-03 May 2017
No patients randomized/enrolled to date
Sweden-19 October 2017
No patients randomized/enrolled to date
ROW-03 May 2017
Sweden-19 October 2017
No patients randomized/enrolled to date
To correct amendment dates.
Letter of Clarification-USM
ROW- 04 April 2018
US - 06 April 2018
ROW- 04 April 2018
US - 06 April 2018
To correct Letter of Clarification dates.
Letter of Clarification 08
20 March 2018
14 March 2018
Letter of Clarification 08
14 March 2018
To correct Letter of Clarification dates.
Letter of Clarification 07
14 March 2018
18 October 2017
Letter of Clarification 07
18 October 2017
Letter of clarification 07 was inadvertently noted and 
was actually applicable for other studies in Sweden 
(Studies TV48125-CNS-30056 and 
TV48125-CNS-30057).
Letter of Clarification 06
19 August 2017
27 August 2017
Letter of Clarification 06
27 August 2017
To correct Letter of Clarification dates.
Synopsis
Changes made in the body of the protocol are reflected in the synopsis for consistency.
Section 1.1.3, Study Purpose
Prior to 15 June 2018, patients rolled over from the 
episodic TV48125-CNS-30056 and chronic 
Prior to 15 June 2018, patients rolled over from the 
episodic TV48125-CNS-30056 and chronic TV48125-
To describe how patients who participated in the 
double-blind study for CCH 


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TV48125-CNS-30057 cluster headache studies into 
the Long Term Safety study (TV48125 CNS-30058). 
As of 15 June 2018, CCH Study TV48125-CNS-
30057 was terminated based on the study meeting 
pre specified stopping criteria (conditional power 
< 25%) during a planned interim analysis. The 
planned interim analysis was for futility evaluation 
based on 50% of patients (ie, the first 150 patients 
who had completed the study or withdrawn from the 
study early). An independent unblinded statistician 
from a third party performed the analysis. The 
futility evaluation was assessed using conditional 
power. The sponsor was notified that the conditional 
power was less than 25% for both comparisons 
(fremanezumab 900 mg iv loading dose group versus 
placebo or fremanezumab 675 mg sc loading dose 
group versus placebo).Thus, all CCH patients 
included in this study have been asked to discontinue 
treatment, and are encouraged to continue in the anti-
ADA and safety follow-up portion of this study.
At the time of unblinding the treatment code in Study 
TV48125-CNS-30057 (planned for Q4 2018), those 
CCH patients who were receiving placebo in Study 
TV48125-CNS-30057 (ie, never received any study 
drug) will not be required to complete additional 
safety follow-up visits, and will be discharged from 
the study.
As of 15 June 2018, only patients from the ECH 
study (Study TV48125-CNS -30056) will enroll in 
this study for active treatment.
CNS-30057 cluster headache studies into the Long 
Term Safety study (TV48125 CNS-30058). 
As of 15 June 2018, CCH Study TV48125-CNS-30057 
was terminated based on the study meeting pre 
specified stopping criteria (conditional power < 25%)
during a planned interim analysis. The planned interim 
analysis was for futility evaluation based on 50% of 
patients (ie, the first 150 patients who had completed 
the study or withdrawn from the study early). An 
independent unblinded statistician from a third party 
performed the analysis. The futility evaluation was 
assessed using conditional power. The sponsor was 
notified that the conditional power was less than 25% 
for both comparisons (fremanezumab 900 mg iv 
loading dose group versus placebo or fremanezumab 
675 mg sc loading dose group versus placebo).Thus, 
all CCH patients included in this study have been 
asked to discontinue treatment, and are encouraged to 
continue in the anti-ADA and safety follow-up portion 
of this study.
At the time of unblinding the treatment code in Study 
TV48125-CNS-30057 (planned for Q4 2018), those 
CCH patients who were receiving placebo in Study 
TV48125-CNS-30057 (ie, never received any study 
drug) will not be required to complete additional safety 
follow-up visits, and will be discharged from the study.
As of 15 June 2018, only patients from the ECH study 
(Study TV48125-CNS-30056) will enroll in this study
for active treatment.
(Study TV48125-CNS-30057) will continue to 
participate in this Long Term Safety study 
(Study TV48125-CNS-30058), since the CCH study 
has been terminated.
Section 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 
The clinical pharmacology development (Phase 1) 
program for fremanezumab in migraine includes 8 
completed studies. A total of 318 healthy subjects were 
enrolled, of which 256 subjects received at least 1 dose 
of fremanezumab. In 6 of the Phase 1 studies, Studies 
B0141001, B0141002, B0141006, B0141007, LBR-
101-008, and LBR-101-011
 
To include updated status/information from the Phase 
1 development program for fremanezumab.


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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). The clinical pharmacology development (Phase 
1) program for fremanezumab in migraine includes 8 
completed studies. A total of 318 healthy subjects 
were enrolled, 256 subjects received at least 1 dose 
of fremanezumab. 
 
 
 
 
. A description of the objectives of these 6 
Phase 1 studies is as follows:

Studies B0141001 and B0141002 were iv 
single-dose-escalation PK and PD studies in 
healthy men.

Study B0141006 was a 2-cohort, placebo-
controlled crossover study to examine the acute 
effects of iv administration of fremanezumab on 
capsaicin flare response in healthy men.

Study B0141007 was a parallel-group, repeat-
dose PK and PD study of iv administration of 
fremanezumab in healthy men and women.

Study LBR-101-008 was a single-dose study 
examining the safety, tolerability, PK, and PD of 
doses up to 2000 mg administered iv to healthy 
women.
fremanezumab were analyzed using the original 
 
 
 A 
description of the objectives of these 6 Phase 1 studies
is as follows:

Studies B0141001 and B0141002 were iv 
single-dose-escalation PK and PD studies in 
healthy men.

Study B0141006 was a 2-cohort, 
placebo-controlled crossover study to examine the 
acute effects of iv administration of 
fremanezumab on capsaicin flare response in 
healthy men.

Study B0141007 was a parallel-group, repeat-dose 
PK and PD study of iv administration of 
fremanezumab in healthy men and women.

Study LBR-101-008 was a single-dose study 
examining the safety, tolerability, PK, and PD of 
doses up to 2000 mg of fremanezumab 
administered iv to healthy women.

Study LBR-101-011 was a randomized, 
placebo-controlled, double-blind, parallel‑group 
study examining the safety, tolerability, absolute 
bioavailability (BA), and PK of 2 different single 
doses of fremanezumab administered iv or sc to 
healthy men and women.
Two additional Phase 1 studies, Studies TV48125-PK-
10078 and TV48125-BE-10114, were conducted using 
the current validated bioanalytical method. A 
description of the objectives of these 2 Phase 1 Studies
is as follows:

Study TV48125-PK-10078 was a randomized, 
double-blind, placebo-controlled study to assess 
the PK, safety, and tolerability of single-dose sc 
administration of fremanezumab (single ascending 
doses and single doses up to 900 mg) in Japanese 
and Caucasian healthy subjects. 


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
Study LBR-101-011 was a randomized, placebo-
controlled, double-blind, parallel‑group study 
examining the safety, tolerability, absolute 
bioavailability (BA), and PK of 2 different 
single doses of fremanezumab administered iv 
or sc to healthy men and women.
Two additional Phase 1 studies, Studies TV48125-
PK-10078 and TV48125-BE-10114, were conducted 
using the current validated bioanalytical method. A 
description of the objectives of these 2 Phase 1 
Studies is as follows:

Study TV48125-PK-10078 was a randomized, 
double-blind, placebo-controlled study to assess 
the PK, safety, and tolerability of single-dose sc 
administration of fremanezumab (single 
ascending doses and single doses up to 900 mg) 
in Japanese and Caucasian healthy subjects. 

Study TV48125-BE-10114 was an open-label, 
single‑dose, randomized, parallel, 
bioequivalence study to compare the PK of 
fremanezumab administered sc using an auto-
injector or a pre-filled syringe in healthy adult 
men and women.

Additional ongoing bioequivalence study 
(TV48125-BE-10145) is an open-label, single‑
dose, randomized, parallel, bioequivalence study 
to compare the PK of fremanezumab 
administered sc using an auto-injector or a pre-
filled syringe in healthy adult men and women.
 
 
 
 
 
 
 
Study TV48125-BE-10114 was an open-label, single‑
dose, randomized, parallel, bioequivalence study to 
compare the PK of fremanezumab administered sc 
using an auto-injector or a pre-filled syringe in healthy 
adult men and women. Additionalongoing 
bioequivalence study (TV48125-BE-10145) is another
open-label, singledose, randomized, parallel, 
bioequivalence study to compare the PK of 
fremanezumab administered sc using an auto-injector 
or a pre-filled syringe in healthy adult men and 
women.
The pharmacokinetics (non-compartmental analysis; 
Study TV48125-PK-10078) of fremanezumab 
demonstrated an increase in Cmaxand AUC values 
slightly greater than the dose proportionality over the 
sc dose range of 225 to 900 mg. Median time to 
maximum observed concentration (tmax) values was 
generally 5 to 7 days post sc doses. Mean values for 
apparent total volume of distribution during the 
terminal phase (V
z/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 plasma clearance (CL/F) ranged 
from 0.0777 to 0.0895 mL/min at this dose range. The 
mean t½ranged from 32.2 to 36.2 days. Fremanezumab 
exposure parameters and overall pharmacokinetic 
profile were similar for healthy Japanese and 
Caucasian subjects.


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The pharmacokinetics (non-compartmental analysis) 
; study TV48125-PK-10078) of fremanezumab 
demonstrated an increase in Cmax and AUC values 
slightly greater than the dose proportionality over the 
sc dose range of 225 to 900 mg. Median time to 
maximum observed concentration (tmax) values was 
generally 5 to 7 days post sc doses. Mean values for 
apparent total volume of distribution during the 
terminal phase (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 plasma 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 were similar for healthy 
Japanese and Caucasian subjects.
 
 
 
.
Section 1.3.1, Known and Potential Benefits and Risks of the Test Investigational Medicinal Product(s) 
Among these events, the following have been 
identified as adverse drug reactions (identified 
risks): injection site erythema, injection site 
rash, injection site induration, and injection site 
pain, injection site pruritus, and injection site 
dermatitis. None of these identified risks are 
Among these events, the following have been 
identified as adverse drug reactions (identified risks): 
injection site erythema, injection site rash, injection 
site induration, and injection site pruritus. None of 
these identified risks are considered important risks.
To clarify the identified risks of fremanezumab.


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considered important risks.
Section 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. 
The benefit and risk assessment for fremanezumab 
has been re-assessed for patients with CCH. As of 
15 June 2018, the CCH study (TV48125-CNS-
30057) was terminated based on the study meeting 
pre-specified stopping criteria (conditional power 
< 25%) during a planned interim analysis. Thus, all 
CCH patients included in this study have been asked 
to discontinue treatment, and are encouraged to 
continue in the ADA and safety follow-up portion of 
this study.
In summary, the benefit and risk assessment for 
fremanezumab is favorable following review of the 
outlined data. 
The benefit and risk assessment for fremanezumab has 
been re-assessed for patients with CCH. As of 15 June 
018, the CCH study (TV48125-CNS-30057) was 
terminated based on the study meeting pre-specified 
stopping criteria (conditional power < 25%) during a 
planned interim analysis. Thus, all CCH patients 
included in this study have been asked to discontinue 
treatment, and are encouraged to continue in the ADA 
and safety follow-up portion of this study.
To describe how patients who participated in the 
double-blind study for CCH 
(Study TV48125-CNS-30057) will continue to 
participate in this Long Term Safety study 
(Study TV48125-CNS-30058), since the CCH study 
has been terminated.
Section 2.1, Primary and Secondary Study Objectives and Endpoints
As of 15 June 2018, only patients from the ECH 
study (Study TV48125-CNS-30056) will enroll in 
this study for active treatment. As of 15 June 2018, 
all CCH patients included in this study have been 
asked to discontinue treatment, and are encouraged 
to continue in the ADA and safety follow-up portion 
of this study. Data from CCH patients enrolled prior 
to 15 June 2018 will be evaluated per all objectives 
of this study.
As of 15 June 2018, only patients from the ECH study 
(Study TV48125-CNS-30056) will enroll in this study
for active treatment. As of 15 June 2018, all CCH 
patients included in this study have been asked to 
discontinue treatment, and are encouraged to continue 
in the ADA and safety follow-up portion of this study 
Data from CCH patients enrolled prior to 15 June 2018 
will be evaluated per all objectives of this study.
To describe how patients who participated in the 
double-blind study for CCH 
(Study TV48125-CNS-30057) will continue to 
participate in this Long Term Safety study 
(Study TV48125-CNS-30058), since the CCH study 
has been terminated.
Section 3.1, General Design and Study Schematic Diagram
Prior to 15 June 2018, up to 360 eligible patients 
with ECH and CCH rolling over from the pivotal 
studies (Studies TV48125-CNS-30056 and 
TV48125-CNS-30057, respectively) will receive 
fremanezumab during this study, as summarized in 
Table 3. After 15 June 2018, only patients who 
participated in the ECH study 
(Study TV48125-CNS-30056) will be enrolled in this 
study for active treatment. At the time of unblinding 
the treatment code in Study TV48125-CNS-30057 
Prior to 15 June 2018, up to 360 eligible patients with 
ECH and CCH rolling over from the pivotal studies 
(Studies TV48125-CNS-30056 and TV48125-CNS-
30057, respectively) will receive fremanezumab during 
this study, as summarized in Table 3. After 
15 June 2018, only patients who participated in the 
ECH study (Study TV48125-CNS-30056) will be 
enrolled in this study for active treatment. At the time 
of unblinding the treatment code in Study 
TV48125-CNS-30057 (planned for Q4 2018), those 
To describe how patients who participated in the 
double-blind study for CCH 
(Study TV48125-CNS-30057) will continue to 
participate in this Long Term Safety study 
(Study TV48125-CNS-30058), since the CCH study 
has been terminated.


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(planned for Q4 2018), those CCH patients who were 
receiving placebo in Study TV48125-CNS-30057 (ie,
never received any study drug) will not be required 
to complete additional safety follow-up visits, and 
will be discharged from the study.
CCH patients who were receiving placebo in Study 
TV48125-CNS-30057 (ie, never received any study 
drug) will not be required to complete additional safety 
follow-up visits, and will be discharged from the study.
Section 3.1, General Design and Study Schematic Diagram (Table 3:Summary of Treatments During Study TV48125-CNS-30058)
Study 
TV48125-
CNS-30057 
(CCH)
Prior to 
15 June 2018 
termination of 
CCH Study 
TV48125-CN
S-30057.
No additional 
CCH patients 
will be 
enrolled after 
15 June 2018
for active 
treatment.
Fremanezumab
900-mg iv 
loading dose 
group
Fremanezumab
at 225 mg sc 
monthly 
(approximately 
every 4 weeks) 
through week 36
Fremanezumab
675-mg sc 
loading dose 
group
Fremanezumab
at 225 mg sc 
monthly 
(approximately 
every 4 weeks) 
through week 36
Placebo group
Fremanezumab
675-mg sc 
loading dose 
followed by 
monthly 
(approximately 
every 4 weeks) 
fremanezumab
at 225 mg sc 
through week 36
Study 
TV48125-
CNS-30057 
(CCH)
Prior to 
15 June 2018 
termination of 
CCH Study 
TV48125-CNS
-30057.
No additional 
CCH patients 
will be 
enrolled after 
15 June 2018
for active 
treatment.
Fremanezumab
900-mg iv 
loading dose 
group
Fremanezumab
at 225 mg sc 
monthly 
(approximately 
every 4 weeks) 
through week 36
Fremanezumab
675-mg sc 
loading dose 
group
Fremanezumab
at 225 mg sc 
monthly 
(approximately 
every 4 weeks) 
through week 36
Placebo group
Fremanezumab
675-mg sc 
loading dose 
followed by 
monthly 
(approximately 
every 4 weeks) 
fremanezumab at 
225 mg sc 
through week 36
To describe how patients who participated in the 
double-blind study for CCH 
(Study TV48125-CNS-30057) will continue to 
participate in this Long Term Safety study 
(Study TV48125-CNS-30058), since the CCH study 
has been terminated.
Section 3.1, General Design and Study Schematic Diagram
Patients with a diagnosis of CCH who experience 
CH remission, defined as no CH attacks for 
24 successive weeks at any time after starting IMP 
(ie, administration of the first dose of IMP in the 
pivotal study), will be offered the possibility to stop 
treatment and continue to attend the subsequent 
scheduled visits. If treatment is stopped and CH 
attacks resume within 12 weeks after stopping 
Patients with a diagnosis of CCH who experience CH 
remission, defined as no CH attacks for 24 successive 
weeks at any time after starting IMP (ie, administration 
of the first dose of IMP in the pivotal study), will be 
offered the possibility to stop treatment and continue to 
attend the subsequent scheduled visits. If treatment is 
stopped and CH attacks resume within 12 weeks after 
stopping treatment, patients will restart fremanezumab 
To describe how patients who participated in the 
double-blind study for CCH 
(Study TV48125-CNS-30057) will continue to 
participate in this Long Term Safety study 
(Study TV48125-CNS-30058), since the CCH study 
has been terminated.


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treatment, patients will restart fremanezumab 
treatment at 225 mg sc monthly through week 36. If 
treatment is stopped and CH attacks resume after 
more than 12 weeks after stopping treatment, patients 
will restart fremanezumab treatment with a 675-mg 
sc loading dose followed by 225-mg sc monthly 
through week 36. After 15 June 2018, only patients 
who participated in the ECH study (Study 
TV48125-CNS-30056) will be enrolled for active 
treatment. All CCH patients included in this study 
have been asked to discontinue treatment, and are 
encouraged to continue in the ADA and safety 
follow-up portion of this study.
treatment at 225 mg sc monthly through week 36. If 
treatment is stopped and CH attacks resume after more 
than 12 weeks after stopping treatment, patients will 
restart fremanezumab treatment with a 675-mg sc 
loading dose followed by 225-mg sc monthly through 
week 36. After 15 June 2018, only patients who 
participated in the ECH study (Study 
TV48125-CNS-30056) will be enrolled for active 
treatment. All CCH patients included in this study have 
been asked to discontinue treatment, and are 
encouraged to continue in the ADA and safety follow-
up portion of this study.
Section 3.1, General Design and Study Schematic Diagram (Figure 1: Overall Study Schematic Diagram)
Updated to reflect amendment changes.
Section 3.1, General Design and Study Schematic Diagram: Wearable Sensor Substudy
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Section 3.2 Planned Number of Patients and Countries
Prior to 15 June 2018, up to 600 patients from the 
Phase 3 pivotal efficacy studies (Studies TV48125-
CNS-30056 and TV48125-CNS-30057) are expected 
to enroll in this study. After 15 June 2018, only 
patients who participated in the ECH study 
(Study TV48125-CNS-30056) will be enrolled in 
this study for active treatment.
Prior to 15 June 2018, up to 600 patients from the 
Phase 3 pivotal efficacy studies (Studies TV48125-
CNS-30056 and TV48125-CNS-30057) are expected 
to enroll in this study. After 15 June 2018, only 
patients who participated in the ECH study
(Study TV48125-CNS-30056) will be enrolled in this 
study for active treatment.
To describe how patients who participated in the 
double-blind study for CCH 
(Study TV48125-CNS-30057) will continue to 
participate in this Long Term Safety study 
(Study TV48125-CNS-30058), since the CCH study 
has been terminated.
Section 3.3 Justification for Study Design and Selection of Population
This study is double-blind to ensure impartiality in 
evaluating the long-term safety and efficacy of
different dose regimens of fremanezumab and to 
avoid unblinding the pivotal studies before they are 
completed. The blind will be maintained according to 
standard blinding procedures (see Section 5.9.2) and 
through the use of dummy injections to ensure that 
number of injections is the same at each visit for 
patients with ECH and patients with CCH (see 
Section 5.1.1.1). After 15 June 2018, only patients 
who participated in the ECH study 
(Study TV48125-CNS-30056) will be enrolled for 
active treatment.
This study is double-blind to ensure impartiality in 
evaluating the long-term safety and efficacy of 
different dose regimens of fremanezumab and to avoid 
unblinding the pivotal studies before they are 
completed. The blind will be maintained according to 
standard blinding procedures (see Section 5.9.2) and 
through the use of dummy injections to ensure that 
number of injections is the same at each visit for 
patients with ECH and patients with CCH (see Section 
5.1.1.1). After 15 June 2018, only patients who 
participated in the ECH study
(Study TV48125-CNS-30056) will be enrolled for 
active treatment.
To describe how patients who participated in the 
double-blind study for CCH 
(Study TV48125-CNS-30057) will continue to 
participate in this Long Term Safety study 
(Study TV48125-CNS-30058), since the CCH study 
has been terminated.
Section 4.1, Patient Inclusion Criteria
Criterion C: The patient completes either the Phase 3 
pivotal study for ECH (Study TV48125 CNS-30056) 
or the Phase 3 pivotal study for CCH (Study 
TV48125-CNS-30057) without important protocol 
deviations related to patient safety and patient 
compliance and at least 75% diary data completion 
during the pivotal study. Prior to 15 June 2018 
patients from the ECH study and the CCH study
were enrolled. After 15 June 2018, only patients who 
participated in the ECH study
(Study TV48125-CNS-30056) will be enrolled for 
active treatment.
Criterion C: The patient completes either the Phase 3 
pivotal study for ECH (Study TV48125 CNS-30056) 
or the Phase 3 pivotal study for CCH (Study TV48125-
CNS-30057) without important protocol deviations 
related to patient safety and patient compliance and at 
least 75% diary data completion during the pivotal 
study. Prior to 15 June 2018 patients from the ECH 
study and the CCH study were enrolled. After 
15 June 2018, only patients who participated in the 
ECH study (Study TV48125-CNS-30056) will be 
enrolled for active treatment.
To describe how patients who participated in the 
double-blind study for CCH 
(Study TV48125-CNS-30057) will continue to 
participate in this Long Term Safety study 
(Study TV48125-CNS-30058), since the CCH study 
has been terminated.
Criterion E: Women of childbearing potential 
Criterion E: Women of childbearing potential 
Revised to apply to patients participating in safety 


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109
(WOCBP) whose male partners are potentially fertile 
(ie, no vasectomy) must use highly effective birth 
control methods (see Appendix E) for the duration of 
the study and for 7.5 months after discontinuation of 
IMP (not applicable for patients participating in 
safety follow up only). 
(WOCBP) whose male partners are potentially fertile 
(ie, no vasectomy) must use highly effective birth 
control methods (see Appendix E) for the duration of 
the study and for 7.5 months after discontinuation of 
IMP 
follow-up only.
Section 5.1.1.1, Starting Dose and Dose Levels
After 15 June 2018, only patients who participated in 
the ECH study (Study TV48125-CNS-30056) will be 
enrolled for active treatment. Patients with CCH will 
be rolled over from Study TV48125-CNS-30057 
until 15 June 2018 as follows (after 15 June 2018 no 
additional CCH patients will be enrolled):
Patients who were in the fremanezumab 900-mg iv 
loading dose group and the fremanezumab 675-mg 
sc loading dose group will receive fremanezumab at 
225 mg as a single sc injection (225 mg/1.5 mL) at 
visit 1 and every 4 weeks thereafter through week 36 
(visit 10). For blinding, these patients will also 
receive 2 sc placebo injections at visit 1. 
Patients who were in the placebo group will receive a 
loading dose of fremanezumab at 675 mg as 3 sc 
injections (225 mg/1.5 mL) at visit 1 and 
fremanezumab at 225 mg administered as a single sc 
injection every 4 weeks thereafter through week 36 
(visit 10). 
 
 
 
 
 
 
 
 
 
 
After 15 June 2018, only patients who participated in 
the ECH study (Study TV48125-CNS-30056) will be 
enrolled for active treatment. Patients with CCH will 
be rolled over from Study TV48125-CNS-30057 until 
15 June 2018 as follows (after 15 June 2018 no 
additional CCH patients will be enrolled):
Patients who were in the fremanezumab 900-mg iv 
loading dose group and the fremanezumab 675-mg sc 
loading dose group will receive fremanezumab at 225 
mg as a single sc injection (225 mg/1.5 mL) at visit 1 
and every 4 weeks thereafter through week 36 (visit 
10). For blinding, these patients will also receive 2 sc 
placebo injections at visit 1.
Patients who were in the placebo group will receive a 
loading dose of fremanezumab at 675 mg as 3 sc 
injections (225 mg/1.5 mL) at visit 1 and 
fremanezumab at 225 mg administered as a single sc 
injection every 4 weeks thereafter through week 36 
(visit 10).
 
 
 
 
 
 
 
 
 
 
 
To describe how patients who participated in the 
double-blind study for CCH 
(Study TV48125-CNS-30057) will continue to 
participate in this Long Term Safety study 
(Study TV48125-CNS-30058), since the CCH study 
has been terminated.


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 After 15 June 2018, only patients 
who participated in the ECH study
(Study TV48125-CNS-30056) will be enrolled for 
active treatment. All CCH patients included in this 
study have been asked to discontinue treatment, and 
are encouraged to continue in the ADA and safety 
follow-up portion of this study. At the time of 
unblinding the treatment code in 
Study TV48125-CNS-30057 (planned for Q4 2018), 
those CCH patients who were receiving placebo in 
Study TV48125-CNS-30057 (ie, never received any 
study drug) will not be required to complete 
additional safety follow-up visits, and will be 
discharged from the study.
 
 After 15 June 2018, only patients who 
participated in the ECH study 
(Study TV48125-CNS-30056) will be enrolled for 
active treatment. All CCH patients included in this 
study have been asked to discontinue treatment, and 
are encouraged to continue in the ADA and safety 
follow-up portion of this study. At the time of 
unblinding the treatment code in 
Study TV48125-CNS-30057 (planned for Q4 2018), 
those CCH patients who were receiving placebo in 
Study TV48125-CNS-30057 (ie, never received any 
study drug) will not be required to complete additional 
safety follow-up visits, and will be discharged from the 
study.
Section 5.7, Temporary Discontinuation of Investigational Medicinal Product
Patients who experience CH remission, defined as no 
CH attacks for 12 successive weeks and 
24 successive weeks for patients with ECH and 
CCH, respectively, at any time after starting IMP (ie, 
administration of the first dose of IMP in the pivotal 
study) will be offered the possibility to stop 
treatment. Patients will restart fremanezumab 
treatment if treatment is stopped and CH attacks 
resume during the 36-week double blind treatment 
period. Refer to Section 5.1.1.1 for additional details 
regarding treatment of these patients. After 
15 June 2018, only patients who participated in the 
ECH study (Study TV48125-CNS-30056) will be 
enrolled for active treatment.
Patients who experience CH remission, defined as no 
CH attacks for 12 successive weeks and 24 successive 
weeks for patients with ECH and CCH, respectively, at 
any time after starting IMP (ie, administration of the 
first dose of IMP in the pivotal study) will be offered 
the possibility to stop treatment. Patients will restart 
fremanezumab treatment if treatment is stopped and 
CH attacks resume during the 36-week double blind 
treatment period. Refer to Section 5.1.1.1 for 
additional details regarding treatment of these patients. 
After 15 June 2018, only patients who participated in 
the ECH study (Study TV48125-CNS-30056) will be 
enrolled for active treatment.
To describe how patients who participated in the 
double-blind study for CCH 
(Study TV48125-CNS-30057) will continue to 
participate in this Long Term Safety study 
(Study TV48125-CNS-30058), since the CCH study 
has been terminated.
Section 5.9.2, Blinding and Unblinding
In the event of an emergency, it will be possible to 
determine which treatment group and dose the 
patient has been allocated to by accessing the 
Randomization and Trial Supply Management 
(RTSM) system. All investigational centers will be 
provided with details of who can access the system 
In the event of an emergency, it will be possible to 
determine which treatment group and dose the patient 
has been allocated to by accessing the Randomization 
and Trial Supply Management (RTSM) system. All 
investigational centers will be provided with details of 
who can access the system for code breaking at the 
New standardized text.


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for code breaking at the start of the study. The 
Medical Monitor or equivalent should be notified 
following unblinding. Any unblinding of the IMP 
performed by the investigator must be recorded in 
the source documents.
In case of a serious adverse event, pregnancy, or in 
cases when knowledge of the IMP treatment
assignment is needed to make treatment decisions, 
the investigator may unblind the patient’s IMP 
assignment as deemed necessary, mainly in 
emergency situations, through specialized access in 
the RTSM system. Breaking of the treatment code 
can always be performed by the investigator without 
prior approval of the sponsor; however, the sponsor 
should be notified that the code was broken, but the 
patient’s IMP assignment should not be revealed to 
the sponsor. 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 revealed. In emergency cases, breaking 
of the randomization code can be performed by the 
investigational center without prior approval by the 
sponsor.
start of the study. The Medical Monitor or equivalent 
should be notified following unblinding. Any 
unblinding of the IMP performed by the investigator 
must be recorded in the source documents.
In case of a serious adverse event, pregnancy, or in 
cases when knowledge of the IMP treatment 
assignment is needed to make treatment decisions, the 
investigator may unblind the patient’s IMP assignment 
as deemed necessary, mainly in emergency situations, 
through specialized access in the RTSM system. 
Breaking of the treatment code can always be 
performed by the investigator without prior approval of 
the sponsor; however, the sponsor should be notified 
that the code was broken, but the patient’s IMP 
assignment should not be revealed to the sponsor. 
Section 7.8, Immunogenicity
Blood samples for serum ADA assessment will be 
collected at the time points detailed in Table 4
(patients enrolling in this study from the pivotal 
efficacy studies) and Table 5 (patients rolling over 
from the pivotal efficacy studies for evaluation of 
ADAs and safety [adverse events and concomitant 
medications] only). Blood samples for ADA 
assessment will also be collected upon observation of 
any severe hypersensitivity reaction and anaphylaxis. 
Bioanalytical personnel should be made aware of 
anaphylaxis occurrence as soon as possible in case an 
anti-fremanezumab IgE assay is needed. After 
15 June 2018, only patients who participated in the 
Blood samples for serum ADA assessment will be 
collected at the time points detailed in Table 4 (patients 
enrolling in this study from the pivotal efficacy 
studies) and Table 5 (patients rolling over from the 
pivotal efficacy studies for evaluation of ADAs and 
safety [adverse events and concomitant medications] 
only). Blood samples for ADA assessment will also be 
collected upon observation of any severe 
hypersensitivity reaction and anaphylaxis. 
Bioanalytical personnel should be made aware of 
anaphylaxis occurrence as soon as possible in case an 
anti-fremanezumab IgE assay is needed. After 
15 June 2018, only patients who participated in the 
To describe how patients who participated in the 
double-blind study for CCH 
(Study TV48125-CNS-30057) will continue to 
participate in this Long Term Safety study 
(Study TV48125-CNS-30058), since the CCH study 
has been terminated.


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ECH study (Study TV48125-CNS-30056) will be 
enrolled for active treatment. All CCH patients 
included in this study have been asked to discontinue 
treatment, and are encouraged to continue in the 
ADA and safety follow-up portion of this study. At 
the time of unblinding the treatment code in 
Study TV48125-CNS-30057 (planned for Q4 2018), 
those CCH patients who were receiving placebo in 
Study TV48125-CNS-30057 (ie, never received any 
study drug) will not be required to complete 
additional safety follow-up visits, and will be 
discharged from the study.
ECH study (Study TV48125-CNS-30056) will be 
enrolled for active treatment. All CCH patients 
included in this study have been asked to discontinue 
treatment, and are encouraged to continue in the ADA 
and safety follow-up portion of this study. At the time 
of unblinding the treatment code in
Study TV48125-CNS-30057 (planned for Q4 2018), 
those CCH patients who were receiving placebo in 
Study TV48125-CNS-30057 (ie, never received any 
study drug) will not be required to complete additional 
safety follow-up visits, and will be discharged from the 
study.
Section 8.6, Ancillary Study – Wearable Sensor Substudy
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 9.1, Sample Size and Power Considerations
There are no statistical considerations for the sample 
size. Up to 600 patients from the Phase 3 pivotal 
efficacy studies (Studies TV48125-CNS-30056 and 
TV48125-CNS-30057) are expected to enroll in this 
study. 
The sample size for each of the pivotal studies 
There are no statistical considerations for the sample 
size. Up to 600 patients from the Phase 3 pivotal 
efficacy studies (Studies TV48125-CNS-30056 and 
TV48125-CNS-30057) are expected to enroll in this 
study.
The sample size for each of the pivotal studies 
To describe how patients who participated in the 
double-blind study for CCH 
(Study TV48125-CNS-30057) will continue to 
participate in this Long Term Safety study 
(Study TV48125-CNS-30058), since the CCH study 
has been terminated.


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TV48125-CNS-30056 for ECH and 
TV48125-CNS-30057 for CCH is 300 patients. All 
of the 600 patients participating in the pivotal studies 
will roll over to the long term safety study. 
Approximately 360 patients (out of the completers 
from the pivotal studies) will be offered to receive 
treatment during 40 weeks, and these patients will 
return for a follow-up visit approximately 7.5 months 
after the last dose of the IMP. Approximately 
240 patients (including early termination patients in 
the pivotal studies) will be offered to continue in a 
long-term safety evaluation collecting AEs, SAEs, 
and for ADA evaluation approximately 7.5 months 
after administration of the last dose of the IMP.
Prior to 15 June 2018 patients from the ECH study
and the CCH study were enrolled. After 
15 June 2018, only patients who participated in the 
ECH study (Study TV48125-CNS-30056) will be 
enrolled for active treatment. At the time of 
unblinding the treatment code in Study 
TV48125-CNS-30057 (planned for Q4 2018), those 
CCH patients who were receiving placebo in 
Study TV48125-CNS-30057 (ie, never received any 
study drug) will not be required to complete 
additional safety follow-up visits, and will be 
discharged from the study.
TV48125-CNS-30056 for ECH and 
TV48125-CNS-30057 for CCH is 300 patients. All of 
the 600 patients participating in the pivotal studies will 
roll over to the long term safety study. Approximately 
360 patients (out of the completers from the pivotal 
studies) will be offered to receive treatment during 
40 weeks, and these patients will return for a follow-up 
visit approximately 7.5 months after the last dose of 
the IMP. Approximately 240 patients (including early 
termination patients in the pivotal studies) will be 
offered to continue in a long-term safety evaluation 
collecting AEs, SAEs, and for ADA evaluation 
approximately 7.5 months after administration of the 
last dose of the IMP. Prior to 15 June 2018 patients 
from the ECH study and the CCH TV48125 studies
were enrolled. After 15 June 2018, only patients who 
participated in the ECH study
(Study TV48125-CNS-30056) will be enrolled for 
active treatment. At the time of unblinding the 
treatment code in Study TV48125-CNS-30057 
(planned for Q4 2018), those CCH patients who were 
receiving placebo in Study TV48125-CNS-30057 (ie,
never received any study drug) will not be required to 
complete additional safety follow-up visits, and will be 
discharged from the study.
Section 9.10, Pharmacokinetics/Pharmacodynamics Analysis
The pharmacokinetics/pharmacodynamics 
parameters may be estimated by compartmental 
techniques. The pharmacokinetics parameters will be 
based on fremanezumab measurements. The 
pharmacodynamics parameters will be the 
efficacy/safety response(s).
The pharmacokinetics/pharmacodynamics parameters 
may be estimated by compartmental techniques. The 
pharmacokinetics parameters will be based on 
fremanezumab measurements. The pharmacodynamics 
parameters will be the efficacy/safety response(s).
Clarification of use of PK/PD data.
Appendix A Clinical Laboratories and Other Departments and Institutions
 
Updated name and contact information for Sponsor’s 
contact point.


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Updated telephone number for Dr. Kessler


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16.1.1.
Letter of Clarification 05 Dated 10 May 2017


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16.1.2.
Letter of Clarification 06 Dated 27 August 2017 to Correct a Typographical 
Error in Sweden Protocol Amendment 02


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16.1.3.
Letter of Clarification 07 Dated 18 October 2017. 
Letter of clarification 07 was inadvertently noted and was actually applicable for other studies in 
Sweden (Studies TV48125-CNS-30056 and TV48125-CNS-30057).


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16.1.4.
Letter of Clarification 08 Dated 14 March 2018


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16.1.5.
Letter of Clarification USM Dated 06 April 2016


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16.2.
Amendment 03 Dated 26 April 2018
The primary reason for this amendment is to provide clarification on concomitant preventive 
medications allowed in the treatment arm of this long-term safety study (Study 
TV48125-CNS-30058). Patients who satisfactorily complete pivotal double-blind studies 
TV48125-CNS-30056 or TV48125-CNS-30057 may be offered the opportunity to enroll in 
Study 30058 either for treatment or for ADA safety follow-up, independent of their concomitant 
preventive medications (ie, verapamil, topiramate, valproate, lithium, or methysergide). For 
those continuing to receive active treatment, tapering of all concomitant preventive medications 
used in the pivotal studies will be required, which is in line with clinical practice. Tapering will 
be based on the investigator’s medical judgment but should not exceed 1 month from the 
beginning of participation in Study 30058 to avoid any potential safety concerns with abrupt 
discontinuation of these concomitant preventive medications. 
Patients in the treatment arm of Study 30058 who restart preventive medication will have to 
discontinue participation in the study per the current protocol; such cases will be treated as 
important protocol deviations. No other exceptions to the protocol will be permitted.
The number of patients who will be offered the opportunity to roll over into the treatment arm 
has been increased: approximately 360 patients may roll over for treatment. The overall sample 
size of the entire 30058 study will not change and will remain at 600 patients. Consequently, the 
number of patients who may roll over for ADA and safety follow-up only is correspondingly 
decreased: approximately 240 patients may roll over for ADA and safety follow-up. The 
justification behind this change is driven from the natural history of patients with chronic CH, 
which is characterized as less than 1 attack-free month in 1 year. Therefore, these patients want 
and have a necessity to continue treatment. This change will offer these patients the opportunity 
to roll over into the treatment arm.
Additionally, the duration of the study has been extended by 6 months because the study 
recruitment rate into Studies 30056 and 30057 has been lower than initially expected. The 
duration will be approximately 42 months, from Q1/2017 to Q2/2020. Extension of the study 
period is needed in order to meet the number of patients planned for this protocol. There is no 
change to the individual treatment period per patient. There is also no change to the procedures 
for patients in the study.
It has been clarified that pharmacogenomics samples are taken only during the pivotal studies 
and will not be collected in Study 30058. 
The assessment “Perform triplicate 12-lead ECGs” at visit 8 (week 28 ± 3 days) has been deleted 
from Appendix B. It was mistakenly added and does not align with Table 4, Study Procedures 
and Assessments for Treated Patients, which schedules triplicate 12-lead ECGs at weeks 12, 24, 
36, and 40/ end-of-study visit.
These changes are unlikely to affect the safety or rights (physical or mental integrity) of the 
patients or the scientific value of the clinical study.


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Original text with changes shown
New wording
Reason/justification for change
Synopsis
Changes made in the body of the protocol are reflected in the synopsis for consistency.
Investigator Agreement page, Sponsor’s Authorize Representative.
 
 
Change of personnel at Teva.
Coordinating Investigator Agreement page
 
Full contact information added.
Section 3.1, General Design and Study Schematic Diagram
Up to 300 360 eligible patients with ECH and CCH 
rolling over from the pivotal studies 
(Studies TV48125-CNS-30056 and TV48125-CNS-
30057, respectively) will receive fremanezumab 
during this study, as summarized inTable 3.
Up to 360 eligible patients with ECH and CCH 
rolling over from the pivotal studies 
(Studies TV48125-CNS-30056 and TV48125-CNS-
30057, respectively) will receive fremanezumab 
during this study, as summarized inTable 3.
This change will offer additional patients the opportunity 
to roll over into the treatment arm and continue treatment 
with fremanezumab.
The study duration will be for approximately 36 42
months, from Q1/2017 to Q4/2019 Q2/2020.
The study duration will be for approximately 42
months, from Q1/2017 to Q2/2020.
Extension of the study period is needed in order to meet 
the number of patients planned for this protocol.
Section 3.2, Planned Number of Patients and Countries
The study is expected to start in Q1/2017 (first 
patient in) and last until approximately Q4/2019
Q2/2020 (last patient last visit)
The study is expected to start in Q1/2017 (first 
patient in) and last until approximately Q2/2020 
(last patient last visit)
Extension of the study period is needed in order to meet 
the number of patients planned for this protocol.


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Reason/justification for change
Section 3.3, Justification for Study Design and Selection of Population
Concomitant medications that are commonly 
prescribed for the preventive treatment of CH (listed 
in Appendix H) are prohibited throughout this study 
so that effects of the test IMP can be distinguished 
from effects of these concomitant preventive 
medications. Thus, patients who were taking 
concomitant preventive medications (up to 2) during 
the pivotal studies will be required to stop taking
taper off these medications during the first month of 
treatment in this study.
Concomitant medications that are commonly 
prescribed for the preventive treatment of CH 
(listed in Appendix H) are prohibited throughout 
this study so that effects of the test IMP can be 
distinguished from effects of these concomitant 
preventive medications. Thus, patients who were 
taking concomitant preventive medications (up to 
2) during the pivotal studies will be required to 
taper off these medications during the first month of 
treatment in this study.
Tapering of all concomitant preventive medications used 
in the pivotal studies will be based on the investigator’s 
medical judgment but should not exceed 1 month from the 
beginning of participation in Study 30058 to avoid any 
potential safety concerns with abrupt discontinuation of 
these concomitant preventive medications. 
Section 4.1, Patient Inclusion Criteria
f. The patient must be willing to stop concomitant 
medications used in clinical practice for the 
prevention of CH (ie, verapamil, topiramate, 
valproate, lithium, or methysergide) for the duration 
of this study. (Note: Patients taking verapamil during 
the pivotal studies must begin tapering verapamil
these preventive medications as soon as they enroll 
begin participation in this study, and they must. The 
period of time needed to taper off these medications 
will be off verapamil within based on the 
investigator’s medical judgment but should not 
exceed 1 month from the beginning of  participation 
in this study [Appendix H) (not applicable for 
patients participating in safety follow-up only).
f. The patient must be willing to stop concomitant 
medications used in clinical practice for the 
prevention of CH (ie, verapamil, topiramate, 
valproate, lithium, or methysergide) for the duration 
of this study. Patients must begin tapering these 
preventive medications as soon as they begin 
participation in this study. The period of time 
needed to taper off these medications will be based 
on the investigator’s medical judgment but should 
not exceed 1 month from the beginning of 
participation in this study (Appendix H) (not 
applicable for patients participating in safety 
follow-up only).
Appropriate tapering of these concomitant preventive 
medications can avoid risks to patients and mitigate 
causing adverse health effects.
Section 4.3, Withdrawal Criteria and Procedures for the Patient
In the event that a patient was incorrectly 
randomized enrolled and has already started taking 
the study drug, a risk/benefit evaluation should take 
place between the investigator and sponsor, and a 
strong clinical justification must be provided if the 
patient is not withdrawn from study drug.
In the event that a patient was incorrectly enrolled 
and has already started taking the study drug, a 
risk/benefit evaluation should take place between 
the investigator and sponsor, and a strong clinical 
justification must be provided if the patient is not 
withdrawn from study drug.
Clarification. Blinding will be retained from the pivotal 
studies. 


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Reason/justification for change
Section 5.5, Prior and Concomitant Medication or Therapy
Patients taking concomitant preventive medications 
(ie, verapamil, topiramate, valproate, lithium, or 
methysergide) during the pivotal studies must begin 
tapering verapamil as soon as they enroll in this 
study, and they must be off verapamil these
medications within 1 month from the beginning of 
participation in the study (not applicable for patients 
participating in safety follow-up only). All other 
medications that are commonly prescribed for the 
preventative treatment of CH and systemic steroids 
are prohibited throughout the double blind treatment 
period of this long term safety extension stud
Patients taking concomitant preventive medications 
(ie, verapamil, topiramate, valproate, lithium, or 
methysergide) during the pivotal studies must begin 
tapering these preventive medications as soon as 
they enroll in this study, and they must be off these 
medications within 1 month from the beginning of 
participation in this study (not applicable for 
patients participating in safety follow-up only).
Appropriate tapering of these concomitant preventive 
medications can avoid risks to patients and mitigate 
causing adverse health effects.
Section 9.1, Sample Size and Power Considerations
All of the 600 patients participating in the pivotal 
studies will roll over to the long-term safety study. 
Approximately 300360 patients (out of the 
completers from the pivotal studies) will be offered 
to receive treatment during 40 weeks, and these 
patients will return for a follow-up visit 
approximately 7.5 months after the last dose of the 
IMP. Approximately 300 240 patients (including 
early termination patients in the pivotal studies) will 
be offered to continue in a long-term safety 
evaluation collecting AEs, SAEs, and for ADA 
evaluation approximately 7.5 months after 
administration of the last dose of the IMP.
All of the 600 patients participating in the pivotal 
studies will roll over to the long-term safety study. 
Approximately 360 patients (out of the completers 
from the pivotal studies) will be offered to receive 
treatment during 40 weeks, and these patients will 
return for a follow-up visit approximately 
7.5 months after the last dose of the IMP. 
Approximately 240 patients (including early 
termination patients in the pivotal studies) will be 
offered to continue in a long-term safety evaluation 
collecting AEs, SAEs, and for ADA evaluation 
approximately 7.5 months after administration of 
the last dose of the IMP.
This change will offer additional patients the opportunity 
to roll over into the treatment arm and continue treatment 
with fremanezumab.
Appendix A, Clinical Laboratories and Other Departments and Institutions
Sponsor’s Authorized Representative


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Change of personnel at Teva.
Legal Representative of the Sponsor in the European Union
 
 
Change of personnel at Teva. 


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Sponsor’s Representative of Global Patient Safety and Pharmacovigilance
 
 
 Change of personnel at Teva.
Pharmacogenomics/Biomarker Evaluation
 
 
 
 
Change of personnel at Teva
Appendix B, Visit 8 (Week 28 ± 3 Days)
Perform triplicate 12 lead ECGs
Mistakenly added and does not align with schedule of 
assessments.


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Appendix H: Preventive Cluster Headache Medications and Disallowed Medications 
The following medications will be considered as 
being used for the prevention of cluster headache 
attacks regardless of the initial indication and are 
disallowed during the double blind treatment period 
of this long term extension study:
The following medications will be considered as 
being used for the prevention of cluster headache 
attacks regardless of the initial indication:
Patients treated in the pivotal studies with any of the 
concomitant preventive medications listed in the protocol 
(verapamil, lithium, methysergide, valproate, topiramate) 
as a concomitant preventive medication or for other 
indication must start tapering as soon as they begin this 
study. The period of time needed to taper off from any 
concomitant preventive medication will be based on the 
investigator’s medical judgment but should not exceed 
1 month from the beginning of participation in this study. 
Appropriate tapering of these concomitant preventive 
medications can avoid risks to patients and mitigate 
causing adverse health effects.
Patients treated with verapamil as a concomitant 
preventive medication or other indication in the 
pivotal studies must start tapering verapamilthese 
preventive medications as soon as they begin this 
study. The period of time needed to taper off 
verapamil these medications will be based on the 
investigator’s medical judgment but should not 
exceed 1 month of from the beginning of
participation in this study.
Patients must start tapering these preventive 
medications as soon as they begin this study. The 
period of time needed to taper off these medications 
will be based on the investigator’s medical 
judgment but should not exceed 1 month from the 
beginning of participation in this study.
Tapering of all concomitant preventive medications used 
in the pivotal studies will be based on the investigator’s 
medical judgment but should not exceed 1 month from the 
beginning of participation in Study 30058 to avoid any 
potential safety concerns with abrupt discontinuation of 
these concomitant preventive medications. 
Appendix P, Exploratory Biomarkers Samples
 
 
.
 
 
 


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16.3.
Amendment 02 Dated 03 May 2017
The primary reason for this amendment is to provide clarification on feedback from participating 
investigators and regulatory agencies and to incorporate nonsubstantial changes to maintain 
alignment with the protocols with protocol Amendment 02 for Studies TV48125-CNS-30056 
and TV48125-CNS-30057. These changes are unlikely to affect the safety or rights (physical or 
mental integrity) of the patients or the scientific value of the clinical study.
Table 4 (Study Procedures and Assessments for Patients Enrolling in the Study from the Pivotal 
Efficacy Studies) and Figure 1 (Overall Study Schematic Diagram) have been revised to reflect 
the changes described below.


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change
Section 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 iv and sc 
routes of administration with once weekly dosing for up to 6 
months.
Fremanezumab was evaluated in nonclinical pharmacology, 
pharmacokinetics, and toxicology studies. Pivotal studies were 
conducted under Good Laboratory Practice (GLP).
Revised for clarification.
 
 
 
 
 
 
 
 
 
 
 
 
 
Added updated 
information for 
nonclinical studies.
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 
(NOAEL), is at least 15054-fold higher 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 profile of fremanezumab based 
on the overall toxicological data.
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 (NOAEL), 
is at least 54-fold higher 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 profile of fremanezumab based on the 
overall toxicological data.
Added updated 
information for 
nonclinical studies.
Section 1.2.2, Clinical Studies
In addition, there are 54 ongoing clinical studies of fremanezumab: 
2 pivotal efficacy studies in patients with migraine (1 study each 
In addition, there are 5 ongoing clinical studies of fremanezumab: 
2 pivotal efficacy studies in patients with migraine (1 study each for 
Added updated 
information for clinical 


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Reason/justification for 
change
for patients with chronic migraine and patients with episodic 
migraine [Studies TV48125-CNS-30049 and TV48125-CNS-
30050]); a long-term safety study in patients with migraine 
(Study TV48125-CNS-30051); and a pharmacokinetic, safety, and 
tolerability Phase 1 study in healthy Japanese and Caucasian 
subjects (Study TV48125-PK-10078); and a Phase 1 study (Study 
TV48125-BE-10114) comparing the pharmacokinetics of 
fremanezumab administered sc using a device referenced to a 
prefilled syringe configuration.).
patients with chronic migraine and patients with episodic migraine 
[Studies TV48125-CNS-30049 and TV48125-CNS-30050]); a 
long-term safety study in patients with migraine 
(Study TV48125-CNS-30051); a pharmacokinetic, safety, and 
tolerability Phase 1 study in healthy Japanese and Caucasian subjects 
(Study TV48125-PK-10078); and a Phase 1 study (Study TV48125-
BE-10114) comparing the pharmacokinetics of fremanezumab 
administered sc using a device referenced to a prefilled syringe 
configuration.
studies.
Section 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 Completed studies included 2 single-ascending-dose 
pharmacokinetics and pharmacodynamics 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 assessingcomparing the safety, tolerability, absolute 
bioavailability, and pharmacokinetics of single iv or sc doses of 
fremanezumab in healthy subjects (Study LBR-101-011).
 
 
 
 
.
A recently completed pharmacokinetic, safety, and tolerability 
study in healthy Japanese and Caucasian subjects (Study TV48125-
PK-10078) dosed fremanezumab as a single sc dose of 225, 675, or 
900 mg. Plasma concentration-time profile was
 
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).
 
 
 
 
.
A recently completed pharmacokinetic, safety, and tolerability study 
in healthy Japanese and Caucasian subjects (Study TV48125-PK-
10078) dosed fremanezumab as a single sc dose of 225, 675, or 900 
mg. Plasma concentration-time profile was measured
 
results are described below. 
The pharmacokinetics (non-compartmental analysis) of 
fremanezumab demonstrated an increase in Cmax and AUC values 
Added updated 
information for 
pharmacology studies.


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results are described below. 
The pharmacokinetics (non-compartmental analysis) of 
fremanezumab demonstrated an increase in Cmax and AUC values 
slightly greater than dose proportionality over the sc dose range of 
225 to 900 mg. Median time to
 
 
maximum observed concentration (tmax) values was generally 
 
to 7 days post sc doses.0 hours postdose after a 1 hour 
 
 
Mean values for apparent total volume of 
distribution during the terminal phase (Vz/F) the Vss after a single 
sciv dose ranged from 5.7 to 
L at 225- to 900-mg sc 
doses of 30 to 2000 mg. The mean apparent total plasma clearance 
(CL/F) ranged from 0.0777
to 0.0895 mL/min276 L/day at this 
dose range. The mean t½ ranged from 32.2 
 
 to 36.2 days. Fremanezumab exposure 
parameters and overall pharmacokinetic profile were 2000 mg.
Absolute bioavailability of the sc dose was similar for healthy 
Japanese and Caucasian subjects. Comparison of exposure 
parameters (Cmax and AUC0-∞)
 
from Studies LBR-101-011 and TV48125-PK-
10078 at the 225- and 900-mg sc dose levels indicate a 2.9-
 
 
slightly greater than dose proportionality over the sc dose range of 
225 to 900 mg. Median time to maximum observed concentration 
(tmax) values was generally 5 to 7 days post sc doses. Mean values for 
apparent total volume of distribution during the terminal phase (Vz/F) 
after a single sc dose ranged from 5.7 to 6.4 L at 225- to 900-mg sc 
doses. The mean apparent total plasma 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 were similar for healthy Japanese and 
Caucasian subjects. Comparison of exposure parameters (Cmax and 
AUC0-∞) from Studies 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 Study LBR-101-
011. The main reason for the difference in exposure appears to be the 
bioanalytical method used in the plasma sample analysis.
Section 1.2.2.2, Clinical Safety and Efficacy Studies
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 first cohort 
of 12 Japanese subjects from the ongoing Phase 1 study (Study 
TV48125 PK 10078), and no serious adverse events considered 
related to the investigational medicinal product (IMP) have been 
reported for the ongoing pivotal efficacy studies (Studies 
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 first cohort of 
12 Japanese subjects from the ongoing Phase 1 study (Study 
TV48125 PK 10078), and no serious adverse events considered 
related to the investigational medicinal product (IMP) have been 
reported for the ongoing pivotal efficacy studies (Studies TV48125-
Updated for clarification.


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change
TV48125-CNS-30049 and TV48125 CNS-30050, as of 23 April 
2016).
CNS-30049 and TV48125 CNS-30050, as of 23 April 2016).
Section 2.2.1, Exploratory Objectives and Endpoints (other section affected by this change: Section 3.1, General Design and Study Schematic Diagram; and 
Section 9.5.3, Exploratory Endpoints)

 
 

 Edited exploratory 
objective for clarity.
Section 3.1, General Design and Study Schematic Diagram (other sections affected by this change: Protocol Title, Section 3.5, Table 5: Study Procedures 
and Assessments for Patients Rolling Over from the Pivotal Efficacy Studies for Evaluation of Antidrug Antibodies and Safety [Adverse Events and 
Concomitant Medications] Only; Section 4.1, Patient Inclusion Criteria; Section 7.8, Immunogenicity; Section 8.3, Immunogenicity Testing; Appendix B, 
Study Procedures and Assessments by Visit)
This is a 68-week extension study to evaluate the long-term safety 
and efficacy of fremanezumab in adult patients with CH. During 
the course of any CH attack, patients will be allowed to use acute 
medications to treat acute headaches, as needed (PRN).
This is a 68-week extension study to evaluate the long-term safety 
and efficacy of fremanezumab in adult patients with CH. During the 
course of any CH attack, patients will be allowed to use acute 
medications to treat acute headaches, as needed (PRN).
Revised for clarification
Upon completion of the final study assessments, early withdrawal 
from the study or discontinuation for any reason, patients will be 
offered the opportunity to enter a 32-week long-term safety study 
(as described in this study protocol for safety and ADA evaluation 
without additional dosing. Patients who satisfactorily complete the 
study may be offered to enroll the long-term safety study 
TV48125-CNS-30058 for 68 weeks (as described in this study 
protocol) to receive additional dosing and a final follow-up visit for 
safety and ADA evaluation. In any case, during the period of the 
long-term safety study, where patients are not receiving additional 
dosing (and are waiting for ADA evaluation), these patients should 
be treated with standard 
Up to 300 eligibleFemale and male patients with CCH and ECH 
who complete the pivotal efficacy studies (Studies TV48125 CNS
30056 and TV48125 CNS 30057) may enter this long term safety 
study if they provide informed consent and meet the 
inclusion/exclusion criteria. In addition, patients who do not 
complete the pivotal efficacy studies, and patients who complete 
the pivotal efficacy studies but do not wish to continue treatment 
during this long term safety study, may enroll in this study for the 
purpose of evaluating ADAs, fremanezumab concentrations, and 
safety (adverse events and concomitant medications) approximately 
Upon completion of the final study assessments, early withdrawal 
from the study or discontinuation for any reason, patients will be 
offered the opportunity to enter a 32-week long-term safety study (as 
described in this study protocol) for safety and ADA evaluation 
without additional dosing. Patients who satisfactorily complete the 
study may be offered to enroll the long-term safety study TV48125-
CNS-30058 for 68 weeks (as described in this study protocol) to 
receive additional dosing and a final follow-up visit for safety and 
ADA evaluation. In any case, during the period of the long-term 
safety study, where patients are not receiving additional dosing (and 
are waiting for ADA evaluation), these patients should be treated 
with standard 
Up to 300 eligible patients with ECH and CCH rolling over from the 
pivotal studies (Studies TV48125 CNS-30056 and TV48125-CNS-
30057, respectively) will receive fremanezumab during this study, as 
summarized in Table 3.
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7.5 months after administration of the last dose of the IMP.
Eligible patients with ECH and CCH rolling over from the pivotal 
studies (Studies TV48125-CNS-30056 and TV48125-CNS-30057, 
respectively) will receive fremanezumab during this study, as 
summarized in Table 3.
All patients will return to the investigational center approximately 
every 4 weeks after administration of the first dose of the IMP 
(visit 1 [week 0]) through the end-of-treatment (EOT) visit (visit 11 
[week 40]), which will occur approximately 4 weeks after 
administration of the lastfinal dose of the IMP (week 36). Patients 
will return for a follow-up visit (visit 12) to evaluate ADAs, 
fremanezumab concentrations, biomarkers, and safety (adverse 
events and concomitant medications) approximately 7.5 months 
after the last dose of the IMP. This visit is for the purpose of 
evaluating ADAs, fremanezumab concentrations, biomarkers, and 
safety only. Patients who withdraw from the study before 
completing the 40-week treatment period will have EOT visit 
procedures and assessments performed on the last day the patients 
received the IMP or as soon as possible thereafter, and they will be 
asked to return for a follow-up visit approximately 7.5 weeks after 
their last dose of IMP. 
Patients who enter the long-term safety follow-up study for safety 
follow-up only will not follow the same visit schedule as that for 
patients receiving treatment. The procedures and assessments for 
the patients participating in the safety follow-up are described in 
Table 5.
All patients will return to the investigational center approximately 
every 4 weeks after administration of the first dose of the IMP (visit 1 
[week 0]) through the end-of-treatment (EOT) visit (visit 11 [week 
40]), which will occur approximately 4 weeks after administration of 
the last dose of the IMP (week 36). Patients will return for a follow-
up visit (visit 12) to evaluate ADAs, biomarkers, and safety (adverse 
events and concomitant medications) approximately 7.5 months after 
the last dose of the IMP. Patients who withdraw from the study 
before completing the 40-week treatment period will have EOT visit 
procedures and assessments performed on the last day the patients 
received the IMP or as soon as possible thereafter, and they will be 
asked to return for a follow-up visit approximately 7.5 weeks after 
their last dose of IMP.
Patients who enter the long-term safety follow-up study for safety 
follow-up only will not follow the same visit schedule as that for 
patients receiving treatment. The procedures and assessments for the 
patients participating in the safety follow-up are described in Table 5.
Updated for clarification.
Section 3.1, General Design and Study Schematic Diagram, Table 3 (footnotes a and b)
a.In order to maintain blinding throughout the study, the number of 
sc injections at each visit will be the same for all patients rolling 
over from Study TV48125-CNS-30056, regardless of their assigned 
treatment group. Thus, patients will receive 3 sc injections of either
test IMP (1.5 -mL injections each containing fremanezumab at a 
concentration of 150 mg/mL) or 1 sc injection of test IMP (1.5-mL 
injection containing fremanezumab at a concentration of 150 
mg/mL) and 2 sc injections of placebo IMP (1.5-mL injections) at 
visits 1, 4, 7, and 10, and a single sc injection of test IMP or 
placebo IMP at visits 2, 3, 5, 6, 8, and 9.
b. In order to maintain blinding throughout the study, the number 
a.In order to maintain blinding throughout the study, the number of sc 
injections at each visit will be the same for all patients rolling over 
from Study TV48125-CNS-30056, regardless of their assigned 
treatment group. Thus, patients will receive 3 sc injections of test 
IMP (1.5-mL injections each containing fremanezumab at a 
concentration of 150 mg/mL) or 1 sc injection of test IMP (1.5-mL 
injection containing fremanezumab at a concentration of 150 mg/mL) 
and 2 sc injections of placebo IMP (1.5-mL injections) at visits 1, 4, 
7, and 10, and a single sc injection of test IMP or placebo IMP at 
visits 2, 3, 5, 6, 8, and 9.
b. In order to maintain blinding throughout the study, the number of 
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of sc injections at each visit will be the same for all patients rolling 
over from Study TV48125-CNS-30057, regardless of their assigned 
treatment group. Thus, patients will receive 3 sc injections of either 
test IMP (1.5 -mL injections each containing fremanezumab at a 
concentration of 150 mg/mL) or 1 sc injection of test IMP (1.5-mL 
injection containing fremanezumab at a concentration of 150 
mg/mL) and 2 sc injections of placebo IMP (1.5-mL injections) at 
visit 1, and patients will receive a single sc injection of test IMP 
(1.5-mL injection containing fremanezumab at a concentration of 
150 mg/mL) at all other visits.
sc injections at each visit will be the same for all patients rolling over 
from Study TV48125-CNS-30057, regardless of their assigned 
treatment group. Thus, patients will receive 3 sc injections of either 
test IMP (1.5-mL injections each containing fremanezumab at a 
concentration of 150 mg/mL) or 1 sc injection of test IMP (1.5-mL 
injection containing fremanezumab at a concentration of 150 mg/mL) 
and 2 sc injections of placebo IMP (1.5-mL injections) at visit 1, and 
patients will receive a single sc injection of test IMP (1.5-mL 
injection containing fremanezumab at a concentration of 150 mg/mL) 
at all other visits.
Section 3.2, Planned Number of Patients and Countries (other section affected by this change: Section 3.1, General Study Design and Study Schematic 
Diagram and Figure 1: Overall Study Schematic Diagram [table note]; and Section 9.1, Sample Size and Power Considerations)
Approximately 300 Up to 600 patients from the Phase 3 pivotal 
efficacy studies (Studies TV48125-CNS-30056 and TV48125-
CNS-30057) are expected to enroll in this study.
Up to 600 patients from the Phase 3 pivotal efficacy studies (Studies 
TV48125-CNS-30056 and TV48125-CNS-30057) are expected to 
enroll in this study. 
Revised text to reflect that 
all subjects will have the 
opportunity to participate 
in either the long-term 
treatment and long-term 
safety follow-up or the 
long-term safety follow-
up only.
Section 3.4, Stopping Rules for the Study (other section affected by this change: Section 4.3, Withdrawal Criteria and Procedures for the Patient)
The investigator and/or sponsor can withdraw a patient from the 
study at any time for any reason (eg, lack of efficacy, protocol 
deviation as defined in Appendix CSection 10, noncompliance, or 
adverse event).
The investigator and/or sponsor can withdraw a patient from the 
study at any time for any reason (eg, lack of efficacy, protocol 
deviation as defined in Appendix C, noncompliance, or adverse 
event).
Added clarification that 
lack of efficacy may 
result in withdrawal from 
the study.
Section 3.5, Schedule of Study Procedures and Assessments, Table 4: Study Procedure and Assessments for Treated Patients
Table 4:Study Procedures and Assessments for Treated
Patients Enrolling in the Study from the Pivotal Efficacy 
Studies
Table 4:Study Procedures and Assessments for Treated Patients
Table title revised for 
clarification.
Section 3.5, Schedule of Study Procedures and Assessments, Table 4: Study Procedure and Assessments for Treated Patients (footnote q; other section 
affected by this change: Appendix B, Study Procedures and Assessments by Visit)
q.
Blood samples for pharmacokinetic analysis will be collected 
prior to dosing, where applicable. Patients who are 
participating insigned consent for the wearable sensor substudy
(at the pivotal studies) only will return to the investigational 
center for up to 2 additional visits after any dose of the IMP for 
blood sampling for pharmacokinetics analysis, triplicate12-
lead ECGs, and inquiries about adverse events and 
q.
Blood samples for pharmacokinetic analysis will be collected 
prior to dosing, where applicable. Patients who signed consent 
for the wearable sensor substudy (at the pivotal studies) only will 
return to the investigational center for up to 2 additional visits 
after any dose of the IMP for blood sampling for 
pharmacokinetics analysis, triplicate12-lead ECGs, and inquiries 
about adverse events and concomitant medications. These visits 
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concomitant medications. These visits should occur during the 
following time periods relative to any dose of the IMP: 3 to 10 
days or 15 to 20 days after IMP.
should occur during the following time periods relative to any 
dose of the IMP: 3 to 10 days or 15 to 20 days after IMP.
Section 3.5, Schedule of Study Procedures and Assessments, Table 5: Study Procedures and Assessments for Patients Rolling Over from the Pivotal 
Efficacy Studies for Evaluation of Antidrug Antibodies and Safety (Adverse Events and Concomitant Medications) Only (other section affected by this 
change: Section 7.11, Injection Site Assessments; and Appendix B, Study Procedures and Assessments by Visit).
Procedures and assessments
Removed “Blood sample for pharmacokinetic analysis” row from 
table
Revised for correctness.
Section 4, Selection and Withdrawal of Patients (other section affected by this change: Appendix C, Quality Control and Quality Assurance)
Prospective waivers (exceptions) from study inclusion and 
exclusion criteria to allow patients to be randomized/enrolled are 
not granted by the sponsor (Appendix C). Any deviation from the 
eligibility criteria will result in study drug discontinuation in the 
event that a patient has not been dosed.
Prospective waivers (exceptions) from study inclusion and exclusion 
criteria to allow patients to be randomized/enrolled are not granted by 
the sponsor (Appendix C). Any deviation from the eligibility criteria 
will result in study drug discontinuation in the event that a patient has 
not been dosed.
Updated for clarification.
Section 4.1, Patient Inclusion Criteria (other section affected by this change: Section 5.5, Prior and Concomitant Medication or Therapy)
Patients may be enrolled included in the treatment portion of the
this study only if they meet all of the following criteria:
Patients may be included in the treatment portion of the study only if 
they meet all of the following criteria:
Revised for clarification.
a. The patient is a male or female and 18 to 70 years of age, 
inclusive, at the start of the pivotal study.
a. The patient is a male or female and 18 to 70 years of age, 
inclusive, at the start of the pivotal study.
Revised for clarification.
c. The patient completes either the Phase 3 pivotal study for ECH 
(Study TV48125-CNS-30056) or the Phase 3 pivotal study for 
CCH (Study TV48125-CNS-30057) without important 
protocol deviations related to patient safety and patient 
compliance and at least 75% diary data completion during the 
pivotal study.
c. The patient completes either the Phase 3 pivotal study for ECH 
(Study TV48125-CNS-30056) or the Phase 3 pivotal study for 
CCH (Study TV48125-CNS-30057) without important protocol 
deviations related to patient safety and patient compliance and at 
least 75% diary data completion during the pivotal study.
Revised for clarification.
d. Women may be included only if they have a negative beta-
human chorionic gonadotropin (β-HCG) test at visit 1; are 
sterile or postmenopausal; and are not lactating (not applicable 
for patients participating in safety follow-up only). Definitions 
of sterile and postmenopausal are given in Appendix E.
d. Women may be included only if they have a negative beta-
human chorionic gonadotropin (β-HCG) test at visit 1, are sterile 
or postmenopausal, and are not lactating (not applicable for 
patients participating in safety follow-up only). Definitions of 
sterile and postmenopausal are given in Appendix E.
Revised for clarification.
e. Women of childbearing potential (WOCBP) whose male 
partners are potentially fertile (ie, no vasectomy) must use 
highly effective birth control methods (see Appendix E) for 
the duration of the study and for 7.5 months after 
discontinuation of IMP (not applicable for patients 
participating in safety follow-up only). 
e. Women of childbearing potential (WOCBP) whose male partners 
are potentially fertile (ie, no vasectomy) must use highly effective 
birth control methods (see Appendix E) for the duration of the 
study and for 7.5 months after discontinuation of IMP (not 
applicable for patients participating in safety follow-up only).
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f. Men must be sterile; or if they are potentially 
fertile/reproductively competent (not surgically [eg,
vasectomy] or congenitally sterile), and their female partners 
are of childbearing potential, must agree to use, together with 
their female partners, acceptable birth control methods for the 
duration of the study and for 7.5 months after administration of
IMP (not applicable for patients participating in safety follow-
up only).
f. Men must be sterile; or if they are potentially 
fertile/reproductively competent (not surgically [eg, vasectomy] or 
congenitally sterile), and their female partners are of childbearing 
potential, must agree to use, together with their female partners, 
acceptable birth control methods for the duration of the study and 
for 7.5 months after administration of IMP (not applicable for 
patients participating in safety follow-up only).
Revised for clarification.
g. The patient must be willing to stop concomitant medications 
used in clinical practice for the prevention of CH for the 
duration of this study. (Note: Patients taking verapamil during 
the pivotal studies must begin tapering verapamil as soon as 
they enroll in this study, and they must be off verapamil within 
1 month of beginning study participation [Appendix H]) (not 
applicable for patients participating in safety follow-up only).
g. The patient must be willing to stop concomitant medications used 
in clinical practice for the prevention of CH for the duration of 
this study. (Note: Patients taking verapamil during the pivotal 
studies must begin tapering verapamil as soon as they enroll in 
this study, and they must be off verapamil within 1 month of 
beginning study participation [Appendix H]) (not applicable for 
patients participating in safety follow-up only).
Revised for clarification.
h. The patient is in good health in the opinion of the investigator, 
as determined by a medical and psychiatric history; medical 
examination; 12-lead ECG; and serum chemistry, hematology, 
coagulation, and urinalysis (not applicable for patients 
participating in safety follow-up only).
h. The patient is in good health in the opinion of the investigator, as 
determined by a medical and psychiatric history; medical 
examination; 12-lead ECG; and serum chemistry, hematology, 
coagulation, and urinalysis (not applicable for patients 
participating in safety follow-up only).
Revised for clarification.
Section 4.2, Patient Exclusion Criteria (other section affected by this change: Section 5.5, Prior and Concomitant Medication or Therapy)
Patients will be excluded from participating in the treatment 
portion ofnot be randomized/enrolled in this study if they meet any 
of the following criteria:
a. The patient has a history of any suicide attempt in the past or 
current active suicidal ideation, as measured by the eC-SSRS.
Patients will be excluded from participating in the treatment portion 
of this study if they meet any of the following criteria:
a. The patient has a history of any suicide attempt in the past or 
current active suicidal ideation, as measured by the eC-SSRS.
Revised for clarification.
Patients rolling over only for safety follow up and ADA who are 
not receiving study medication are not required to fulfil all 
inclusion exclusion criteria.
Patients rolling over only for safety follow up and ADA who are not 
receiving study medication are not required to fulfil all inclusion 
exclusion criteria.
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Section 4.3, Withdrawal Criteria and Procedures for the Patient (other section affected by this change: Appendix C, Quality Control and Quality 
Assurance)
8.
Investigator may discontinue an individual patient from the 
study at any time for any reason, such as lack of efficacy, 
protocol deviation as defined in Section 10, noncompliance, or 
adverse event). In addition, patients with positive eC-SSRS 
findings or abnormal hepatic laboratory values (eg, ALT, AST, 
ALP, GGT, bilirubin [total, direct, or indirect], or INR) may 
meet criteria for discontinuation from the IMP as summarized
in Appendix J.
8.
Investigator may discontinue an individual patient from the study 
at any time for any reason, such as lack of efficacy, protocol 
deviation as defined in Section 10, noncompliance, or adverse 
event). In addition, patients with positive eC-SSRS findings or 
abnormal hepatic laboratory values (eg, ALT, AST, ALP, GGT, 
bilirubin [total, direct, or indirect], or INR) may meet criteria for 
discontinuation from the IMP as summarized inAppendix J.
Added text for 
clarification.
In the event that a patient was incorrectly randomized and has 
already started taking the study drug, a risk/benefit evaluation 
should take place between the investigator and sponsor and a strong 
clinical justification must be provided if the patient is not 
withdrawn from study drug.
In the event that a patient was incorrectly randomized and has already 
started taking the study drug, a risk/benefit evaluation should take 
place between the investigator and sponsor, and a strong clinical 
justification must be provided if the patient is not withdrawn from 
study drug.
Added text for 
clarification.
Section 4.5, Rescreening 
A patient who is screened and does not meet study inclusion and 
exclusion criteria will not be considered for screening again.
A patient who is screened and does not meet study inclusion and 
exclusion criteria will not be considered for screening again.
New section added.
Section 4.6, Screening Failure
Screening failures are defined as participants who consent to 
participate in the clinical study but are not subsequently 
randomized/enrolled in the study. Minimal information includes 
but is not limited to demography, screening failure details, 
eligibility criteria, and any adverse events or serious adverse 
events.
Screening failures are defined as participants who consent to 
participate in the clinical study but are not subsequently 
randomized/enrolled in the study. Minimal information includes but 
is not limited to demography, screening failure details, eligibility 
criteria, and any adverse events or serious adverse events.
New section added.
Section 5.1.1,Test Investigational Medicinal Product
Fremanezumab is a fully humanized IgG2a/kappa monoclonal 
antibody derived from a murine precursor.
Fremanezumab is a fully humanized IgG2a/kappa monoclonal 
antibody derived from a murine precursor.
Revised for clarification.
Section 5.9.2, Blinding and Unblinding
In the event that the IRT system is not functioning for emergency 
unblinding, the next course of action is to contact via phone the 
IRT on-call customer support helpline for manual emergency 
unblinding.
In the event that the IRT system is not functioning for emergency 
unblinding, the next course of action is to contact via phone the IRT 
on-call customer support helpline for manual emergency unblinding.
Added text for 
clarification.
Section 6.2, Electronic Diary Device
Exploratory efficacyEfficacy endpoints related to CH attacks will 
be derived from data collected daily during the double blind 
treatment period using an electronic diary device. Eligible patients 
will receive comprehensive training at screening from the 
Efficacy endpoints related to CH attacks will be derived from data 
collected daily using an electronic diary device. Eligible patients will 
receive comprehensive training at screening from the investigational 
site personnel on the use of the electronic diary device. 
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investigational centersite personnel on the use of the electronic 
diary device at screening during the pivotal studies. Investigational 
centersite personnel will also instruct patients on the requirement 
for timely and daily completion of the electronic diary.
Patients will complete electronic headache diary entries with 
questions about the previous day, starting from the day after the 
screening visit through the end of treatment (EOT)/early 
withdrawal visit. The electronic headache diary device will allow 
entry of headache information for up to 2 days after a given day.
On each day, the patient will be asked to record real time diary data 
regarding the CH attacks. Patients who report a CH attack will 
answer questions about the attack (ie, occurrence and number of 
CH attacks, duration of CH attack[s], severity of CH attack[s], and 
acute CH-specific medication and oxygen use). The last day of the 
run-in period should be reported in the morning of the visit 
day.use) in real time or retrospectively for the previous 24 hour 
period. 
Patients will be asked about their performance at work or at school 
on CH attack-free days. Additional details regarding the questions 
patients will answer can be found in the electronic diary device 
training manual.
If a patient fails to complete the diary for the preceding day, the 
patient will be prompted to enter the missed day’s information the 
next time he/she accesses the electronic diary provided that no 
more than 48 hours2 days have elapsed since completion of that 
day. If more than 48 hours2 days have elapsed since completion of 
a diary day, the patient will not be allowed to enter diary 
information for that day, and it will be considered a missed day. 
If a CH is reported, then CH intensity will be subjectively rated by 
the patient as follows:

Mild

Moderate

Severe

Very severe
Investigational site personnel will also instruct patients on the 
requirement for timely and daily completion of the electronic diary.
Patients will complete electronic headache diary entries with 
questions about the previous day, starting from the day after the 
screening visit through the end of treatment (EOT)/early withdrawal 
visit. The electronic headache diary device will allow entry of 
headache information for up to 2 days after a given day.
Patients who report a CH attack will answer questions about the 
attack (ie, occurrence and number of CH attacks, duration of CH 
attack[s], severity of CH attack[s], and acute CH-specific medication 
and oxygen use). The last day of the run-in period should be reported 
in the morning of the visit day use) in real time or retrospectively for 
the previous 24-hour period.
Patients will be asked about their performance at work or at school on 
CH attack-free days. Additional details can be found in the electronic 
diary device training manual.
If a patient fails to complete the diary for the preceding day, the 
patient will be prompted to enter the missed day’s information the 
next time he/she accesses the electronic diary provided no more than 
2 days have elapsed since completion of that day. If more than 2 days 
have elapsed since completion of a diary day, the patient will not be 
allowed to enter diary information for that day, and it will be 
considered a missed day.
If a CH is reported, then CH intensity will be subjectively rated by 
the patient as follows:

Mild

Moderate

Severe

Very severe
Section 7.1.8, Protocol Deviations Because of an Adverse Event (other sections affected by this change: Section 4, Selection and Withdrawal of Patients; 
Section 7.3, Medication Error and Special Situations Related to the Investigational Medicinal Products; and Appendix C, Quality Control and Quality 
Assurance)


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If a patient experiences an adverse event or medical emergency, 
deviations from the protocol may be warranted toallowed on a case 
by case basis. To ensure patient safety. aAfter 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. The same reporting process as for all other protocol 
deviations will apply. A noncompliant patient may continue taking 
the study treatment only if this does not jeopardize the patient’s 
safety. The sponsor will assess each protocol deviation and decide 
whether any of these noncompliances should be reported to the 
Regulatory Authority as a serious breach of Good Clinical Practice 
(GCP) and the protocol.
If a patient experiences an adverse event or medical emergency, 
deviations from the protocol may be warranted 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. The same reporting process as for all other 
protocol deviations will apply. A noncompliant patient may continue 
taking the study treatment only if this does not jeopardize the 
patient’s safety. The sponsor will assess each protocol deviation and 
decide whether any of these noncompliances should be reported to 
the Regulatory Authority as a serious breach of Good Clinical 
Practice (GCP) and the protocol.
Revised for clarification.
Section 7.3, Medication Error and Special Situations Related to the Investigational Medicinal Products
Any administration of IMP that is not in accordance with the study 
protocol should be reported as an important deviation, if it meets 
the important deviation criteria specified in the protocol (Appendix 
C), or as a deviation, in the patient’s source documents, regardless 
of whether or not an adverse event occurs as a result. A non-
compliant patient may continue taking the study treatment only if 
this does not jeopardize the patient’s safety
Any administration of IMP that is not in accordance with the study 
protocol should be reported as an important deviation, if it meets the 
important deviation criteria specified in the protocol (Appendix C), or 
as a deviation, in the patient’s source documents, regardless of 
whether or not an adverse event occurs as a result. A non-compliant 
patient may continue taking the study treatment only if this does not 
jeopardize the patient’s safety
Revised for clarification.
Section 7.4.1, Serum Chemistry, Hematology, and Urinalysis
Clinical laboratory tests (serum chemistry, hematology, and
coagulation, urinalysis) will be performed at the time points 
detailed in Table 4. Clinical laboratory tests will be performed 
using the central laboratory. However, if other specific urgent tests 
are required, a local retest can be authorized by the sponsor or 
designee on a case-by-case basis. Specific laboratory tests to be 
performed are provided in Appendix M.
Clinical laboratory tests (serum chemistry, hematology, and 
urinalysis) will be performed at the time points detailed in Table 4. 
Clinical laboratory tests will be performed using the central 
laboratory. However, if other specific urgent tests are required, a 
local retest can be authorized by the sponsor or designee on a case-
by-case basis. Specific laboratory tests to be performed are provided 
in Appendix M.
Revised for clarification.
Section 7.8, Immunogenicity
Blood samples for serum ADA assessment will be collected at the 
time points detailed in Table 4 (patients enrolling in this study from 
the pivotal efficacy studies) and Table 5 (patients rolling over from 
the pivotal efficacy studies for evaluation of ADAs and safety [, 
fremanezumab concentrations, adverse events, and concomitant 
Blood samples for serum ADA assessment will be collected at the 
time points detailed in Table 4 (patients enrolling in this study from 
the pivotal efficacy studies) and Table 5 (patients rolling over from 
the pivotal efficacy studies for evaluation of ADAs and safety 
[adverse events and concomitant medications] only). Blood samples 
Text added to clarify the 
procedure in the event of 
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medications] only). Blood samples for ADA assessment will also 
be collected upon observation of any severe hypersensitivity 
reaction and anaphylaxis. Bioanalytical personnel should be made 
aware of anaphylaxis occurrence as soon as possible in case an 
anti-fremanezumab IgE assay is needed.
for ADA assessment will also be collected upon observation of any 
severe hypersensitivity reaction and anaphylaxis. Bioanalytical 
personnel should be made aware of anaphylaxis occurrence as soon 
as possible in case an anti-fremanezumab IgE assay is needed.
Section 7.11, Injection Site Assessments (other sections affected by this change: Section 3.5, Schedule of Study Procedures and Assessments, Table 4: Study 
Procedure and Assessments for Treated Patients(footnote x and Appendix B, Study Procedures and Assessments by Visit)
Injection site assessments will be performed immediately (+10 
minutes) and 1 hour (±15 minutes) after receiving each dose of the 
IMP. The injection site(s) will be assessed for erythema, induration, 
and ecchymosis, and pain.
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. 
• For spontaneous report of local pain after the injection, 
itInjection site pain will be measured as summarized in Table 
85.
Injection site assessments will be performed immediately (+10 
minutes) and 1 hour (±15 minutes) after receiving each dose of the 
IMP. The injection site(s) 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. 
• For spontaneous report of local pain after the injection, it will be 
measured as summarized in Table 8.
Added clarification for 
injection site assessment 
windows.
If a patient has severe injection site induration, erythema, 
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.
If a patient has severe injection site induration, erythema, 
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.
Added visit windows for 
clarification.
Injection-site reactions (injection site erythema, induration, 
ecchymosis, and pain) shouldwill also be recorded as adverse 
events.
Injection-site reactions (injection site erythema, induration, 
ecchymosis, and pain) should be recorded as adverse events.
Added for clarification.
Section 9.1, Sample Size and Power Considerations
There are no statistical considerations for the sample size. A total 
of approximately 300Up to 600 patients from the Phase 3 pivotal 
efficacy studies (Studies TV48125-CNS-30056 and TV48125-
CNS-30057) are expected to enroll in this study. All patients will 
receive (sc) fremanezumab during this study.
The sample size for each of the pivotal studies TV48125-CNS-
30056 for ECH and TV48125 CNS-30057 for CCH is 300 patients. 
All of the 600 patients participating in the pivotal studies will roll 
over to the long-term safety study. Approximately 300 patients (out 
There are no statistical considerations for the sample size. Up to 600 
patients from the Phase 3 pivotal efficacy studies (Studies TV48125-
CNS-30056 and TV48125-CNS-30057) are expected to enroll in this 
study.
The sample size for each of the pivotal studies TV48125-CNS-30056 
for ECH and TV48125 CNS-30057 for CCH is 300 patients. All of 
the 600 patients participating in the pivotal studies will roll over to 
the long-term safety study. Approximately 300 patients (out of the 
completers from the pivotal studies) will be offered to receive 
Revised for clarification.


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of the completers from the pivotal studies) will be offered to 
receive treatment during 40 weeks and these patients will return for 
a follow-up visit approximately 7.5 months after the last dose of the 
IMP. Approximately 300 patients (including early termination 
patients in the pivotal studies) will be offered to continue in a long-
term safety evaluation collecting AEs, SAEs, and for ADA 
evaluation approximately 7.5 months after administration of the 
last dose of the IMP.
treatment during 40 weeks, and these patients will return for a follow-
up visit approximately 7.5 months after the last dose of the IMP. 
Approximately 300 patients (including early termination patients in 
the pivotal studies) will be offered to continue in a long-term safety 
evaluation collecting AEs, SAEs, and for ADA evaluation 
approximately 7.5 months after administration of the last dose of the 
IMP.
Appendix E, Women of Childbearing Potential and Birth Control Methods
Women of non-childbearing potential are defined as:

notSurgically (documented hysterectomy, bilateral 
oophorectomy, or bilateral salpingectomy) or 
congenitally sterile

One 1 year postmenopausal (stable amenorrhea no 
menses for 12 months without alternative medical 
cause plus highincreased concentration of follicle-
stimulating hormone, (FSH) serum level in the 
postmenopausal range of more than 2335 U/L) in 
women not using hormonal contraception or 
hormonal replacement therapy

Women in stable post-menopause, but are taking 
hormone replacement therapy for treatment of 
menopausal symptoms may be considered eligible for 
the study even with the lower serum FSH. They do 
not need to use other contraception.
Women of non-childbearing potential are defined as:

Surgically (hysterectomy, bilateral oophorectomy, or 
bilateral salpingectomy) or congenitally sterile

One year postmenopausal (stable amenorrhea for 12 
months without alternative medical cause plus high 
follicle-stimulating hormone, FSH serum level in the 
postmenopausal range) in women not using hormonal 
contraception or hormonal replacement therapy

Women in stable post-menopause, but are taking 
hormone replacement therapy for treatment of 
menopausal symptoms may be considered eligible for 
the study even with the lower serum FSH. They do not 
need to use other contraception.
Revised for clarification.

Bilateral tubal occlusion and 

vVasectomized partner provided that he is the sole 
sexual partner and has received medical assessment of 
the surgical process.

Bilateral tubal occlusion 

Vasectomized partner provided that he is the sole sexual 
partner and has received medical assessment of the 
surgical process.
Revised for clarification.
Appendix F, Lost to Follow-Up
A patient will be considered lost to follow-up if he/she repeatedly 
fails to return for scheduled visits and if the site is unable to 
establish contact with the patient after 3 documented attempts via 2 
different methods (phone, text, e-mail, certified letter, etc)be 
contacted by the investigational center.
A patient will be considered lost to follow-up if he/she repeatedly 
fails to return for scheduled visits and if the site is unable to establish 
contact with the patient after 3 documented attempts via 2 different 
methods (phone, text, e-mail, certified letter, etc).
Revised for clarification.
Appendix G, Handling, Labeling, Storage, and Accountability for Investigational Medicinal Product(s)
Preparation instructions for subcutaneous (sc) injections: 
Preparation instructions for subcutaneous (sc) injections: 
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Investigational medicinal product (IMP) should be allowed to 
equilibrate at room temperature for 1545 to 3060 minutes before sc 
administration.
Investigational medicinal product (IMP) should be allowed to 
equilibrate at room temperature for 45 to 60 minutes before sc 
administration.
Appendix H, Preventive Cluster Headache Medications and Disallowed Medications
Note that intra articular steroid injections, steroid ear drops, 
steroids for ocular use, and steroid creams for topical use are 
permitted during the study.Note that the only allowed steroids are 
intra-articular injection or ocular, ear drops, intranasal, inhaled, and 
creams for topical use.
Note that the only allowed steroids are intra-articular injection or 
ocular, ear drops, intranasal, inhaled, and creams for topical use.
Revised for clarification.
Appendix L, Total Blood Volume (other sections affected by this change: Section 3.5, Schedule of Study Procedures and Assessments, Table 4: Study 
Procedure and Assessments for Treated Patients [footnote s]; Section 5.10, Total Blood Volume; Appendix B, Study Procedures and Assessments by Visit; 
and Appendix P, Exploratory Biomarkers Samples)
Total blood volume to be collected for each patient in this study is 
approximately 185.5205.5 mL for scheduled tests.
Total blood volume to be collected for each patient in this study is 
approximately 205.5 mL for scheduled tests.
Revised for clarification.
Serum chemistry sample volume was revised from 3 mL to 3.5 mL
Serum pregnancy sample volume was revised from 3 mL to 3.5 mL 
and number of samples was changed from 4 to 1
Hematology sample volume was revised from 3 mL to 2 mL
Coagulation sample of 4.5 mL (4 samples in total) was added
Number of pharmacokinetic samples was revised from up to 13 to 
13
Biomarker serum sample volume was revised from 14.5 mL to 8.5 
mL
Serum chemistry: 3.5 mL at 4 time points
Serum pregnancy: 3.5 mL at 1 time point
Hematology: 2 mL at 4 time points
Coagulation: 4.5 mL at 4 time points
Pharmacokinetics: 4 mL at 13 time points
Biomarker serum: 8.5 mL at 5 time points
Revised for clarification.
 
 
 
 
 
 
 
 
 
Revised for clarification.
 
 
 
Revised for clarification.
Appendix N, Pharmacokinetics Samples (other section affected by this change: Appendix O, Immunogenicity Samples)
Separated plasma will be transferred in approximately equal 
portions in 2 labeled 2-mL polypropylene tubes (Sets A and B).
Separated plasma will be transferred in approximately equal portions 
in 2 labeled 2-mL polypropylene tubes (Sets A and B).
Revised for clarification.
Set A samples will be transported frozen, with a temperature data 
Set A samples will be transported frozen, with a temperature data 
Revised for clarification.


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logger and with dry ice sufficient for 4 days, on a monthly basis by 
next day courier to the central laboratory or bioanalytical 
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 CSR 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.
logger and with dry ice sufficient for 4 days, on a monthly basis to 
the central laboratory.
Set B samples will be sent to the same laboratory as that for Set A. 
Instructions as to the disposition of the Set B samples will be 
provided by the sponsor.


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16.4.
Amendment 01 Dated 30 November 2016
The primary reason for this amendment is to incorporate nonsubstantial changes to maintain 
alignment with the protocols with protocol Amendment 01 for Studies TV48125-CNS-30056 
and TV48125-CNS-30057. 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 4 (Study Procedures and Assessments for Patients Enrolling in the Study from the Pivotal 
Efficacy Studies) and Figure 1 (Overall Study Schematic Diagram) have been revised to reflect 
the changes described below.


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Global change (except for protocol title)
fremanezumabTEV 48125
fremanezumab
Generic name will now be 
used rather than the Teva-
assigned number.
Section 2.2.2, Wearable Sensor Substudy Exploratory Objectives and Endpoints (other section affected by the change: Section 9.5.3, Exploratory 
Endpoints)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
.


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and sleep efficiency and headache intensity during CH 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 3.1, General Design and Study Schematic Diagram
This is a 68-week extension study to evaluate the long-term safety 
of fremanezumabTEV 48125 in adult patients with CH. During the 
course of any CH attack, patients will be allowed to use acute 
medications to treat acute headaches, as needed.
This is a 68-week extension study to evaluate the long-term 
safety of fremanezumab in adult patients with CH. During 
the course of any CH attack, patients will be allowed to use 
acute medications to treat acute headaches, as needed.
Added sentence to 
emphasize/clarify that acute 
medications are allowed.
Section 3.1, General Design and Study Schematic Diagram (other section affected by this change: Section 5.1.1.1 Starting Dose and Dose Levels
Patients with a diagnosis of ECH who experience CH remission, 
defined as no CH attacks for 12 successive weeks at any time after 
starting IMP (ie, administration of the first dose of IMP in the 
pivotal study), will be offered the possibility to stop treatment and 
continue to attend the subsequent scheduled visits. If treatment is 
stopped and CH attacks resume within 12 weeks after stopping 
treatment, patients will restart treatment at their previous dose 
regimen through week 36. If treatment is stopped and CH attacks 
resume after more than 12 weeks after stopping treatment, patients 
will restart fremanezumabTEV 48125 treatment at 675 mg sc 
Patients with a diagnosis of ECH who experience CH 
remission, defined as no CH attacks for 12 successive weeks 
at any time after starting IMP (ie, administration of the first 
dose of IMP in the pivotal study), will be offered the 
possibility to stop treatment and continue to attend the 
subsequent scheduled visits. If treatment is stopped and CH 
attacks resume within 12 weeks after stopping treatment, 
patients will restart treatment at their previous dose regimen 
through week 36. If treatment is stopped and CH attacks 
resume after more than 12 weeks after stopping treatment, 
Specified that patients who 
experience remission will 
have the option to either 
continue taking IMP or to 
discontinue taking IMP. 
Clarified that patients who 
elect to discontinue taking 
the IMP will be required to 
continue to attend study 
visits after stopping 


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treatment with the IMP.
Section 3.2, Planned Number of Patients and Countries
Approximately 300 patients from 342 patients with CH are expected 
to complete the Phase 3 pivotal efficacy studies (Studies TV48125-
CNS-30056 and TV48125-CNS-30057) are expected to enroll in 
this study; 274 of these patients (182 patients who received TEV
48125 during the Phase 3 pivotal efficacy studies and 92 patients 
who received placebo during the Phase 3 pivotal efficacy studies) 
are anticipated to enroll in this study, and 192 of these patients are 
anticipated to complete this study. 
The study is planned to be conducted in approximately 1215
countries in approximately 8060 investigational centers. The study 
is expected to start in Q1/2017 and last until approximately 
Q4/2019.
Approximately 300 patients from the Phase 3 pivotal 
efficacy studies (Studies TV48125-CNS-30056 and 
TV48125-CNS-30057) are expected to enroll in this study.
The study is planned to be conducted in approximately 12 
countries in approximately 80 investigational centers. The 
study is expected to start in Q1/2017 and last until 
approximately Q4/2019
Updated the number of 
patients based on 
characteristics of CH 
(typical durations of cluster 
periods, etc).
The numbers of 
investigational centers and 
countries were updated to 
align with the numbers in 
for the pivotal studies.
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 Appendix C, 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 Appendix C, noncompliance, or adverse 
event).
Change to terminology 
(violation changed to 
deviation) to align with 
guidance from the ICH.
Section 4.1, Patient Inclusion Criteria
c.
The patient completes either the Phase 3 pivotal study for ECH 
(Study TV48125-CNS-30056) or the Phase 3 pivotal study for 
CCH (Study TV48125-CNS-30057) without important protocol 
deviations related to patient safety and patient compliancemajor 
c.
The patient completes either the Phase 3 pivotal study 
for ECH (Study TV48125-CNS-30056) or the Phase 3 
pivotal study for CCH (Study TV48125-CNS-30057) 
without important protocol deviations related to patient 
Change to terminology 
(violation changed to 
deviation) to align with 
guidance from the ICH.


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protocol violations.
safety and patient compliance.
The types of important 
protocol deviations that are 
exclusionary are now 
specified for clarity.
g.
The patient must be willing to stop concomitant medications 
used in clinical practice for the prevention of CH for the 
duration of this study. (Note: Patients taking verapamil during 
the pivotal studies must begin tapering verapamil as soon as 
they enroll in this study, and they must be off verapamil within 
1 month of beginning study participation [Appendix H].)
g.
The patient must be willing to stop concomitant 
medications used in clinical practice for the prevention 
of CH for the duration of this study. (Note: Patients 
taking verapamil during the pivotal studies must begin 
tapering verapamil as soon as they enroll in this study, 
and they must be off verapamil within 1 month of 
beginning study participation [Appendix H].)
For safety reasons, 
verapamil should be 
tapered. 
Section 5.1.1.1, Starting Dose and Dose Levels
Of note, blinding of the pivotal studies and the initial treatments 
during this long-term safety extension study will be maintained 
throughout study participation.
Of note, blinding of the pivotal studies and the initial 
treatments during this long-term safety extension study will 
be maintained throughout study participation.
Added to clarify this point.
Section 5.3.1, Justification for Dose of Test Investigational Medicinal Product
 
 
 
 
 
 
 
 
 
Update made to reflect the 
option for patients who 
experience CH remission to 
either continue or 
discontinue taking the IMP.
Section 5.5, Prior and Concomitant Medication or Therapy
Patients taking verapamil during the pivotal studies must begin 
tapering verapamil as soon as they enroll in this study, and they 
must be off verapamil within 1 month of beginning study 
participation. All other mMedications that are commonly prescribed 
for the preventive treatment of CH and systemic steroids are 
prohibited throughout the double-blind treatment period of this long-
term safety extension study. See Appendix H for details.
Patients taking verapamil during the pivotal studies must 
begin tapering verapamil as soon as they enroll in this study, 
and they must be off verapamil within 1 month of beginning 
study participation. All other medications that are commonly 
prescribed for the preventive treatment of CH and systemic 
steroids are prohibited throughout the double-blind treatment 
period of this long-term safety extension study. See 
Appendix H for details.
For safety reasons, 
verapamil should be 
tapered.
Section 5.7, Temporary Discontinuation of Investigational Medicinal Product
Patients who experience CH remission, defined as no CH attacks for Patients who experience CH remission, defined as no CH 
Update made to reflect the 


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option for patients who 
experience CH remission to 
either continue or 
discontinue taking the IMP.
Section 5.10, Total Blood Volume (other sections affected by this change: Section 3.5, Schedule of Procedures and Assessments and Appendix L, Total 
Blood Volume)
The total blood volume to be collected for each patient enrolling in 
this study for treatment with fremanezumabTEV 48125 is 
approximately 18205.5 mL for scheduled tests. An additional 30 mL 
of blood may be collected in the event of follow-up for liver 
enzymes as detailed in Appendix J.
The total blood volume to be collected for each patient 
enrolling in this study for treatment with fremanezumab is 
approximately 185.5 mL for scheduled tests. An additional 
30 mL of blood may be collected in the event of follow-up 
for liver enzymes as detailed in Appendix J.
The PAXGene RNA sample 
will be collected into the 
PAXGene RNA tube, which 
requires 2.5 mL of blood. 
The blood volume was 
updated from 6.5 mL to 2.5 
mL to reflect this. Since 5 
PAXGene RNA samples are 
to be collected, the total 
blood volume is reduced by 
20 mL.
This text was also updated 
to clarify that additional 
blood may be collected in 
the case of elevated liver 
function tests as detailed in 
Appendix J.
Section 6.2, Electronic Diary Device
If a patient fails to complete the diary for the preceding day within 
the allowed timeframe (ie, by 1200 on the latter day), the patient 
will be prompted to enter the missed day’s information the next time 
he/she accesses the electronic diary provided that no more than 48 
hours have elapsed since completion of that day. If more than 48 
hours have elapsed since completion of a diary day, the patient will 
not be allowed to enter the diary information for that daymissed 
day’s information, and it will be considered a missed day. 
If a patient fails to complete the diary for the preceding day, 
the patient will be prompted to enter the missed day’s 
information the next time he/she accesses the electronic 
diary provided that no more than 48 hours have elapsed 
since completion of that day. If more than 48 hours have 
elapsed since completion of a diary day, the patient will not 
be allowed to enter diary information for that day, and it will 
be considered a missed day. 
The window of time to 
complete the diary entry has 
been extended to enable 
more flexibility for CH 
patients due to the severity 
of the disease.
Section 6.8, Patient-Perceived Satisfactory Improvement (other section affected by this change: Section 3.5, Schedule of Procedures and Assessments)
The PPSI was developed by ten Klooster et al (2006) and is 
composed of an unmarked 100 mm visual analog scalefor Pain 
The PPSI was developed by ten Klooster et al (2006) for 
pain intensity and was adjusted for CH symptoms 
In the e-diary, a VAS 
cannot be used. 


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Intensity (VAS PI) with “no pain” and “unbearable pain” as anchors 
and a question regarding change in pain intensity and was adjusted 
for CH symptoms improvement. Patients will mark the level of CH-
associated pain on the VAS PI and indicate if pain is “much worse,” 
“moderately worse,” “slightly worse,” “unchanged,” 
“unsatisfactoryslightly improved,” “satisfactorymoderately
improved,” or “good to very goodmuch improved” compared with 
baseline (visit 2 [day 0] of the Phase 3 pivotal efficacy studies)4 
weeks ago. PPSI will be defined as the change in pain on the VAS
PIthat corresponds with a minimal rating of “satisfactoryslightly
improved.”
improvement. Patients will mark the level of CH-associated 
pain and indicate if pain is “much worse,” “moderately 
worse,” “slightly worse,” “unchanged,” “slightly improved,” 
“moderately improved,” or “much improved” compared 
with 4 weeks ago. PPSI will be defined as the change in pain 
that corresponds with a minimal rating of “slightly 
improved.”
Understanding that CH 
causes pain, the report to 
measure improvement or 
not is adapted for CH.
Section 6.9, 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 the change in their overall health and wellbeinghow they 
feel now compared with how they felt before receiving IMPat the 
start of the study (the time after the patient received the first IMP 
dose) on a 7 point scale, where 1 isas “much worse,” “moderately 
worse,” “slightly worse,” “stayed the same,” “a little better,” 
“moderately better,” or “much better.”no change (or condition has 
got worse),” 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.”
The PGIC scale is a validated generic tool for the assessment 
of overall change in the severity of illness following 
treatment. Patients will rate the change in their overall health 
and wellbeing compared with how they felt at the start of the 
study (the time after the patient received the first IMP dose) 
as “much worse,” “moderately worse,” “slightly worse,” 
“stayed the same,” “a little better,” “moderately better,” or 
“much better.”
Updated the text to align 
with the e-diary.
Section 7.1.3, Severity of an Adverse Event
For severity grading of local tolerability (injection site erythema, 
induration, ecchymosis, and pain), refer to Section 7.11.
For severity grading of local tolerability (injection site 
erythema, induration, ecchymosis, and pain), refer to 
Section 7.11.
Added reference to Section 
7.11 to clarify how local 
tolerability findings will be 
graded.


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Section 7.3 Medication Error and Special Situations Related to the Investigational Medicinal Products (other section affected by this change: Appendix 
C, Quality Control and Quality Assurance)
Any administration of IMP that is not in accordance with the study 
protocol should be reported on the CRF either as an important 
deviationviolation, if it meets the important deviationviolation
criteria specified in the protocol (Appendix C), or as a deviation, in 
the patient’s source documents, regardless of whether or not an 
adverse event occurs as a result. When meeting important protocol 
violation deviation criteria, all instances of incorrect IMP 
administration should be categorizedreported in the clinical trial 
management system.on the CRF as “Non Compliance to IMP.”
Any administration of IMP that is not in accordance with the 
study protocol should be reported as an important deviation, 
if it meets the important deviation criteria specified in the 
protocol (Appendix C), in the patient’s source documents, 
regardless of whether or not an adverse event occurs as a 
result. When meeting important protocol deviation criteria, 
all instances of incorrect IMP administration should be 
categorized in the clinical trial management system.
Change to terminology 
(violation to deviation) to 
align with guidance from 
the ICH. In addition, the 
CRF will no longer be used 
to record protocol deviation 
information. 
Section 7.8, Immunogenicity
Blood samples for ADA assessment will also be collected upon 
observation of any severe hypersensitivity reaction and(eg,
anaphylaxis).
Blood samples for ADA assessment will also be collected 
upon observation of any severe hypersensitivity reaction and 
anaphylaxis.
Correction to align with the 
rest of the protocol. 
Section 7.9, Assessment of Suicidality
A positive finding will be defined as a current suicide ideation with 
some intent to act and no plan. The investigator, based on his 
medical judgment, score ≥4 for suicidal ideation and/or a suicide 
attempt. If the patient scores a 4 for suicidal ideation, then the 
investigator will determine if the patient should be seen by a mental 
health specialist and if he/she should continue participating in the 
study. If athe patient reports current suicide ideation with specific 
plan and intentscores a 5 for suicidal ideation and/or there is a 
suicide attempt, then the patient should be immediately discontinued 
from the study and seen by a mental health specialist. 
Any patient should be excluded if any suicidal behaviors are 
reported.
Any patient with lifetime behaviors (actual, interrupted, and aborted 
attempts and preparatory actions) should be excluded and/or 
discontinued from the study.
A positive finding will be defined as current suicide ideation 
with some intent to act and no plan. The investigator, based 
on his medical judgment, will determine if the patient should 
be seen by a mental health specialist and if he/she should 
continue participating in the study. If a patient reports 
current suicide ideation with specific plan and intent, then 
the patient should be immediately discontinued from the 
study and seen by a mental health specialist. 
Any patient should be excluded if any suicidal behaviors are 
reported.
Any patient with lifetime behaviors (actual, interrupted, and 
aborted attempts and preparatory actions) should be 
excluded and/or discontinued from the study.
Adapted text to the eC-
SSRS electronic 
questionnaire format.
Section 7.11, Injection Site Assessments (other section affected by this change: Section 3.5, Schedule of Procedures and Assessments)
Injection site assessments will be performed immediately (+ 10 
minutes) and 1 hour after receiving each dose of the IMP. The 
injection site(s) will be assessed for erythema, induration, 
ecchymosis, and pain.; and
sSeverity will be graded according to the following criteria:
Injection site assessments will be performed immediately (+ 
10 minutes) and 1 hour after receiving each dose of the IMP. 
The injection site(s) will be assessed for erythema, 
induration, ecchymosis, and pain.
Severity will be graded according to the following criteria:
Deleted grade 4 to align 
severity grading with 
severity scale for adverse 
events.


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New wording
Reason/justification for 
change
Injection-site erythema, injection site induration, and injection site
ecchymosis will be graded according to measurements: absent, 5 
mm 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. 
…
Symptom
Severity
Ggrade
Assessment
Pain
0
AbsentNo pain
1 (mild)
Painful on touchMild
2 (moderate)
Pain on 
ambulationModerate
3 (severe)
Spontaneously 
painfulSevere
4
Worst possible
If a patient has severe injection site induration, erythema, and/or
ecchymosis, and/or grade 3 (severe) or grade 4 (worst possible) 
injection site pain at 1 hour after completion of the IMP 
administration, the patient will be reassessed at 3 hours after 
completion ofreceiving the IMP administration and hourly thereafter 
until the reaction/pain 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) will also be recorded as adverse events as 
described in Section 7.1.
Injection-site erythema, induration, and ecchymosis will be 
graded according to measurements: absent, 5 mm 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. 
…
Symptom
Severity grade
Assessment
Pain
0
Absent
1 (mild)
Painful on touch
2 (moderate)
Pain on 
ambulation
3 (severe)
Spontaneously 
painful
If a patient has severe injection site induration, erythema, 
ecchymosis, or pain at 1 hour after completion of IMP 
administration, the patient will be reassessed at 3 hours after 
completion of IMP administration and hourly 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) will also be recorded as adverse 
events.
Section 8.6, Ancillary Studies – Wearable Sensor Substudy
 
 
 
 
 
 
 


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Reason/justification for 
change
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 9.1, Sample Size and Power Considerations
There are no statistical considerations for the sample size. A total of 
approximately 300 patients from342 patients with CH are expected 
to complete the Phase 3 pivotal efficacy studies (Studies TV48125-
CNS-30056 and TV48125-CNS-30057) are expected to enroll in 
this study; 274 of these patients (182 patients who received TEV
48125 during the Phase 3 pivotal efficacy studies and 92 patients 
who received placebo during the Phase 3 pivotal efficacy studies) 
are anticipated to enroll in this study, and 192 of these patients are 
anticipated to complete this study. All patients will receive (sc) 
fremanezumabTEV 48125 during this study.
There are no statistical considerations for the sample size. A 
total of approximately 300 patients from the Phase 3 pivotal 
efficacy studies (Studies TV48125-CNS-30056 and 
TV48125-CNS-30057) are expected to enroll in this study. 
All patients will receive (sc) fremanezumab during this 
study.
Updated the number of 
patients based on 
characteristics of CH 
(typical durations of cluster 
periods, etc).
Section 10, Quality Control and Quality Assurance
This includes information about protocol amendments, deviations 
and violations, responsibilities of the investigator to study personnel, 
study monitoring, and audit and inspection.
This includes information about protocol amendments, 
deviations, responsibilities of the investigator to study 
personnel, study monitoring, and audit and inspection.
Removed violations to align 
with guidance on 
terminology from ICH.
Appendix B, Study Procedures and Assessments by Visit
Edit in each instance of the following:
Perform local injection site assessment immediately (+ 10 minutes) 
and at 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.
Perform local injection site assessment immediately (+ 10 
minutes) and at 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.
To align with changes in 
Section 7.11.
Week 1 (Day 7)
Patients will complete the Patient Global Impression of Change 
Week 1 (Day 7)
Patients will complete the Patient Global Impression of 
To align with changes in 
Section 6.8.


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Original text with changes shown
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Reason/justification for 
change
(PGIC) scale and the Patient Perceive Satisfactory Improvement 
(PPSI) (complete the Visual Analog Scale for Pain Intensity [VAS
PI] and respond to question about change in pain intensity) at 
1 week after receiving IMP using the electronic diary device. 
Change (PGIC) scale and the Patient Perceive Satisfactory 
Improvement (PPSI) at 1 week after receiving IMP using the 
electronic diary device.
Edit in each instance of the following:

Complete the PPSI (complete the VAS PI and respond to 
question about change in pain intensity).
Edit in each instance of the following:

Complete the PPSI.
To align with changes in 
Section 6.8.
Edit in each instance of the following:

Obtain an 148.5-mL blood sample (6 mL each for serum and 
plasma and 26.5 mL for RNA) for biomarker analysis.
Edit in each instance of the following:

Obtain a 14.5-mL blood sample (6 mL each for 
serum and plasma and 2.5 mL for RNA) for 
biomarker analysis.
The PAXGene RNA sample 
will be collected into the 
PAXGene RNA tube, which 
requires 2.5 mL of blood. 
The blood volume was 
updated from 6.5 mL to 2.5 
mL to reflect this.
Added at visit 10 

Perform triplicate 12-lead ECGs.

Perform triplicate 12-lead ECGs.
To align with the schedule 
of procedures and 
assessments for patients 
enrolling in the study from 
the pivotal efficacy studies.
Appendix H, Preventive Cluster Headache Medications and Disallowed Medications
Patients treated with verapamil as a concomitant preventive 
medication or other indication in the pivotal studies must start 
tapering verapamil as soon as they begin this study. The period of 
time needed to taper off verapamil will be based on the 
investigator’s medical judgment but should not exceed 1 month.
Patients treated with verapamil as a concomitant preventive 
medication or other indication in the pivotal studies must 
start tapering verapamil as soon as they begin this study. The 
period of time needed to taper off verapamil will be based 
on the investigator’s medical judgment but should not 
exceed 1 month.
For safety reasons, 
verapamil should be 
tapered.
Appendix N, Pharmacokinetics Samples (other section affected by this change: Appendix O, Immunogenicity Samples)
Samples will be stored at a temperature of -70°C to± -20°C 
(inclusive) in an upright position until they are shipped to the central 
laboratory.
Samples will be stored at a temperature of -70°C to -20°C 
(inclusive) in an upright position until they are shipped to 
the central laboratory.
Pharmacokinetic and ADA 
samples can be stored in 
a -70°C to -20°C freezer at 
the clinical sites before 
shipping.
Appendix P, Exploratory Biomarkers Samples
 
 
 
 
 
 
 
 
 
 
 
 


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Reason/justification for 
change
 
ADA=antidrug antibody; CCH=chronic cluster headache; CH=cluster headache; CRF=case report form; eC-SSRS= electronic Columbia-Suicide Severity Rating 
Scale; ECG=electrocardiogram; ECH=episodic cluster headache; ICH=International Council on Harmonisation; IMP=investigational medicinal product; 
PGIC=Patient Global Impression of Change; PPSI=Patient-Perceived Satisfactory Improvement; sc=subcutaneous; RNA=ribonucleic acid; VAS=visual analog 
scale; VAS-PI-visual analog scale for pain intensity


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16.5.
Letter of Clarification 04 Dated 13 December 2016


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APPENDIX A. CLINICAL LABORATORIES AND OTHER 
DEPARTMENTS AND INSTITUTIONS
Sponsor’s Authorized Representative
 
 
 
Legal Representative of the Sponsor in 
the European Union
Sponsor’s Medical Expert/Contact Point 
designated by the Sponsor for Further 
Information on the Study
 


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Sponsor’s Contact Point designated by 
the sponsor for further information on 
the study
 
 
 
Study Principal Investigator
 


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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. 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.
 
 
Contract Research Organization
PRA
4130 Park Lake Avenue
Suite 400
Raleigh, NC 27612
NCGS, Inc.
288 Meeting Street
Suite 400
Charleston, SC 29401
Central Clinical Laboratory
Q2 Solutions Central Laboratory
Central Electrocardiogram Evaluation
eResearch Technology, Inc.
1818 Market Street
Philadelphia, PA 19103
Bioanalytical Pharmacokinetics 
Evaluation
 
 
 


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Bioanalytical Immunogenicity 
Evaluation
 
Pharmacogenomics/Biomarker 
Evaluation
 
 
 
Electronic Clinical Outcome Assessment
eResearch Technology, Inc.
1818 Market Street
Philadelphia, PA 19103
Web and Phone Integrated Interactive 
Response Technology
Y-PRIME


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APPENDIX B. STUDY PROCEDURES AND ASSESSMENTS BY VISIT
Patients Enrolling in the Study from the Pivotal Studies
1. Procedures Before Investigational Medicinal Product (IMP) Treatment (Visit 1)
Visit 1 of the current study corresponds with the end-of-treatment (EOT) visit (visit 5) of the 
pivotal efficacy studies. EOT visit procedures/assessments must be completed before the 
patient begins participation in this study, and the EOT procedures/assessments will not be 
repeated at visit 1 of this study. The EOT visit procedures/assessments are detailed in the 
protocols for Studies TV48125-CNS-30056 and TV48125-CNS-30057. The following 
procedures will be performed before receiving investigational medicinal produce (IMP) at 
visit 1:

Obtain written informed consent before any other study-related procedures are 
performed. In addition to the patient, the partner or family member who will complete 
the Impact on Partner and Family questionnaire, if applicable, will also provide 
written informed consent.

Patients participating in the wearable sensor substudy will be asked to provide 
consent to continue participating in the substudy during this long-term safety study.

Perform urine beta-human chorionic gonadotropin (β-HCG) test (women of 
childbearing potential [WOCBP] only).

Review inclusion and exclusion criteria.
Patients enrolled in the wearable sensor substudy will continue to wear the digital wearable 
device on the wrist throughout the double-blind treatment period of this study provided they 
consent to continued participation in the substudy. 
2. Treatment Period (Visits 1 Through 11 [Weeks 0 Through 40 ± 3 Days])
Patients will complete entries of cluster headache (CH) attack information (ie, occurrence 
and number of CH attack[s]) using electronic diary devices daily from visit 1 through visit 11 
(week 40). Refer to Section 6.2 for additional details. 
Procedures/assessments by visit during the double-blind treatment period are detailed in the 
following sections.
Visit 1 (Day 0 [Week 0])
After completing predose assessments (see Procedures Before IMP Treatment), patients who 
are not in CH remission will be treated with IMP. Refer to Section 5.1.1.1 for details.
The following procedures/assessments will be performed after dosing:

Perform local injection site assessment immediately (+ 10 minutes) and at 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. See Section 7.11 for additional details.

Evaluate for anaphylaxis and hypersensitivity reactions.


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
Inquire about postdose adverse events before the patient leaves the investigational 
center.
Week 1 (Day 7)
Patients will complete the Patient Global Impression of Change (PGIC) scale and the 
Patient-Perceived Satisfactory Improvement (PPSI) at 1 week after receiving IMP using the 
electronic diary device.
Visit 2 (Week 4 ± 3 Days)
The following predose procedures/assessments will be performed at visit 2:

Review electronic diary data.

Review study compliance.

Perform vital signs measurements (includes systolic and diastolic blood pressure, 
pulse, and body temperature).

Perform full physical examination, including weight measurement.

Inquire about adverse events.

Inquire about concomitant medications.

Perform urine β-HCG test (WOCBP only).

Complete the electronic Columbia-Suicide Severity Rating Scale (eC-SSRS) Since 
Last Visit version.

Obtain a 4-mL blood sample for pharmacokinetics analysis.

Administer the Hospital Anxiety and Depression Scale (HADS), EuroQol-5 
Dimension (EQ-5D) questionnaire, 12-Item Short-Form Health Survey (SF-12), 
Impact on Partner and Family questionnaire, and Work Productivity and Activity 
Impairment (WPAI).

Complete the PPSI.

Complete the PGIC scale.

Each patient’s partner/family member completes the Impact on Partner and Family 
questionnaire. Partners/family members will be asked to attend the study visit with 
the patient or to return to the investigational center within ±3 days of the patient’s 
visit if unable to appear at the same time.

Perform wearable sensor device check and compliance check for patients enrolled in 
the wearable sensor substudy. 
After completing predose assessments, patients who are not in CH remission will be treated 
with IMP. Refer to Section 5.1.1.1 for details.


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The following procedures/assessments will be performed after dosing:

Perform local injection site assessment immediately (+10 minutes) and at 1 
(±15 minutes) hour after completing IMP administration. Additional injection site 
assessments may be performed based on the severity of any observed injection site 
reaction. See Section 7.11 for additional details.

Evaluate for anaphylaxis and hypersensitivity reactions.

Inquire about postdose adverse events before the patient leaves the investigational 
center.
Visit 3 (Week 8 ± 3 Days)
The following predose procedures/assessments will be performed at visit 3:

Review electronic diary data.

Review study compliance.

Perform vital signs measurements (includes systolic and diastolic blood pressure, 
pulse, and body temperature).

Inquire about adverse events.

Inquire about concomitant medications.

Perform urine β-HCG test (WOCBP only).

Obtain a 4-mL blood sample for pharmacokinetics analysis.

Complete the eC-SSRS Since Last Visit version.

Complete the PPSI.

Complete the PGIC scale.

Perform wearable sensor device check and compliance check for patients enrolled in 
the wearable sensor substudy. 
After completing predose assessments, patients who are not in CH remission will be treated 
with IMP. Refer to Section 5.1.1.1 for details.
The following procedures/assessments will be performed after dosing:

Perform local injection site assessment immediately (+10 minutes) and at 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. See Section 7.11 for additional details.

Evaluate for anaphylaxis and hypersensitivity reactions.

Inquire about postdose adverse events before the patient leaves the investigational 
center.


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Visit 4 (Week 12 ± 3 Days)
The following predose procedures/assessments will be performed at visit 4:

Review electronic diary data.

Review study compliance.

Perform vital signs measurements (includes systolic and diastolic blood pressure, 
pulse, and body temperature).

Perform triplicate 12-lead electrocardiograms (ECGs).

Perform a physical examination (including weight).

Inquire about adverse events.

Inquire about concomitant medications.

Perform clinical laboratory tests (serum chemistry, hematology, coagulation, and 
urinalysis).

Perform urine β-HCG test (WOCBP only).

Obtain a 4-mL blood sample for pharmacokinetics analysis.

Obtain a 5-mL blood sample for serum antidrug antibody (ADA) analysis.

Obtain a 5-mL urine sample for biomarker analysis.

Obtain a 17-mL blood sample for biomarker analysis (8.5 mL for serum, 6 mL for 
plasma, and 2.5 mL for RNA).

Complete the eC-SSRS Since Last Visit version.

Administer the HADS, EQ-5D questionnaire, SF-12 questionnaire, and WPAI 
questionnaire. 

Complete the PPSI.

Complete the PGIC scale.

Each patient’s partner/family member completes the Impact on Partner and Family 
questionnaire. Partners/family members will be asked to attend the study visit with 
the patient or to return to the investigational center within ±3 days of the patient’s 
visit if unable to appear at the same time.

Perform wearable sensor device check and compliance check for patients enrolled in 
the wearable sensor substudy. 
After completing predose assessments, patients who are not in CH remission will be treated 
with IMP. Refer to Section 5.1.1.1 for details.


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The following procedures/assessments will be performed after dosing:

Perform local injection site assessment immediately (+10 minutes) and at 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. See Section 7.11 for additional details.

Evaluate for anaphylaxis and hypersensitivity reactions.

Inquire about postdose adverse events before the patient leaves the investigational 
center.
Visit 5 (Week 16 ± 3 Days)
The following procedures/assessments will be performed at visit 5:

Review electronic diary data.

Review study compliance.

Perform vital signs measurements (includes systolic and diastolic blood pressure, 
pulse, and body temperature).

Perform a physical examination (including weight).

Inquire about adverse events.

Inquire about concomitant medications.

Perform urine β-HCG test (WOCBP only).

Obtain a 4-mL blood sample for pharmacokinetics analysis.

Complete the eC-SSRS Since Last Visit version.

Perform wearable sensor device check and compliance check for patients enrolled in 
the wearable sensor substudy. 
After completing predose assessments, patients who are not in CH remission will be treated 
with IMP. Refer to Section 5.1.1.1 for details.
The following procedures/assessments will be performed after dosing:

Perform local injection site assessment immediately (+10 minutes) and at 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. See Section 7.11 for additional details.

Evaluate for anaphylaxis and hypersensitivity reactions.

Inquire about postdose adverse events before the patient leaves the investigational 
center.
Visit 6 (Week 20 ± 3 Days)
The following predose procedures/assessments will be performed at visit 6:

Review electronic diary data.


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
Review study compliance.

Perform vital signs measurements (includes systolic and diastolic blood pressure, 
pulse, and body temperature).

Inquire about adverse events.

Inquire about concomitant medications.

Perform urine β-HCG test (WOCBP only).

Obtain a 4-mL blood sample for pharmacokinetics analysis.

Complete the eC-SSRS Since Last Visit version.

Perform wearable sensor device check and compliance check for patients enrolled in 
the wearable sensor substudy. 
After completing predose assessments, patients who are not in CH remission will be treated 
with IMP. Refer to Section 5.1.1.1 for details.
The following procedures/assessments will be performed after dosing:

Perform local injection site assessment immediately (+10 minutes) and at 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. See Section 7.11 for additional details.

Evaluate for anaphylaxis and hypersensitivity reactions.

Inquire about postdose adverse events before the patient leaves the investigational 
center.
Visit 7 (Week 24 ± 3 Days)
The following predose procedures/assessments will be performed at visit 7:

Review electronic diary data.

Review study compliance.

Perform vital signs measurements (includes systolic and diastolic blood pressure, 
pulse, and body temperature).

Perform triplicate 12-lead ECGs.

Perform a physical examination (including weight).

Inquire about adverse events.

Inquire about concomitant medications.

Perform clinical laboratory tests (serum chemistry, hematology, coagulation, and 
urinalysis).

Perform urine β-HCG test (WOCBP only).

Obtain a 4-mL blood sample for pharmacokinetics analysis.


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
Obtain a 5-mL blood sample for serum ADA analysis.

Obtain a 5-mL urine sample for biomarker analysis.

Obtain a 17-mL blood sample (8.5 mL for serum, 6 mL for plasma, and 2.5 mL for 
RNA) for biomarker analysis.

Complete the eC-SSRS Since Last Visit version.

Administer the HADS, EQ-5D questionnaire, SF-12 questionnaire, and WPAI 
questionnaire. 

Complete the PPSI.

Complete the PGIC scale.

Each patient’s partner/family member completes the Impact on Partner and Family 
questionnaire. Partners/family members will be asked to attend the study visit with 
the patient or to return to the investigational center within ±3 days of the patient’s 
visit if unable to appear at the same time.

Perform wearable sensor device check and compliance check for patients enrolled in 
the wearable sensor substudy.
After completing predose assessments, patients who are not in CH remission will be treated 
with IMP. Refer to Section 5.1.1.1 for details.
The following procedures/assessments will be performed after dosing:

Perform local injection site assessment immediately (+10 minutes) and at 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. See Section 7.11 for additional details.

Evaluate for anaphylaxis and hypersensitivity reactions.

Inquire about postdose adverse events before the patient leaves the investigational 
center.
Visit 8 (Week 28 ± 3 Days)
The following predose procedures/assessments will be performed at visit 8:

Review electronic diary data.

Review study compliance.

Perform vital signs measurements (includes systolic and diastolic blood pressure, 
pulse, and body temperature).

Perform a physical examination (including weight).

Inquire about adverse events.

Inquire about concomitant medications.

Perform urine β-HCG test (WOCBP only).


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
Obtain a 4-mL blood sample for pharmacokinetics analysis.

Complete the eC-SSRS Since Last Visit version.

Perform wearable sensor device check and compliance check for patients enrolled in 
the wearable sensor substudy. 
After completing predose assessments, patients who are not in CH remission will be treated 
with IMP. Refer to Section 5.1.1.1 for details.
The following procedures/assessments will be performed after dosing:

Perform local injection site assessment immediately (+10 minutes) and at 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. See Section 7.11 for additional details.

Evaluate for anaphylaxis and hypersensitivity reactions.

Inquire about postdose adverse events before the patient leaves the investigational 
center.
Visit 9 (Week 32 ± 3 Days)
The following predose procedures/assessments will be performed at visit 9:

Review electronic diary data.

Review study compliance.

Perform vital signs measurements (includes systolic and diastolic blood pressure, 
pulse, and body temperature).

Inquire about adverse events.

Inquire about concomitant medications.

Perform urine β-HCG test (WOCBP only).

Obtain a 4-mL blood sample for pharmacokinetics analysis.

Complete the eC-SSRS Since Last Visit version.

Perform wearable sensor device check and compliance check for patients enrolled in 
the wearable sensor substudy. 
After completing predose assessments, patients who are not in CH remission will be treated 
with IMP. Refer to Section 5.1.1.1 for details.
The following procedures/assessments will be performed after dosing:

Perform local injection site assessment immediately (+10 minutes) and at 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. See Section 7.11 for additional details.

Evaluate for anaphylaxis and hypersensitivity reactions.


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
Inquire about postdose adverse events before the patient leaves the investigational 
center.
Visit 10 (Week 36 ± 3 Days)
The following predose procedures/assessments will be performed at visit 10:

Review electronic diary data.

Review study compliance.

Perform vital signs measurements (includes systolic and diastolic blood pressure, 
pulse, and body temperature).

Perform triplicate 12-lead ECGs.

Perform a physical examination (including weight).

Inquire about adverse events.

Inquire about concomitant medications.

Perform clinical laboratory tests (serum chemistry, hematology, coagulation, and 
urinalysis).

Perform urine β-HCG test (WOCBP only).

Obtain a 4-mL blood sample for pharmacokinetics analysis.

Obtain a 5-mL blood sample for ADA analysis.

Obtain a 5-mL urine sample for biomarker analysis.

Obtain a 17-mL blood sample for biomarker analysis (8.5 mL for serum, 6 mL for 
plasma, and 2.5 mL for RNA).

Complete the eC-SSRS Since Last Visit version.

Administer the HADS, EQ-5D questionnaire, SF-12 questionnaire, and WPAI 
questionnaire.

Complete the PPSI.

Complete the PGIC scale.

Each patient’s partner/family member completes the Impact on Partner and Family 
questionnaire. Partners/family members will be asked to attend the study visit with 
the patient or to return to the investigational center within ±3 days of the patient’s 
visit if unable to appear at the same time.

Perform wearable sensor device check and compliance check for patients enrolled in 
the wearable sensor substudy.
After completing predose assessments, patients who are not in CH remission will be treated 
with IMP. Refer to Section 5.1.1.1 for details.


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The following procedures/assessments will be performed after dosing:

Perform local injection site assessment immediately (+10 minutes) and at 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. See Section 7.11 for additional details.

Evaluate for anaphylaxis and hypersensitivity reactions.

Inquire about postdose adverse events before the patient leaves the investigational 
center.
Additional Visit(s) for Patients in the Wearable Sensor Substudy
 
 
End-of-Treatment Visit (Visit 11 [Week 40 ± 3 Days])/Early Withdrawal Visit
The following procedures/assessments will be performed at the EOT/early withdrawal visit:

Review electronic diary data.

Review study compliance.

Perform vital signs measurements (includes systolic and diastolic blood pressure, 
pulse, and body temperature).

Perform triplicate 12-lead ECGs.

Perform a physical examination (including weight).

Inquire about adverse events.

Inquire about concomitant medications.

Perform clinical laboratory tests (serum chemistry, hematology, coagulation, and 
urinalysis).

Perform a serum β-HCG test (WOCBP only).

Obtain a 4-mL blood sample for pharmacokinetics analysis.

Obtain a 5-mL blood sample for ADA analysis.

Obtain a 5-mL urine sample for biomarker analysis.

Obtain a 17-mL blood sample (8.5 mL for serum, 6 mL for plasma, and 2.5 mL for 
RNA) for biomarker analysis.


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
Complete the eC-SSRS Since Last Visit version.

Administer the HADS, EQ-5D questionnaire, SF-12 questionnaire, and WPAI 
questionnaire.

Complete the PPSI and the PGIC scale.

Collect the electronic diary device. 

Each patient’s partner/family member completes the Impact on Partner and Family 
questionnaire. Partners/family members will be asked to attend the study visit with 
the patient or to return to the investigational center within ±3 days of the patient’s 
visit if unable to appear at the same time.

Perform wearable sensor device check and compliance check for patients enrolled in 
the wearable sensor substudy.

Collect wearable sensor device from patients enrolled in the wearable sensor 
substudy.
3. Procedures after IMP Treatment
Follow-up Visit (Visit 12 [Week 68 ± 1 Week])
Patients who participate in the study in compliance with the protocol for the entire treatment 
period (ie, from visit 1 through visit 11) will be considered to have completed the study. 
Patients may be treated with standard of care following completion of visit 11. See 
Section 3.1 for the definition of the end of study.
Patients who complete the double-blind treatment period will have a follow-up visit 
approximately 7.5 months (5 half-lives) after the final dose of IMP. The following 
procedures/assessments will be performed at this visit:

Perform vital signs measurements (includes systolic and diastolic blood pressure, 
pulse, and body temperature).

Perform physical examination (including weight).

Inquire about adverse events.

Inquire about concomitant medications.

Complete the eC-SSRS Since Last Visit version.

Obtain a 5-mL blood sample for ADA analysis.

Obtain a 5-mL urine sample for biomarker analysis.

Obtain a 17-mL blood sample (8.5 mL for serum, 6 mL for plasma, and 2.5 mL for 
RNA) for biomarker analysis.
Patients who discontinue treatment prematurely must be encouraged to continue to attend the 
regular scheduled visits, and complete the prescribed safety and efficacy evaluations through 
the EOT visit (visit 11 [week 36]) and the follow-up visit (visit 12 [week 40]), if at all 
possible.


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Patients who both discontinue treatment and also withdraw from the study should have EOT 
(early withdrawal) visit procedures/assessments (see Table 4) performed on the last day the 
patient receives the IMP, or as soon as possible thereafter. The patient should also return for 
the follow-up visit approximately 7.5 months after the last dose of IMP if at all possible.
Procedures for patients who withdraw prematurely from the study are described in 
Section 4.3. Patients should be treated with standard of care after termination of the study as 
appropriate.
Patients with ongoing adverse events or clinically significant abnormal laboratory test results 
(as interpreted by the investigator) will be monitored as described in Section 7.1.2.
4. Unscheduled Visits
An unscheduled visit may be performed at any time during the study, at the patient’s request 
or 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 (eg, adverse 
events, concomitant medications and treatments, and results from procedures or tests).
Procedures performed during unscheduled visits include the following:

Review electronic diary data (if applicable).

Review study compliance.

Perform vital signs measurements (including systolic and diastolic blood pressure, 
pulse, and body temperature). 

Inquire about adverse events.

Inquire about concomitant medications.

Complete the eC-SSRS Since Last Visit version.
Other procedures may be performed at the discretion of the investigator.
Patients Enrolling in This Study for Evaluation of Antidrug Antibodies and 
Safety (Adverse Events and Concomitant Medications)
1. Visit 1
The following procedures/assessments will be performed at visit 1 for patients who enroll in 
this study for the purpose of evaluating ADAs, and safety (adverse events and concomitant 
medications):

Obtain written informed consent before any other study-related procedures are 
performed.

Inquire about adverse events.

Inquire about concomitant medications.
2. Follow-up Visit (Visit 12 – Approximately 7.5 months after the last dose of IMP 
during the pivotal efficacy study)


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Patients enrolling in this study for the purpose of evaluating ADAs and safety (adverse 
events and concomitant medications) only will attend a visit approximately 7.5 months after 
receiving the last dose of IMP (during the pivotal efficacy studies). The following 
procedures/assessments will be performed at this visit:

Inquire about adverse events.

Inquire about concomitant medications.

Obtain a 5-mL blood sample for ADA analysis.


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APPENDIX C. QUALITY CONTROL AND QUALITY ASSURANCE
Protocol Amendments and Protocol Deviations
Protocol Amendments
No changes from the final approved (signed) protocol will be initiated without the prior written 
approval or favorable opinion of a written amendment by the Independent Ethics 
Committee/Institutional Review Board (IEC/IRB) and national and local competent authorities, 
as applicable, except when necessary to address immediate safety concerns to the patients or 
when the change involves only nonsubstantial logistics or administration. The principal 
investigator at each investigational center, the coordinating investigator (if applicable), and the 
sponsor will sign the protocol amendment.
Protocol Deviations
Any deviation from the protocol that affects, to a significant degree, (a) the safety, physical, or 
mental integrity of the patients in the study and/or (b) the scientific value of the study will be 
considered an important protocol deviation. Important protocol deviations may include non-
adherence on the part of the patient, the investigator, or the sponsor to protocol-specific inclusion 
and exclusion criteria, primary objective variable criteria, or Good Clinical Practice (GCP) 
guidelines; noncompliance to investigational medicinal product administration; and use of 
prohibited medications. All protocol deviations will be reported to the responsible IEC/IRB, as 
required.
When an important protocol deviation is reported, the sponsor will determine whether to 
discontinue the patient from the study or permit the patient to continue in the study, with 
documented approval from the medical expert. The decision will be based on ensuring the safety 
of the patient and preserving the integrity of the study. A noncompliant patient may continue 
taking the study treatment only if this does not jeopardize the patient’s safety. The sponsor will 
assess each protocol deviation and decide whether any of these noncompliances should be 
reported to the Regulatory Authority as a serious breach of Good Clinical Practice (GCP) and the 
protocol.
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. A deviation from the eligibility criteria will always result in 
study drug discontinuation in case the patient has not been dosed. In case a patient who was 
wrongly enrolled has already started taking the study drug, a risk/benefit evaluation has to take 
place and a strong clinical justification must be provided in case the patient is not withdrawn 
from the study drug. 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 


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


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APPENDIX D. ETHICS
Informed Consent
The investigator, or a qualified person designated by the investigator, should fully inform the 
patient of all pertinent aspects of the study, including the written information approved by the 
Independent Ethics Committee/Institutional Review Board (IEC/IRB). All written and oral 
information about the study will be provided in a language as nontechnical as practical to be 
understood by the patient. The patient should be given ample time and opportunity to inquire 
about details of the study and to decide whether or not to participate in the study. The above 
should be detailed in the source documents.
Written informed consent will be obtained from each patient before any study-specific 
procedures or assessments are done and after the aims, methods, anticipated benefits, and
potential hazards are explained. The patient’s willingness to participate in the study will be 
documented in the informed consent form (ICF), which will be signed and personally dated by 
the patient and by the person who conducted the informed consent discussion. The investigator 
will keep the original ICFs, and copies will be given to the patient. It will also be explained to 
the patient that a patient is free to refuse participation in the study and free to withdraw from the 
study at any time without prejudice to future treatment.
Competent Authorities and Independent Ethics Committees/Institutional Review Boards
Before this study starts, the protocol will be submitted to the national competent authority and to 
the respective IEC/IRB for review. As required, the study will not start at a given investigational 
center before the IEC/IRB and the 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 confidential 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 E. WOMEN OF CHILDBEARING POTENTIAL AND BIRTH 
CONTROL METHODS
Assessment of likelihood of possible interaction between investigational medicinal products 
(IMPs) or concomitant medications and hormonal contraception should be conducted. Hormonal 
contraception may be susceptible to interaction with the IMP, which may reduce the efficacy of 
the contraception method.
Drug interaction studies have not been conducted with fremanezumab. Like other therapeutic 
antibodies, fremanezumab is expected to be primarily metabolized via proteolytic catabolism. 
Therefore, interaction with and impact on drug metabolizing enzymes (eg, cytochrome P450 
[CYP] isoforms) is considered unlikely in humans.
In addition, fremanezumab is not expected to indirectly influence the CYP enzymes. In general, 
protein products that are cytokine modulators have been reported to affect the metabolism or 
disposition of co-administered medication by altering CYP enzymes/transporters (FDA 2012). 
Fremanezumab is an 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 proinflammatory 
cytokine release in human whole blood (Study 111320). Fremanezumab did not elicit significant 
cytokine release (TNF α, IL-6, INF γ, or IL-1β) in any donor including at concentrations up to 
100 μg/mL. As such, there is no reason to suspect that fremanezumab may influence CYP 
activity.
Women of non-childbearing potential are defined as:

Surgically (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy) or 
congenitally sterile

One year postmenopausal (stable amenorrhea for 12 months without alternative 
medical cause plus high follicle-stimulating hormone (FSH) in the postmenopausal 
range) in women not using hormonal contraception or hormonal replacement therapy

Women in stable post-menopause, but are taking hormone replacement therapy for 
the treatment of menopausal symptoms, may be considered eligible for the study even 
with the lower serum FSH. They do not need to use other contraception.
Highly effective birth control methods:
Highly effective birth control methods are methods that can achieve a failure rate of less than 1% 
per year when used consistently and correctly. Such methods include:

Combined estrogen and progestogen hormonal contraception (oral, intravaginal, 
transdermal) associated with inhibition of ovulation; these should be initiated at least 
7 days before dosing of IMP.

Progestogen-only hormonal contraception (oral, injectable, implantable) associated 
with inhibition of ovulation; these should be initiated at least 7 days before dosing of 
IMP.


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
Intrauterine device and intrauterine hormone-releasing system need to be in place at 
least 2 months before screening.

Bilateral tubal occlusion 

Vasectomized partner provided that he is the sole sexual partner and has received 
medical assessment of the surgical process.

Sexual abstinence is only considered a highly effective method if defined as 
refraining from heterosexual intercourse in the defined period. The reliability of 
sexual abstinence needs to be evaluated in relation to the duration of the clinical study 
and the preferred and usual lifestyle of the patient.

Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods), 
declaration of abstinence for the duration of a study, and withdrawal are not 
acceptable methods of contraception (according to Medicines and Healthcare 
Products Regulatory Agency).
Acceptable birth control methods:
Acceptable birth control methods that result in a failure rate of more than 1% per year include: 
progestogen-only oral hormonal contraception for which the inhibition of ovulation is not the 
primary mode of action; male or female condom with or without spermicide; and cap, 
diaphragm, or sponge with spermicide. The combination of male condom with either cap, 
diaphragm, or sponge with spermicide (double barrier methods) are also considered acceptable 
but not highly effective methods of birth control.
Unacceptable birth control methods:
Periodic abstinence (calendar, symptothermal, postovulation 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 applies also to vasectomized men.
Pregnant female partners of male study participants:
Male study participants must use condoms during intercourse if their female partners are 
pregnant.


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APPENDIX F.
LOST TO FOLLOW-UP
A patient will be considered lost to follow-up if he/she repeatedly fails to return for scheduled 
visits and if the site is unable to establish contact with the patient after 3 documented attempts 
via 2 different methods (phone, text, e-mail, certified letter, etc).
The following actions must be taken if a patient fails to return to the investigational center for a 
required study visit:

The investigational center must attempt to contact the patient and reschedule the 
missed visit as soon as possible, counsel the patient on the importance of maintaining 
the assigned visit schedule, and ascertain whether or not the patient wishes to and/or 
should continue in the study.

In cases in which the patient is deemed lost to follow-up, the investigator or designee 
must make every effort to regain contact with the patient (where possible, 3 telephone 
calls and, if necessary, a certified letter to the patient’s last known mailing address or 
local equivalent methods). These contact attempts should be documented in the 
patient’s medical record.

Should the patient continue to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of ‘lost to follow-up’.


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APPENDIX G. HANDLING, LABELING, STORAGE, AND 
ACCOUNTABILITY FOR INVESTIGATIONAL 
MEDICINAL PRODUCT(S)
Preparation of Investigational Medicinal Products
Fremanezumab and placebo will be provided in prefilled syringes contained in uniquely 
numbered kits and stored (refrigerated at 2°C to 8°C) at the investigational center. At the time of
each study visit, the interactive response technology will be queried, and site personnel will 
retrieve the appropriately numbered kit(s). Kit numbers will be entered into the case report form.
Preparation instructions for subcutaneous (sc) injections: 
 
 
 A 1.5 mL volume from each syringe in each visit’s kit(s) must be injected sc for 
dosing to be considered complete. Refer to Appendix U for additional details regarding 
recommended sc injection sites.
Storage and Security
The investigator or designee must confirm appropriate temperature conditions have been 
maintained for all IMPs received and any discrepancies are reported and resolved before use of 
the IMPs.
The test IMP (fremanezumab) and placebo IMP must be stored refrigerated at 2°C to 8°C (36°F 
to 46°F) and protected from light; the investigational center should have a process for monitoring 
the IMP storage temperature.
Diversion is considered to have occurred when the legal supply chain of prescription medicinal 
products is broken, and medicinal products are transferred from a licit to an illicit channel of 
distribution or use.
Labeling
Supplies of IMPs will be labeled 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.
Accountability
Each IMP shipment will include a packing slip listing the contents of the shipment, return 
instructions, and any applicable forms.
The investigator is responsible for ensuring that deliveries of IMPs and other study materials 
from the sponsor are correctly received, recorded, handled, and stored safely and properly in 
accordance with the Code of Federal Regulations or national and local regulations, and used in 
accordance with this protocol.
Only patients enrolled in the study may receive IMPs and only authorized staff at the 
investigational center may supply or administer IMPs. All IMPs must be stored in a secure, 
environmentally-controlled, and monitored (manual or automated) area in accordance with the 


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labeled storage conditions or appropriate instructions with access limited to the investigator and 
authorized staff at the investigational center.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for IMP accountability, reconciliation, and record maintenance (ie, receipt, 
reconciliation, and final disposition records).
A record of IMP accountability (ie, IMP and other study materials received, used, retained, 
returned, or destroyed) must be prepared and signed by the principal investigator or designee, 
with an account given for any discrepancies. Empty and partially used prefilled syringes should 
be destroyed, and the investigational center should provide a certificate of destruction. If the 
investigational center does not have the capability to destroy the used and partially used prefilled 
syringes, the prefilled syringes should be sent back to the sponsor. Unused prefilled syringes of 
the IMP will be returned to the sponsor or designee.


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APPENDIX H. PREVENTIVE CLUSTER HEADACHE MEDICATIONS 
AND DISALLOWED MEDICATIONS
Disallowed Medications Commonly Prescribed for Cluster Headache
The following medications will be considered as being used for the prevention of cluster 
headache attacks regardless of the initial indication:

verapamil

lithium

methysergide

valproate

topiramate
Patients must start tapering these preventive medications as soon as they begin this study. The 
period of time needed to taper off these medications will be based on the investigator’s medical 
judgment but should not exceed 1 month from the beginning of participation in this study.
Disallowed Concomitant Medications
Systemic steroids are not allowed during the double-blind treatment period of this long-term 
extension study. 
Note that the only allowed steroids are intra-articular injection or ocular, ear drops, intranasal, 
inhaled, and creams for topical use.


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APPENDIX I.
ICHD-3 BETA DIAGNOSTIC CRITERIA
Refer to the International Classification of Headache Disorders, third edition (ICHD-3 beta) 
Diagnostic Criteria (Headache Classification Committee of the International Headache 
Society 2013) for additional details.
3.1 Cluster headache
Diagnostic criteria:
A) at least 5 attacks fulfilling criteria B-D
B) severe or very severe unilateral orbital, supraorbital and/or temporal pain lasting 15 to 
180 minutes (when untreated) 1
C) either or both of the following:
1) at least 1 of the following symptoms signs, ipsilateral to the headache:
a) conjunctival injection and/or lacrimation
b) nasal congestion and/or rhinorrhea
c) eyelid edema
d) forehead and facial sweating
e) forehead and facial flushing
f)
sensation of fullness in the ear
g) miosis and/or ptosis
2) a sense of restlessness or agitation
D) attacks have a frequency of between 1 every other day and 8 per day for more than half of the 
time when the disorder is active
E) not better accounted for by another ICHD-3 beta diagnosis
3.1.1 Episodic cluster headache
Diagnostic criteria:
A) attacks fulfilling criteria for 3.1 Cluster headache and occurring in bouts (cluster period)
B) at least 2 cluster periods lasting from 7 days to 1 year (when untreated) and separated by 
pain-free remission periods of ≥1 month
3.1.2 Chronic cluster headache
Diagnostic criteria:
A) Attacks fulfilling criteria for 3.1 Cluster headache and criterion B 
                                                
1 During part (but less than half) of the time course of 3.1 Cluster headache, attacks may be less severe and/or of 
shorter or longer duration


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B) Occurring without a remission period or with remissions lasting <1 month, for ≥1 year


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


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
the 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:

serology for hepatitis A (antibody and immunoglobulins M and G), B (core antibody 
total, core immunoglobulin M, and surface antigen), and C viruses (central 
laboratory)

serology for autoimmune hepatitis: anti-nuclear antibodies (titer), anti-smooth muscle 
antibodies, and anti-liver kidney microsomal antibodies (central laboratory); further 
testing may be required in case of a positive result for hepatitis B or C

ultrasound examination of the liver and biliary tract at the investigator’s discretion

other diagnostic tests/consultations as deemed necessary by the investigator 
(eg, serology for hepatitis E virus in case of travel to endemic geography)

observation and follow-up (to be performed after the abnormality was confirmed as 
above)
ALT or AST ≥3 × (>3.5 × the ULN if the Baseline Value is >2.5 × the ULN) but <5 × the 
ULN
In addition to the above procedures required for any elevation to levels >3 × the ULN:

Alanine aminotransferase, AST, GGT, ALP, total bilirubin, direct bilirubin, indirect 
bilirubin, CBC and differential (to assess for eosinophilia), and INR) should be 
monitored on days 5 (±2 days), 8 (±2 days), 14 (±3 days), and 28 (±3 days). On at 
least 1 of these days, the test should be performed centrally. (The INR should be sent 
to a local laboratory only.)

In cases where a local laboratory is used, the results should be recorded in the CRF, 
accompanied by the reference range of the relevant measurements.

Should the abnormality (≥3 × the ULN in case baseline was within the normal range 
or ≥2 × the ULN in case the baseline value was above ULN but still <5 × the ULN) 
persist further, the patient will be followed according to the investigator’s discretion, 
but a blood sample for ALT, AST, GGT, ALP, and total bilirubin, direct bilirubin, 
indirect bilirubin should be sent to the central laboratory at least once a month.
ALT or AST ≥5 × but <8 × the ULN
In addition to the above procedures required for any elevation to levels >3 × the ULN:

Alanine aminotransferase, AST, GGT, ALP, total bilirubin, direct bilirubin, indirect 
bilirubin, CBC and differential count (to assess for eosinophilia), and INR should be 
monitored twice a week.

At least for every other measurement, the tests should be sent to the central 
laboratory. The rest of the tests may be sent to a local laboratory. The INR should 
always be sent to a local laboratory.


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ALT or AST ≥8 × the ULN
In addition to the above procedures required for any elevation to levels >3 × the ULN:

The IMP should be discontinued immediately, and the early withdrawal visit should 
be performed.

For follow-up guidance, please see below section “Follow-Up of Liver Enzymes after 
Stopping Rules Are Met.”
Stopping Rules
In the following circumstances, the IMP will be discontinued immediately:

any increase in ALT or AST to ≥3 × the ULN, combined with INR >1.5 × the ULN 
or total bilirubin >2 × the ULN

any increase in ALT or AST to ≥3 × the ULN, which is accompanied by symptoms 
clearly associated with impaired liver function (eg, vomiting, nausea, fever, rash, and 
eosinophilia) and not deemed related to other diseases (eg, vomiting or nausea 
triggered by cluster headache)

any increase in ALT or AST to levels ≥5 but <8 × the ULN, which is persistent for 
≥2 weeks of repeated measurements

any increase in ALT or AST to levels ≥8 × the ULN

in any case where monitoring of liver enzymes cannot be performed according to the 
protocol guidance
Follow-Up of Liver Enzymes after Stopping Rules Are Met

A patient who meets the above criteria for discontinuation of the IMP should be 
invited to the investigational center to return the IMP. Early withdrawal visit 
activities should be performed as soon as possible.

Liver enzymes should be monitored until normalization or stabilization of the 
abnormality, according to the discretion of the investigator.

In any case, following the early withdrawal visit, the minimal follow-up period will 
be 30 days and will include measurement of liver enzymes at least once weekly (may 
be performed in local laboratory, with at least 1 test being sent to the central 
laboratory).

Every effort should be made to complete the additional tests/evaluations, as described 
above.


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


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APPENDIX L. TOTAL BLOOD VOLUME
Total blood volume to be collected for each patient in this study is approximately 205.5 mL for 
scheduled tests. An additional 30 mL of blood may be collected in the event of follow-up for 
liver enzymes as detailed in Appendix J.
Total Blood Volumes
Type of samples
Volume per sample
(mL)
Total number of 
samples
Total volume
(mL)
Serum chemistry 
3.5
4
14
Serum pregnancy
3.5
1
3.5
Hematology
2
4
8
Coagulation
4.5
4
18
Pharmacokinetics
4
13a
52
ADAb
5
5
25
Biomarker Serum
8.5
5
42.5
Biomarker Plasma
6
5
30
Biomarker RNA
2.5
5
12.5
Total
--
22
205.5
 
 
.
b ADA assessment will also be collected upon observation of severe hypersensitivity or anaphylaxis or if there is a 
suspected causal relationship of an adverse event potentially being related to immunogenicity (eg, lack of 
efficacy).
ADA=antidrug antibody; ECG=electrocardiogram; IMP=investigational medicinal product.
The total blood volume to be collected for each patient enrolling in this for evaluation of ADAs 
(one 5-mL blood sample) and safety (adverse events and concomitant medications) is 
approximately 5 mL.


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APPENDIX M. CLINICAL LABORATORY TESTS
Clinical Laboratory Tests
Serum Chemistry
Hematology and Coagulation
Urinalysis
Calcium
Phosphate
Sodium
Potassium
Chloride
Magnesium
Creatinine
Glucose
Blood urea nitrogen
Alanine aminotransferase 
Aspartate aminotransferase
Lactate dehydrogenase 
Gamma-glutamyl transpeptidase 
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 
Color and appearance
Protein
Glucose
Albumin
Ketones
Leukocyte esterase
Nitrite
Bilirubin
Hemoglobin
pH
Specific gravity
Microscopic tests
Bacteria
Erythrocytes
Leucocytes
Crystals
Casts


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APPENDIX N. 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, 2-mL polypropylene tubes (Sets A and B).
Labels for samples should include study number, patient randomization number, nominal 
collection time, Set A or B, and indication that they are pharmacokinetic samples. Samples will 
be stored at a temperature of –70°C to -20°C (inclusive) in an upright position until they are 
shipped to the central laboratory.
Shipment and Analysis of Samples
Serum or 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 a temperature data logger and with dry ice 
sufficient for 4 days, on a monthly basis to the central laboratory. Central laboratory will ship the 
Set A samples on a monthly basis to the bioanalytical laboratory with dry ice sufficient for 4 
days and with a temperature data logger.
Set B samples will be sent to the same laboratory as that for Set A. 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 intact.


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APPENDIX O. 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, for approximately 10 minutes, at 2 C 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, Set A or B, and indication that they are antidrug antibody (ADA) samples. 
Serum samples will be stored at a temperature of -70 ºC to -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 a temperature data logger and with dry ice 
sufficient for 4 days, on a monthly basis to the central laboratory. Central laboratory will ship the 
Set A samples on a monthly basis to the bioanalytical laboratory with dry ice sufficient for 
4 days and with a temperature data logger.
Set B samples will be sent to the same laboratory as that for Set A. 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 intact.


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APPENDIX P.
EXPLORATORY BIOMARKERS SAMPLES
 
 
 
 
 
 
Shipment and Analysis of Samples
 
 
 
 
 
 
 
 
 


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APPENDIX Q. PHARMACOGENOMIC ASSESSMENTS
 
 
 
 
 
 
 
 
 
 
.
Pharmacogenomic assessment will be performed based on study results. Samples collected 
during the pivotal efficacy studies will be used only for investigations related to headache or 
response to test IMP or related IMPs.
Details on processes for collection and shipment of these samples can be found in the procedural 
manual.


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APPENDIX R. 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 
 within 48 hours of becoming aware of the issue.
For complaints involving a device or other retrievable item, it is required that the device (or 
item) be sent back to the sponsor for investigative testing whenever possible. For complaints 
involving an IMP, all relevant samples (eg, the remainder of the patient’s IMP supply) should be 
sent back to the sponsor for investigative testing whenever possible.
1. Product Complaint Information Needed from the Investigational Center
In the event that the product complaint form cannot be completed, the investigator will provide 
the following information, as available:

investigational center number and principal investigator name

name, phone number, and address of the source of the complaint

clinical protocol number

patient identifier (patient study number) and corresponding visit numbers, if 
applicable

product name and strength for open-label studies

patient number, bottle, and kit numbers (if applicable) for double-blind or open-label 
studies

product available for return (Yes/No)

product was taken or used according to protocol (Yes/No)


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


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APPENDIX S.
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 
the equivalent, before they are transcribed to the case report form (CRF). Data may not be 
recorded directly on the CRF and considered as source data unless the sponsor provides written 
instructions specifying which data are permitted to be recorded directly to the CRF.
If data are processed from other institutions or by other means (eg, clinical laboratory, central 
image center, or electronic diary data) the results will be sent to the investigational center, where 
they will be retained but not transcribed to the CRF, unless otherwise noted in the protocol. 
These data may also be sent electronically to the sponsor (or organization performing data 
management).
The medical experts, study monitors, auditors, Independent Ethics Committee/Institutional 
Review Board (IEC/IRB), and inspectors from competent authority (or their agents) will be 
given direct access to source data and documents (eg, medical charts/records, laboratory test 
results, printouts, and 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, and site 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.


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Data Quality Control
Data Management is responsible for the accuracy, quality, completeness, and internal 
consistency of the data from this study. Oversight will be carried out as described in the 
sponsor’s standard operating procedures (SOPs) for clinical studies. Day to day data 
management tasks for this study are delegated to a contract organization, and these functions 
may be carried out as described in the SOPs for clinical studies at that organization. These SOPs 
will be reviewed by the sponsor before the start of data management activities.
Data will be verified by the study monitor using the data source, and reviewed by Data 
Management using both automated logical checks and manual review. Data identified as 
erroneous, or data that are missing, will be referred to the investigational center for resolution 
through data queries. Any necessary changes will be made in the clinical database, and data 
review and validation procedures will be repeated as needed. Data from external sources will be 
compared with the information available in the CDMS and any discrepancies will be queried.
Applicable terms will be coded according to the coding conventions for this study.
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, and 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


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The investigator will retain all records related to the study and any additional records required, as 
indicated by the protocol and according to applicable laws and regulations, until the contract 
research organization or sponsor notifies the institution in writing that records may be destroyed. 
If, after 25 years from study completion, or earlier in the case of the investigational center 
closing or going out of business, the investigator reasonably determines that study record 
retention has become unduly burdensome, and sponsor has not provided written notification of 
destruction, then the investigator may submit a written request to sponsor at least 60 days before 
any planned disposition of study records. After receipt of such request, the sponsor may make 
arrangements for appropriate archival or disposition, including requiring that the investigator 
deliver such records to the sponsor. The investigator shall notify the sponsor of any accidental 
loss or destruction of study records.


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


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APPENDIX U. NATIONAL INSTITUTES OF HEALTH PATIENT 
EDUCATION GUIDELINES OF SEPTEMBER 2015


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Uncontrolled Study–Cluster Headache
Statistical Analysis Plan
Study TV48125-CNS-30058
1
 
Statistical Analysis Plan
Study TV48125-CNS-30058
A Multicenter, Double-Blind, Double-Dummy Study to Explore the Long-Term Safety and 
Efficacy of TEV-48125 for the Prevention of Cluster Headache
Phase 3
IND number: 129606;         EudraCT number: 2016-003172-43
Approval Date: 15 July 2019
Sponsor
Teva Branded Pharmaceutical 
Products R&D, Inc.
41 Moores Road
Frazer, Pennsylvania 19355
United States
Prepared by:


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Statistical Analysis Plan
Study TV48125-CNS-30058
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STATISTICAL ANALYSIS PLAN APPROVAL


Uncontrolled Study–Cluster Headache
Statistical Analysis Plan
Study TV48125-CNS-30058
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TABLE OF CONTENTS
TITLE PAGE...................................................................................................................................1
STATISTICAL ANALYSIS PLAN APPROVAL..........................................................................2
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..................................................7
INTRODUCTION ...........................................................................................................................9
1.
STUDY ENDPOINTS................................................................................................10
1.1.
Primary Objective and Endpoints...............................................................................10
1.2.
Secondary Objective and Endpoints...........................................................................10
1.3.
Immunogenicity Objective and Endpoints .................................................................10
2.
STUDY DESIGN .......................................................................................................13
2.1.
General Design ...........................................................................................................13
2.2.
Randomization and Blinding......................................................................................16
2.3.
Data Monitoring Committee.......................................................................................16
2.4.
Sample Size and Power Considerations .....................................................................16
2.5.
Sequence of Planned Analyses ...................................................................................17
2.5.1.
Planned Interim Analyses...........................................................................................17
2.5.2.
Final Analyses and Reporting.....................................................................................17
3.
ANALYSIS SETS ......................................................................................................18
3.1.
Enrolled Patients.........................................................................................................18
3.2.
Intent-to-Treat Analysis Set........................................................................................18
3.3.
Safety Analysis Set.....................................................................................................18
3.5.
Antidrug Antibody Only Patients...............................................................................18
4.
GENERAL ISSUES FOR DATA ANALYSIS..........................................................19
4.1.
General........................................................................................................................19
4.2.
Specification of Baseline Values................................................................................19
4.3.
Handling Withdrawals and Missing Data...................................................................19
4.4.
Study Days and Visits.................................................................................................19
5.
STUDY POPULATION.............................................................................................21


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5.1.
General........................................................................................................................21
5.2.
Patient Disposition......................................................................................................21
5.3.
Demographics and Baseline Characteristics...............................................................21
5.4.
Medical History ..........................................................................................................22
5.5.
Prior Therapy and Medication....................................................................................22
5.6.
Childbearing Potential and Methods of Contraception ..............................................23
5.7.
Physical Examinations................................................................................................23
5.8.
Study Protocol Deviations..........................................................................................23
 
 
 
 
 
7.
MULTIPLE COMPARISONS AND MULTIPLICITY ............................................30
8.
SAFETY ANALYSIS ................................................................................................31
8.1.
General........................................................................................................................31


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8.2.
Duration of Exposure to Study Drug..........................................................................31
8.3.
Adverse Events ...........................................................................................................31
8.4.
Injection Site Assessments .........................................................................................32
8.5.
Hypersensitivity/Anaphylaxis.....................................................................................32
8.6.
Electronic Columbia Suicide Severity Rating Scale ..................................................33
8.7.
Deaths .........................................................................................................................33
8.8.
Clinical Laboratory Tests ...........................................................................................33
8.8.1.
Laboratory Values Meeting Hy’s Law Criteria..........................................................35
8.9.
Physical Examinations................................................................................................35
8.10.
Vital Signs ..................................................................................................................35
8.11.
Electrocardiography....................................................................................................36
8.12.
Concomitant Medications or Therapies......................................................................36
9.
TOLERABILITY VARIABLES AND ANALYSIS..................................................37
10.
PHARMACOKINETIC ANALYSIS.........................................................................38
11.
PHARMACOGENOMIC ANALYSIS ......................................................................39
12.
BIOMARKER ANALYSIS........................................................................................40
13.
IMMUNOGENICITY ANALYSIS............................................................................41
14.
ANCILLARY STUDY ANALYSIS – WEARABLE SENSOR SUBSTUDY .........42
15.
PLANNED INTERIM ANALYSIS ...........................................................................43
16.
STATISTICAL SOFTWARE ....................................................................................44
17.
CHANGES TO ANALYSES SPECIFIED IN THE STUDY PROTOCOL..............45
18.
REFERENCES ...........................................................................................................46
APPENDIX A.
E-DIARY QUESTIONNAIRE..........................................................................47
APPENDIX B.
LOGICS FOR CLUSTER HEADACHE DERIVATION.................................50
APPENDIX C.
EUROQOL-5 DIMENSION QUESTIONNAIRE (EQ-5D).............................51
APPENDIX D.
HOSPITAL ANXIETY AND DEPRESSION SCALE (HADS)......................53
APPENDIX E.
12-ITEM SHORT-FORM HEALTH SURVEY (SF-12) ..................................55
APPENDIX F.
IMPACT ON PARTNER AND FAMILY QUESTIONNAIRE -
PATIENTS .................................................................................................................57
APPENDIX G.
IMPACT ON PARTNER AND FAMILY QUESTIONNAIRE -
PARTNERS................................................................................................................59
APPENDIX H.
WORK PRODUCTIVITY AND ACTIVITY IMPAIRMENT 
QUESTIONNAIRE: GENERAL HEALTH V2.0(WPAI:GH)..................................61


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LIST OF TABLES
Table 1:
Summary of Treatments .............................................................................................13
Table 2:
Study Visits for Treated Patients................................................................................19
Table 3:
Study Visits and Assessments for Patients Enrolled in the Study for 
Evaluation of Antidrug Antibodies and Safety (Adverse Events and 
Concomitant Medications) Only.................................................................................20
Table 4:
Criteria for Potentially Clinically Significant Laboratory Values..............................34
Table 5:
Criteria for Potentially Clinically Significant Vital Signs..........................................35
LIST OF FIGURES
Figure 1:
Overall Study Schematic Diagram .............................................................................15


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation
Term
ADA
antidrug antibodies
β-HCG
beta-human chorionic gonadotropin
CCH
chronic cluster headache 
CH
cluster headache 
CNS
central nervous system
CRF
case report form
CV
coefficient of variation
e-diary 
electronic diary
ECG
electrocardiogram/electrocardiography
ECH
episodic cluster headache
eC-SSRS
electronic Columbia Suicide Severity Rating Scale
EOT
end of treatment
EQ-5D
EuroQol-5 Dimension
GCRP
genetic polymorphisms within the calcitonin gene-related peptide
HADS
Hospital Anxiety and Depression Scale
IMP
investigational medicinal product
IRT
interactive response technology
ITT
intent-to-treat
iv
intravenous(ly)
MCS
Mental Health Composite Scores
MedDRA
Medical Dictionary for Regulatory Activities
NSAID
non-steroidal anti-inflammatory drug
PCS
Physical Composite Scores
PGIC
Global Impression of Change
PPSI
Patient-Perceived Satisfactory Improvement
R&D
Research and Development
SAP
statistical analysis plan
sc
subcutaneous(ly)
SD
standard deviation
SE
standard error
SF-12
12-Item Short-Form Health Survey


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Abbreviation
Term
SI
standard international
SOC
system organ class
SOP
standard operating procedure
ULN
upper limit of normal
WHO Drug
World Health Organization Drug Dictionary
WPAI
Work Productivity and Activity Impairment


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INTRODUCTION
This statistical analysis plan (SAP) describes the planned analysis and reporting for Teva 
Branded Pharmaceutical Products R&D, Inc. Study TV48125-CNS-30058, (a multicenter, 
double-blind, double-dummy study to explore the long-term safety and efficacy of TEV-48125 
for the prevention of cluster headache), 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. 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.


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1.
STUDY ENDPOINTS
1.1.
Primary Objective and Endpoints
The primary objective of this study is to evaluate the long-term safety of fremanezumab in adult 
patients with cluster headache (CH).
Safety endpoints are as follows:

occurrence of adverse events throughout the study 

changes from baseline (day 0 of the Phase 3 pivotal efficacy studies) in clinical 
laboratory (serum chemistry, hematology, coagulation, and urinalysis) test results

changes from baseline (day 0 of the Phase 3 pivotal efficacy studies) in vital signs 
(pulse, systolic and diastolic blood pressure, and oral temperature) measurements
Note: Oxygen saturation will be measured in cases of suspected anaphylaxis and 
severe hypersensitivity. Respiratory rate will also be measured in these cases but not 
as a standard vital sign.

abnormal standard 12-lead electrocardiogram (ECG) findings

clinically significant changes in physical examination, including body weight

occurrence of injection site reactions (ie, erythema, induration, and ecchymosis) 
and/or injection site pain

occurrence of anaphylaxis and hypersensitivity reactions

use of concomitant medications during the study

suicidal ideation and behavior as measured by the electronic Columbia Suicide 
Severity Rating Scale (eC-SSRS)
1.2.
Secondary Objective and Endpoints
There are no secondary objectives and secondary endpoints in this study.
1.3.
Immunogenicity Objective and Endpoints
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).
1.4.
Exploratory Efficacy Endpoints
Exploratory efficacy endpoints are:
 


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2.
STUDY DESIGN
2.1.
General Design
This is a 68-week extension study to evaluate the long-term safety and efficacy of fremanezumab 
in adult patients with CH. During the course of any CH attack, patients will be allowed to use 
acute medications to treat acute headaches, as needed.
Upon completion of the final study assessments, early withdrawal from the study, or 
discontinuation for any reason, patients will be offered the opportunity to enter a 32-week 
long-term safety study (as described in the study protocol of TV48125-CNS-30058) for safety 
and ADA evaluation without additional dosing. Patients who satisfactorily complete the study 
may be offered to enroll the long-term safety study TV48125-CNC-30058 for 68 weeks (as 
described in the study protocol) to receive additional dosing and a final follow-up visit for safety 
and ADA evaluation. In any case, during the period of the long-term safety study, where patients 
are not receiving additional dosing (and are waiting for ADA evaluation), these patients should 
be treated with standard of care as appropriate. 
It was planned that 360 eligible patients with ECH and CCH rolling over from the pivotal studies 
(Studies TV48125-CNS-30056 and TV48125-CNS-30057, respectively) will receive 
fremanezumab during this study, 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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The end of study is defined as the date the last patient attends the follow-up visit.
The study duration will be for approximately 42 months from Q1/2017 to Q2/2020. Note, the 
study is completed Q2/2019 due to early terminations of pivotal Studies TV48125-CNS-30056 
and TV48125-CNS-30057.
The study schematic diagram for patients enrolling in this study for the purpose of evaluating the 
long-term safety and efficacy of fremanezumab is presented in Figure 1. 
Study procedures and assessments with their timing are summarized in Table 4 of the study 
protocol (patients enrolling in this study from the pivotal efficacy studies) and Table 5 of the 
study protocol (patients rolling over from the pivotal efficacy studies for evaluation of ADAs, 
adverse events, and concomitant medications only).


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Figure 1:
Overall Study Schematic Diagram


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a The run-in period for patients with ECH lasted at least 7 days (+3 days), and the run-in period for patients with 
CCH lasted at least 28 days (+3 days).
b Screening will occur at visit 1 of the Phase 3 pivotal efficacy studies.
c Visit 1 of this study corresponds to the EOT visit (visit 5) of the pivotal efficacy studies. The EOT visit 
procedures/assessments for the pivotal efficacy study must be completed before beginning visit 1 
procedures/assessments. EOT visit procedures/assessments will not be repeated at visit 1 of this study. The EOT 
visit procedures/assessments are detailed in the protocols for Studies TV48125-CNS-30056 and TV48125-CNS-
30057.
CCH=chronic cluster headache; ECH=episodic cluster headache; EOT=end-of-treatment; iv=intravenous; 
pts=patients; sc= subcutaneous; V=visit; W=week.
Note: Up to 600 patients from the Phase 3 pivotal efficacy studies (Studies TV48125-CNS-30056 and TV48125-
CNS-30057) are expected to enroll in this study.
 
 
 
 
 
 
2.2.
Randomization and Blinding
This is a double-blind study; blinding will be retained from the pivotal studies and throughout 
this long-term safety extension study. Patients will be assigned to treatments as described in 
Table 1 and Section 5.1.1.1 of the study protocol based on their randomization in the pivotal 
studies (Studies TV48125-CNS-30056 and TV48125-CNS-30057).
2.3.
Data Monitoring Committee
Not applicable.
2.4.
Sample Size and Power Considerations
There are no statistical considerations for the sample size. Up to 600 patients from the Phase 3 
pivotal efficacy studies (Studies TV48125-CNS-30056 and TV48125-CNS-30057) are expected 
to enroll in this study.
 
 
 
 


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2.5.
Sequence of Planned Analyses
2.5.1.
Planned Interim Analyses
Not applicable.
2.5.2.
Final Analyses and Reporting
All analyses identified in this SAP will be performed after the final database lock for study 
completion. The study will be unblinded after the pivotal studies (TV48125-30056 and 
TV48125-30057) are completed and unblinded.


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3.
ANALYSIS SETS
3.1.
Enrolled Patients
The enrolled patients will include all patients who are enrolled in the study for any reason.
3.2.
Intent-to-Treat Analysis Set
The intent-to-treat (ITT) analysis set will include all patients who are enrolled in this study for 
additional fremanezumab treatment and long-term safety evaluation, regardless if they receive 
study treatment or not.
This analysis set does not include patients who are enrolled in this study for the evaluation of 
ADA and safety only. 
3.3.
Safety Analysis Set
The safety analysis set will include all patients who receive any dose of IMP. 
 
 


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4.
GENERAL ISSUES FOR DATA ANALYSIS
4.1.
General
Descriptive statistics for continuous variables include count (n), mean, standard deviation (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
Baseline values will be the baseline values from the pivotal studies for both safety 
 
analyses. 
4.3.
 
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 for patients who are enrolled the study for full study assessments are in Table 2.
Study procedures and assessments are detailed in the Table 4 of the study protocol.
Table 2:
Study Visits for Treated Patients
Double-blind treatment period
Follow-up period
Visit #
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12 
Week
0
4
8 
12 
16 
20 
24 
28 
32 
36 
40
EOT/early 
withdrawal
68 
Notes: Visit 1 of the current study corresponds with the EOT visit (visit 5) of the pivotal efficacy studies. The EOT 
visit procedures/assessments are detailed in the protocols for Studies TV48125-CNS-30056 and 
TV48125-CNS-30057. EOT=end of treatment.
Study visits and assessments for patients who are enrolled in the study for the purpose of 
evaluating ADAs and safety only are detailed in Table 3.


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Table 3:
Study Visits and Assessments for Patients Enrolled in the Study for 
Evaluation of Antidrug Antibodies and Safety (Adverse Events and 
Concomitant Medications) Only
Procedures and assessments
Enrollment 
visit
Follow-up visit
Visit 1
a
Visit 12
Day 0
Approximately 7.5 months (approximately 5 half-lives of 
the IMP) after the last dose of the IMP during the pivotal 
efficacy study
Informed consent
X
Adverse events
b
X
X
Concomitant medication inquiry
X
X
Blood sample for ADA analysis
X
a Visit 1 of the current study corresponds with the EOT visit/early withdrawal visit of the pivotal efficacy studies. 
EOT visit procedures/assessments must be completed before the patient begins participation in this study. The 
EOT visit procedures/assessments are detailed in the protocols for Studies TV48125-CNS-30056 and TV48125-
CNS-30057. 
b Patients will return for unscheduled visits in the event of any safety concern.
ADA=antidrug antibody; EOT=end-of-treatment; IMP=investigational medicinal product. 
‘Last Assessment’ may be derived for analysis purpose and is defined as the last observed 
postbaseline data. For patients who withdraw from the study, their data at the early withdrawal
visit will be excluded from the by-visit sections but will be included in the Last Assessment 
section.
Study days are numbered relative to the first day of the IMP administration in this study. The 
start of treatment (day 1) is defined as the date on which a patient takes the first dose of the IMP 
in this study, 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 first day of the IMP administration 
and day –1 being the day before the first day of the IMP administration).


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5.
STUDY POPULATION
5.1.
General
The ITT analysis set (see Section 3.2) will be used for all study population summaries unless 
otherwise specified. Summaries will be presented by treatment groups and overall. Treatment 
groups are

Fremanezumab at 225 mg sc monthly (approximately every 4 weeks) through 
week 36
Note: for patients in 900 mg iv loading dose group from both Study TV48125-CNS-
30056 and TV48125-CNS-30057 and patients in 675-mg sc loading dose group from 
Study TV48125-CNS-30057

Fremanezumab at 675 mg sc quarterly (approximately every 12 weeks) through 
week 36
Note: for patients in 675 mg sc and placebo group from Study TV48125-CNS-30056

Fremanezumab 675-mg sc loading dose followed by monthly (approximately 
every 4 weeks) fremanezumab at 225 mg sc through week 36
Note: for patients in placebo group from Study TV48125-CNS-30057
In addition, summaries will be presented by indication (Episodic CH [patients from TV48125-
CNS-30056] and Chronic CH [patients from TV48125-CNS-30057]) and the treatment groups.
5.2.
Patient Disposition
Data from patients screened; patients screened but not enrolled and reason for not enrolled; 
patients who are enrolled; patients enrolled for ADA only; patients in ITT analysis set (enrolled 
for treatment), patients in ITT analysis set but not treated; patients in the safety and other 
analysis sets; patients who complete the treatment; patients who did not complete the treatment 
and reason; patients who complete the study; patients who withdraw from the study early and the
reason will be summarized using descriptive statistics.
 
.
The summary will be presented for all patients.
5.3.
Demographics and Baseline Characteristics
Patient’s demographics and baseline characteristics data including age, age group (<40 years or 
≥40 years), gender, race, race group (white or other), ethnicity, region (US/Canada or other), 
baseline weight (kg), baseline height (cm), baseline body mass index (kg/m2), and preventive 
medication use (yes or no) at screening will be summarized using descriptive statistics for all 
analysis sets.
Baseline weight, baseline height, and baseline body mass index are the same baseline values in 
the pivotal studies, the last observed data before the administration of the first dose of the IMP in 
the pivotal study.


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Data for ADA only patients will also be presented separately.
5.4.
Medical History
Medical history refers to data collected in the pivotal studies.
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.
Data for ADA only patients will also be presented separately.
5.5.
Prior Therapy and Medication
Prior medications will include all medications taken prior to the administration of the first dose 
of the IMP in the pivotal studies. 
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. 
The prior medications will be summarized by the following indications categories: 

preventive medication from Appendix H of the study protocol for CH

preventive medication from Appendix H of the study protocol for other reason than 
CH

butalbital for CH

butalbital for other reason than CH

triptans for CH

triptans for other reason than CH

ergots for CH

ergots for other reason than CH

non-steroidal anti-inflammatory drugs (NSAIDs) for CH

NSAIDs for other reason than CH

opioids for CH

opioids for other reason than CH

other
Data for ADA only patients will also be presented separately.


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5.6.
Childbearing Potential and Methods of Contraception
Information related to reproductive system findings will be collected at visit 1. 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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6.4.1.
 
 
 
 
6.4.2.
 
 
 
 
6.4.3.
 
6.4.4.
 
 
 
 
 
 
 
.
6.4.4.1.
 
 
 
 


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6.4.4.2.
 
 
 
 
 
 
 
 
 
 
 
 


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7.
MULTIPLE COMPARISONS AND MULTIPLICITY
No inferential analysis will be performed in this study.


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8.
SAFETY ANALYSIS
8.1.
General
The safety analysis set will be used for all safety analyses unless otherwise specified. Summaries 
will be presented by treatment groups as actually received and overall. In addition, summaries 
will be presented by indication (Episodic CH [patients from TV48125-CNS-30056] and Chronic 
CH [patients from TV48125-CNS-30057]) and the treatment groups.
8.2.
Duration of Exposure to Study Drug 
Study IMP will be administrated visit 1 through visit 10 with three treatment groups as follows:

Fremanezumab at 225 mg sc monthly (approximately every 4 weeks) through 
week 36
Note: for patients in 900 mg iv loading dose group from Study TV48125-CNS-30056 
or TV48125-CNS-30057 and patients in 675-mg sc loading dose group from Study 
TV48125-CNS-30057

Fremanezumab at 675 mg sc quarterly (approximately every 12 weeks) through 
week 36
Note: for patients in 675 mg sc and placebo group from Study TV48125-CNS-30056

Fremanezumab 675-mg sc loading dose followed by monthly (approximately 
every 4 weeks) fremanezumab at 225 mg sc through week 36
Note: for patients in placebo group from Study TV48125-CNS-30057
There are total 10 dosing visits (see Figure 1). Patients will receive either injection(s) of test IMP 
or injection(s) of placebo IMP at each visit. 
Duration of treatment (days) and number of doses (≥1 dose, ≥2 doses, ≥3 doses, . . ., 10 dose) 
will be summarized using descriptive statistics. 
 
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 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 (aspartate aminotransferase or alanine aminotransferase ≥3 × the upper limit of 


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normal [ULN], total bilirubin ≥2 × the ULN, or international normalized ratio >1.5), Hy’s Law 
events, or events of anaphylaxis and severe hypersensitivity reactions.
All adverse events will be coded using MedDRA (version 18.1). 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 
and by severity), serious adverse events, 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 and protocol-defined adverse events of special 
interest will be presented (overall and by severity).
Listings for deaths, serious adverse events, adverse events leading to discontinuation, injection 
site adverse events, and protocol-defined adverse events of special interest 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.
Adverse event (overall) will also be presented for ADA only patients.
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 visits 1 through 10. The injection sites will be assessed for 
erythema, induration, and ecchymosis. More details are in Section 7.11 of the study protocol.
Injection-site reactions should be recorded as adverse events. Injection-site related adverse 
events will be summarized as indicated in Section 8.3.
8.5.
Hypersensitivity/Anaphylaxis 
Patients will be assessed for suspected anaphylaxis reaction during and after administration of 
the IMP (through 1 hour postdose) at visits 1 through 10. Data will be summarized using 
descriptive statistics.
The number of patients with suspected anaphylaxis reactions and number of suspected 
anaphylaxis 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.


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Data will be listed.
8.6.
Electronic Columbia Suicide Severity Rating Scale
The eC-SSRS Since Last Visit version will be completed by the patient at visits 2 through 12, 
including unscheduled visits. Any positive findings on the eC-SSRS ‘Since Last Visit’ version 
requires 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 M) will be performed at visits 4, 7, 10 and 11 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 and Last Assessment will be 
summarized using descriptive statistics. Shifts (below [low], within [normal], and above [high] 
the normal range) from baseline to each postbaseline visit and the Last Assessment will be 
summarized using patient counts. Baseline is defined as the last observed data before the 
administration of the first dose of the IMP in the pivotal study.
The potentially clinically significant abnormal values will be derived using criteria specified in 
Table 4 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.


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Table 4:
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
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
Serum beta-human chorionic gonadotropin (β-HCG) tests will be performed for all women of 
childbearing potential at visit 11. Urine β-HCG tests will be performed for women of 
childbearing potential at visits 1 through 10. Positive pregnancy test results will be listed.
Currently menstruating (yes, no, n/a) information will be collected from each female patient 
prior to blood and urine collection for clinical laboratory tests. Data will be listed.


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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 2, 4, 5, 7, 8, 10, 11, and 12. 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 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 
at each (visit 2 through 12). Weight will be measured at visits 2, 4, 5, 7, 8, 10, 11, and 12. 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 and the Last 
Assessment 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 in the pivotal study.
Table 5 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.
Table 5:
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


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8.11.
Electrocardiography
Triplicate 12-lead ECGs will be collected at visits 4, 7, 10 and 11. 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 the 3 measurements at a visit will be 
calculated. The mean results and mean changes from baseline to each visit and Last Assessment 
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 in the pivotal study.
For ECG findings, the worst value of recorded 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 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 collected up to the end of 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.
Concomitant medications for patients who are enrolled in this study for the evaluation of ADA 
only will be listed.


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9.
TOLERABILITY VARIABLES AND ANALYSIS
Tolerability was not specifically defined for this study.


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10.
PHARMACOKINETIC ANALYSIS
There are no prespecified pharmacokinetic endpoints.
Summary of plasma concentration of the study drug will be based on the safety population and 
will be presented by visit for each of the indication (CCH or ECH) and active treatment groups
(and the treatment received in 056 and 057 studies). The plasma concentration will be listed by
indication, active treatments, scheduled visits, and time points.


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11.
PHARMACOGENOMIC ANALYSIS
Pharmacogenomic analysis results will be summarized for each gene tested. An attempt will be 
made to correlate clinical observations (pharmacokinetics, safety, efficacy, or other effects) with 
the genotypes observed. Additional pharmacogenomic analysis may be conducted at a later time 
and will be reported in a separate addendum report.
This analysis is not included in this SAP.


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12.
BIOMARKER ANALYSIS
Biomarker analysis will include logistic regression, receiver operating characteristic curves, and 
summary statistics. This analysis will be reported separately. Measurements will be made using 
validated assays.
This analysis is not included in this SAP.


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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, IMP efficacy, 
and clinical safety will be evaluated. This ADA impact analysis will be reported separately.
This analysis is not included in this SAP.


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14.
 
 
 
 
 


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15.
PLANNED INTERIM ANALYSIS
Not applicable.


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


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


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18.
REFERENCES
 
U.S.A.


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APPENDIX A.
 
 
 
 
 
 
 
 
 
 


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APPENDIX B.
 
 
 
 
 


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APPENDIX C.
 
 
 
 
 





Self-Care
 
 
 
 
 





        
 
 
 
 
 





 
 
 
 
 





 
 
 







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APPENDIX D.
 
D
A
Question/Response 
D
A
Question/Response
2
 


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D
A
Question/Response 
D
A
Question/Response
1
Scoring:


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APPENDIX E.
Scale
Label
Item#
Question
Response
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5=None of the time
 
 
 


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Scale
Label
Item#
Question
Response
 
 
 
 


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APPENDIX F.
 
Question (baseline visit)
Response
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Question (baseline visit)
Response
 
 


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APPENDIX G.
 
Question (at baseline visit)
Response
 
 
 
 
 
 
 
 
 
 
 
 


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Question (at baseline visit)
Response
 


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APPENDIX H.
 
 
 
 
 
 
 
 
  
 
 
 
 
 
.
 
 
 
 
 
 
 
 
 
 
 


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