Clinical trial NCT02945046
Conditions: Episodic Cluster Headache
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc.
Start date: 2017-01-19; Completion date: 2019-05-13
Enrollment: 169 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a 13-week, multicenter, randomized, double-blind, double-dummy, placebo-controlled, parallel-group study to compare the efficacy and safety of 2 dose regimens of TEV-48125 (Fremanezumab) versus placebo in adult participants for the prevention of ECH.

Detailed description:

Arms: arm 1: Participants will receive placebo administered via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injection at Weeks 4 and 8, respectively. arm 2: Participants will receive placebo as an approximately 1-hour intravenous infusion followed by fremanezumab at 675 milligrams (mg) administered as 3 subcutaneous injections (225 mg/1.5 milliliters \[mL\]) at Week 0 and placebo administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively. arm 3: Participants will receive fremanezumab at 900 mg administered via an approximately 1-hour intravenous infusion followed by 3 placebo subcutaneous injections at Week 0 and fremanezumab at 225 mg administered as single subcutaneous injection (225 mg/1.5 mL) at Weeks 4 and 8, respectively.
Interventions: intervention 1: Fremanezumab intervention 2: Placebo
Intervention descriptions: intervention 1: Fremanezumab will be administered per dose and schedule specified in the arm. intervention 2: Placebo matching to fremanezumab will be administered per schedule specified in the arm.

Protocol documents:
Prot_000.pdf: 
 
 
 
Clinical Study Protocol 
 
 
A Multicenter, Randomized, Double-Blind, Double-Dummy, Placebo-
Controlled, Parallel-Group Study Comparing the Efficacy and Safety of 2 
Dose Regimens (Intravenous/Subcutaneous and Subcutaneous) of TEV-48125 
versus Placebo for the Prevention of Episodic Cluster Headache 
 
Study Number TV48125-CNS-30056 
 
 
NCT02945046 
 
 
Protocol with Amendment 02 Approval Date: 01 May 2017 


Placebo-Controlled Study–Episodic Cluster Headache
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Clinical Study Protocol with Amendment 02
Study Number TV48125-CNS-30056
A Multicenter, Randomized, Double-Blind, Double-Dummy, Placebo-Controlled, 
Parallel-Group Study Comparing the Efficacy and Safety of 2 Dose Regimens 
(Intravenous/Subcutaneous and Subcutaneous) of TEV-48125 versus Placebo for the 
Prevention of Episodic Cluster Headache
Efficacy and Safety Study (Phase 3)
IND number: 129606
EudraCT number: 2016-003278-42
EMA Decision Number of Pediatric Investigation Plan: Not Applicable
Article 45 or 46 of 1901/2006 does not apply
Protocol with Amendment 02 Approval Date: 01 May 2017
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.
© 2017 Teva Branded Pharmaceutical Products R&D, Inc. All rights reserved.


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AMENDMENT HISTORY
The protocol for Study TV48125-CNS-30056 (original protocol dated 08 August 2016) has been 
amended and reissued as follows:
Amendment 02
01 May 2017
6 patients randomized/enrolled to date
Amendment 01
30 November 2016
No patients randomized/enrolled to date
Letter of Clarification 04
04 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.


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INVESTIGATOR AGREEMENT


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COORDINATING INVESTIGATOR AGREEMENT
Clinical Study Protocol with Amendment 02
Original Protocol Dated 08 August 2016
IND number: 129606;
EudraCT number: 2016-003278-42
EMA Decision Number of Pediatric Investigation Plan: Not Applicable
Article 45 or 46 of 1901/2006 does not apply
A Multicenter, Randomized, Double-Blind, Double-Dummy, Placebo-Controlled, 
Parallel-Group Study Comparing the Efficacy and Safety of 2 Dose Regimens 
(Intravenous/Subcutaneous and Subcutaneous) of TEV-48125 versus Placebo for the 
Prevention of Episodic Cluster Headache 
Coordinating Investigator: 
Title: ________________________________________________
Address of Investigational Center: __________________________________
__________________________________
__________________________________
Tel: ______________
I have read the protocol with Amendment 02 and agree that it contains all necessary details for 
carrying out this study. I am qualified by education, experience, and training to conduct this 
clinical research study. The signature below constitutes 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 are 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
Signature
Date


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CLINICAL STUDY PROTOCOL SYNOPSIS
with Amendment 02
Study TV48125-CNS-30056
Title of Study: A Multicenter, Randomized, Double-Blind, Double-Dummy, 
Placebo-Controlled, Parallel-Group Study Comparing the Efficacy and Safety of 2 Dose 
Regimens (Intravenous/Subcutaneous and Subcutaneous) of TEV-48125 versus Placebo for the 
Prevention of Episodic Cluster Headache 
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc.
Investigational New Drug (IND) Number: 129606
EudraCT Number: 2016-003278-42
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: Efficacy and Safety Study (Phase 3)
Indication: Episodic cluster headache (ECH)
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: Q4/2016 (first patient in) to Q2/2018 (last patient last visit)
Number of Patients Planned (total): Approximately 300 patients (approximately 100 patients 
per treatment group) are planned to be enrolled in this study to have approximately 
258 completers (approximately 86 completers per treatment group); a 14% drop-out rate is 
anticipated.
Study Population: The study population will be composed of male and female patients, 18 to 
70 years of age, inclusive, with a history of ECH (as defined by International Classification of 
Headache Disorders, third revision beta [ICHD 3-Beta] criteria [Headache Classification 
Committee of the International Headache Society (IHS) 2013]) for ≥12 months prior to 
screening.


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Primary and Secondary Objectives and Endpoints
The primary and secondary study objectives and endpoints are as follows:
Objectives
Endpoints
The primary objective of this
study is to demonstrate the 
efficacy of fremanezumab in
the prevention of ECH in adult 
patients.
The primary efficacy endpoint of this study is the mean change 
from baseline (run-in period) in the weekly average number of 
cluster headache (CH) attacks during the 4-week period after 
administration of the first dose of the IMP, ie, based on week 0 
to 4 data.
A secondary objective of this
study is to further demonstrate 
the efficacy of fremanezumab
in the prevention of ECH in 
adult patients.
The secondary efficacy endpoints to further demonstrate 
efficacy are:
the proportion of patients with a ≥50% reduction from 
baseline (run-in period) in the weekly average number 
of CH attacks during the 4-week period after the first 
dose of the IMP, ie, based on week 0 to 4 data
the mean change from baseline (run-in period) in the 
number of CH attacks during the 12-week period after 
administration of the first dose of the IMP, ie, based on 
week 0 to 12 data
the mean change from baseline (run-in period) in the 
number of CH attacks during the 4-week period after 
administration of the third dose of the IMP, ie, based on 
week 8 to 12 data
the mean change from baseline (run-in period) in the 
weekly average number of days with use of cluster-
specific acute headache medications (triptans and ergot 
compounds) during the 12-week period after 
administration of the first dose of the IMP, ie, based on 
week 0 to 12 data
the mean change from baseline (run-in period) in the 
weekly average number of days oxygen is used to treat 
ECH during the 12-week period after administration of 
the first dose of the IMP, ie, based on week 0 to 12 data
assessment of patient’s perceived improvement, as 
measured by the Patient-Perceived Satisfactory 
Improvement (PPSI) at 1, 4, 8, and 12 weeks after 
administration of the first dose of the IMP relative to 
baseline (day 0)


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Objectives
Endpoints
A secondary objective of this
study is to evaluate the safety 
of fremanezumab in adult 
patients with ECH. 
The secondary safety endpoints are as follows:
occurrence of adverse events throughout the study
clinical laboratory (serum chemistry, hematology, 
coagulation, and urinalysis) test results at each visit
vital signs (systolic and diastolic blood pressure, oral 
temperature, and pulse rate) measurements at each visit. 
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.
12-lead electrocardiogram (ECG) findings at screening, 
baseline, and week 12
use of concomitant medication during the study
clinically significant changes in physical examinations, 
including body weight 
injection site reaction (ie, erythema, induration, and 
ecchymosis) and injection site pain assessments 
occurrence of hypersensitivity/anaphylaxis reactions
suicidal ideation and behavior as measured by the 
electronic Columbia Suicide Severity Rating Scale (eC-
SSRS)
Immunogenicity Assessment Objectives and Endpoints:
The immunogenicity objective is the following:

to evaluate the immunogenicity of fremanezumab and the impact of antidrug 
antibodies (ADAs) on clinical outcomes in patients exposed to intravenous (iv) and 
subcutaneous (sc) fremanezumab
The immunogenicity endpoints are the following:

ADA incidence and characteristics (eg, titer, kinetics, and neutralizing activities)
Exploratory Objectives and Endpoints
The exploratory objectives are as follows:

 


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
 
 
 
The exploratory endpoints are as follows:

 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 


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
 
 
 
 
Wearable sensor substudy exploratory objectives are the following:

 
 
 
 
 
 
 
 
Wearable sensor substudy exploratory endpoints are the following:

 
 
 
 


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
 
 
 
 
 
 
 
 
 
 
 
General Design:
This is a 13-week, multicenter, randomized, double-blind, double-dummy, placebo-controlled, 
parallel-group study to compare the efficacy and safety of 2 dose regimens of fremanezumab
versus placebo in adult patients for the prevention of ECH. The study will consist of a screening 
visit, a run-in period lasting at least 1 week (+3 days), and a 12-week double-blind treatment 
period. During the course of any CH attack, patients will be allowed to use acute medications to 
treat acute headaches, as needed (PRN).
Patients will complete a screening visit (visit 1) after providing written informed consent, and 
eligible patients will enter a run-in period lasting at least 1 week (+3 days) during which they 
will enter baseline CH attack information into an electronic diary device daily. Patients will 
return to the study center after completing the run-in period (visit 2 [week 0]). Patients who had 
at least 7 CH attacks during the run-in period and who continue to meet eligibility criteria 
(including entry of CH attack information in an electronic diary demonstrating compliance for 
85% of days during the run-in period) will be randomly assigned at visit 2 (week 0) in a 
1:1:1 ratio to 1 of 3 treatment groups as follows:

fremanezumab 900-mg iv loading dose group: fremanezumab at 900 mg administered 
via an approximately 1-hour iv infusion at visit 2 (week 0) followed by 
fremanezumab at 225 mg administered as single sc injections (225 mg/1.5 mL) at 
visits 3 and 4 (weeks 4 and 8, respectively)

fremanezumab 675-mg sc quarterly group: fremanezumab at 675 mg administered as 
3 sc injections (225 mg/1.5 mL) at visit 2 (week 0) followed by placebo administered 
as single sc injections at visits 3 and 4 (weeks 4 and 8, respectively)


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
placebo group: placebo administered via an approximately 1-hour iv infusion and as 
3 sc injections at visit 2 (week 0) followed by placebo administered as single sc 
injections at visits 3 and 4 (weeks 4 and 8, respectively)
In order to maintain blinding throughout the study, the number of infusions and injections at each 
visit will be the same for all patients regardless of the treatment group to which they are 
randomized. Thus, all patients will receive an iv infusion of test IMP or placebo IMP followed 
by 3 sc injections of test IMP or placebo IMP at visit 2 (week 0), and all patients will receive 
single sc injections of test IMP or placebo IMP at visits 3 and 4 (weeks 4 and 8, respectively).
Patients will also return for an end of treatment (EOT) visit, approximately 4 weeks after the 
administration of the last dose of IMP, in order to evaluate ADAs, fremanezumab concentrations, 
biomarkers, and safety assessments.
CH attack information will be captured daily during the double-blind treatment period using an 
electronic diary device. Assessments of change in quality of life 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 PPSI 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 prespecified time points. 
Wearable Sensor Substudy: A subset of patients in selected investigational sites will be offered 
the opportunity to participate in a substudy
 
 
Brief Summary of Study Design for the Trial Registry(s): This is a 13-week study to evaluate 
the efficacy and safety of 2 dose regimens of fremanezumab versus placebo in adult patients for 
the prevention of ECH. Patients who provide written informed consent and complete a screening 
visit (visit 1) will enter a run-in period lasting at least 1 week (+3 days) during which they will 
enter baseline CH attack information into an electronic diary device daily. Patients will return to 
the study center after completing the run-in period (visit 2 [week 0]), and patients who continue 
to meet eligibility requirements will be randomized to receive test IMP (fremanezumab 900-mg 
iv or 675-mg sc followed by fremanezumab or placebo 225 mg sc monthly) or placebo IMP 
(placebo iv and sc followed by single placebo doses sc monthly). An EOT visit will occur 
approximately 4 weeks after the administration of the last dose of IMP to evaluate ADAs, 
fremanezumab concentrations, biomarkers, and safety.
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. The 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 reaction/pain 
assessments, assessments for anaphylaxis and hypersensitivity, and administration of the eC-
SSRS. In addition, blood will be collected for pharmacokinetic, immunogenicity, biomarker, and 
pharmacogenomic (unless not allowed per local regulation) analyses, and urine will be collected 
for biomarker analysis.


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Method of Randomization and Blinding: Randomization will be performed using electronic 
interactive response technology (IRT). Patients will be randomly assigned with stratification 
based on gender, country, and baseline concomitant preventive medications (yes/no) to the 
fremanezumab 900-mg iv loading dose group, the fremanezumab 675-mg sc quarterly group, or 
the placebo group in a 1:1:1 ratio. The sponsor, investigators, study staff (except for staff 
involved in bioanalytical analyses and interim analyses [by a third-party, unblinded statistician]), 
and patients will be blinded to treatment assignment throughout the study.
The IRT will manage initial drug supply, maintenance of adequate IMP supplies on site, and 
study randomization centrally. 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. 
The randomization code will be generated by the IRT third-party vendor, following 
specifications from the Biostatistics Department. A Teva statistician will be responsible for 
reviewing the dummy randomization codes, and the final randomization code will be maintained 
by the third-party vendor in a secure location.
At the time of analysis (after the end of the study), after receiving an unblinding request from the 
Teva statistician, the service provider will provide the unblinded IMP assignments according to 
the processes defined in the relevant Standard Operating Procedure.
Investigational Medicinal Products: Dose, Pharmaceutical Form, Route of Administration, 
and Administration Rate
IMPs are defined as the test IMP and placebo IMP (Table 1).
Table 1:
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
900 mg iv loading dose followed by 
225 mg sc monthly
or
675 mg sc loading dose
n/a
Route of Administration
Fremanezumab will be administered 
as iv infusions and sc injections by 
qualified study personnel at the 
investigational center.
Placebo will be administered as iv 
infusions and sc injections by 
qualified study personnel at the 
study center.


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IMP Name
Test IMP
Placebo IMP
Packaging
Fremanezumab will be provided in 
prefilled syringes contained in 
uniquely numbered kits and stored 
(refrigerated at 2°C to 8°C) on site. 
Prefilled syringes 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) on site. 
Prefilled syringes 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; iv=intravenous; n/a=not applicable; sc=subcutaneous.
The fremanezumab doses, regimens, and routes of administration to be evaluated in this 
double-blind, double-dummy, placebo-controlled study were selected on the basis of 3 key 
factors. First, simulations suggest that maximum observed concentration (Cmax) is the most 
significant pharmacokinetic parameter in the efficacy of fremanezumab (in migraine). As CH is 
considered one of the most severe forms of pain a person can experience, treatments that provide 
quick and lasting relief (ie, for the duration of the cluster period) are a priority for this patient 
population. Second, the biological nature of the disease mandates the need for any treatment to 
desensitize the third order neuron, not the second (as is the case in migraine), suggesting that 
high levels of blockade at the first neuron would be necessary. Third, the favorable safety profile 
of the drug as well as clinical and nonclinical safety data on exposure suggest that the proposed 
doses, regimens, and routes of administration will not present any safety concerns.
In the current study, high doses are planned for the first dose (900 mg iv or 675 mg sc) in order 
to provide a rapid response, especially following iv infusion where higher peak plasma Cmax
generally occur at or shortly after the end of infusion compared with 5 to 7 days postdose for sc 
injections. The 2 forms of loading dose will provide data to confirm the benefit of either the iv or 
sc as loading dose. Monthly doses of fremanezumab at 225 mg sc were added to the initial dose 
of 900 mg iv for maintenance of efficacy. Based on modelling, the inclusion of a loading dose 
should allow patients to reach steady state faster. The dose of 675 mg sc quarterly in this ECH 
population will allow for the evaluation of a single treatment dose taking into account the periods 
of remission seen with this CH form.
A placebo-controlled design is appropriate given the purpose and objectives of this clinical 
study. Inclusion of a placebo-control group is consistent with the IHS guidelines for controlled 
trials of drugs in CH, first edition (Lipton et al 1995).
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: Patient participation will 
last for approximately 13 weeks (including a run-in period lasting at least 1 week (+3 days) and a 
12-week double-blind treatment period). 
Study Duration: 21 months from Q4/2016 to Q2/2018


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End of Study: End of study is defined as the date the last patient attends the EOT/early 
withdrawal visit.
Plans for Treatment or Care after the Patient Has Ended Participation in the Study: 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-CNC-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 either 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. A separate protocol was issued for the long-term safety study.
Inclusion Criteria: Patients may be included in the study only if they meet all of the following 
criteria: 
a.
Patients are capable of giving signed informed consent as described in Appendix D which 
includes compliance with the requirements and restrictions listed in the informed consent 
form and in this protocol.
b. The patient is a man or woman 18 to 70 years of age, inclusive.
c.
The patient has a history of ECH according to ICHD-3 beta criteria (Headache 
Classification Committee of the IHS 2013) for ≥12 months prior to screening including 
the following:

Attacks of severe, strictly unilateral pain which is orbital, supraorbital, temporal or in 
any combination of these sites, lasting 15 to 180 minutes and occurring from once 
daily every other day to 8 times a day for more than half of the time when the 
disorder is active.

The pain is associated with at least 1 of the following symptoms or signs: ipsilateral 
conjunctival injection, lacrimation, nasal congestion, rhinorrhea, forehead and facial 
sweating, miosis and/or ptosis and/or eyelid edema, and/or sense of restlessness or 
agitation.

CH attacks occurring in periods lasting from 7 days to 1 year, separated by pain-free 
periods lasting at least 1 month.
d. CH attacks of a new cluster cycle have started within ≤2 weeks (14 days, inclusive) prior 
to screening and, based on the patient’s previous medical history, it is expected that the 
patient’s CH attacks will continue for ≥6 weeks after the screening visit.
e.
The patient has a total body weight of ≥45 kg.
f.
The patient is not using or using ≤2 concomitant medications that are commonly 
prescribed as preventive treatments for CH (Appendix H), regardless of the indication for 
which the medication was prescribed. Patients must be on a stable dose and regimen for 
at least 2 weeks prior to screening and throughout the study.
g. If a patient is receiving Botox, it should be in a stable dose regimen, considered as having 
≥2 cycles of Botox prior to screening. The patient should not receive Botox during the 


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run-in period up to the evaluation period (4 weeks) where the primary endpoint is 
evaluated.
h. The patient has demonstrated compliance with the electronic headache diary during the 
run-in period by entry of headache data on 85% of days during the run-in period.
i.
The patient has at least 7 CH attacks during the run-in period.
j.
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. 
k. Women may be included only if they have a negative serum beta-human chorionic 
gonadotropin test at screening, are sterile or postmenopausal, and are not lactating. 
Definitions of sterile and postmenopausal are given in Appendix E.
l.
Women of childbearing potential (WOCBP) whose male partners are potentially fertile
(ie, no vasectomy) must use highly effective birth control methods (see Appendix E) for 
the duration of the study (ie, starting at screening) and for 7.5 months after 
discontinuation of IMP.
m. 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 
discontinuation of the IMP. Definitions of women of non-childbearing potential, sterile
women, and postmenopausal women; male contraception; and highly effective and 
acceptable birth control methods including examples are given in Appendix E.
n. The patient must be willing and able to comply with study restrictions, to remain at the 
clinic for the required duration during the study period and to return to the clinic for 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 used systemic steroids for any medical reason (including treatment of the
current CH cycle) within ≤7 days prior to screening.
b. The patient reports using butalbital on more than 7 days during the 4 weeks prior to 
screening or using butalbital on more than 3 days during the screening/run-in period.
c.
The patient reports using opioids on more than 15 days during the 4 weeks prior to 
screening or using opioids on more than 4 days during the screening/run-in period.
d. The patient has used an intervention/device (eg, scheduled nerve blocks) for headache 
during the 4 weeks prior to screening.
e.
The patient has clinically significant hematological, renal, endocrine, immunologic, 
pulmonary, gastrointestinal, genitourinary, cardiovascular, neurologic, hepatic, or ocular 
disease at the discretion of the investigator.
f.
The patient has evidence or medical history of clinically significant psychiatric issues 
determined at the discretion of the investigator.


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g. The patient has a history of any suicide attempt in the past or current active suicidal 
ideation, as measured by the eC-SSRS.
h. The patient has a history of clinically significant cardiovascular disease or vascular 
ischemia (such as myocardial, neurological [eg, cerebral ischemia], peripheral extremity 
ischemia, or other ischemic event) or thromboembolic events (arterial or venous 
thrombotic or embolic events), such as cerebrovascular accident (including transient 
ischemic attacks), deep vein thrombosis, or pulmonary embolism.
i.
The patient has a past or current history of cancer or malignant tumor in the past 5 years, 
except for appropriately treated non-melanoma skin carcinoma. 
j.
The patient is pregnant or lactating.
k. The patient has a history of hypersensitivity reactions to injected proteins, including 
monoclonal antibodies.
l.
The patient has participated in a clinical study of a new chemical entity or a prescription 
medicine within 2 months or 5 half-lives before administration of the first dose of the 
IMP, whichever is longer.
m. The patient has participated in a clinical study of a monoclonal antibody within 3 months 
or 5 half-lives before administration of the first dose of the IMP, whichever is longer, 
unless it is known that the patient received placebo during the study.
n. The patient has a history of prior exposure to a monoclonal antibody targeting the CGRP 
pathway (AMG 334, ALD304, LY2951742, or fremanezumab). If patient has participated 
in a clinical study with any of these monoclonal antibodies, it has to be confirmed that the 
patient received placebo in order to be eligible for this study.
o. The patient has any finding in the baseline 12-lead ECG considered clinically significant 
in the judgment of the investigator.
p. The patient has 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).
q. The patient has hepatic enzymes (alanine aminotransferase and aspartate 
aminotransferase) >1.5 × the upper limit of normal (ULN) range after confirmation in a 
repeat test, or the patient has suspected hepatocellular damage that fulfills criteria for 
Hy’s law at screening.
r.
The patient has serum creatinine >1.5 × the ULN or evidence of clinically significant 
renal disease in the judgement of the investigator.
s.
The patient cannot participate or successfully complete the study, in the opinion of their 
healthcare provider or the investigator, for any of the following reasons:

mentally or legally incapacitated or unable to give consent for any reason

in custody due to an administrative or a legal decision, under tutelage, or being
admitted to a sanitarium or social institution

unable to be contacted in case of emergency


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
has any other condition, which, in the opinion of the investigator, makes the patient 
inappropriate for inclusion in the study
t.
The patient is an employee of the sponsor/participating study center who is directly 
involved in the study or is the relative of such an employee.
u. The patient has an active implant for neurostimulation used in the treatment of CH.
v. The patient is a member of a vulnerable population (eg, people kept in detention).
w. The patient has a history of alcohol and/or drug abuse that in the investigator’s opinion 
could interfere with the study evaluations or the patient’s safety.
Statistical Considerations:
 
 
 
 
Analysis of Primary Endpoint: The primary efficacy endpoint for this study will be derived 
from CH attack data (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) collected daily using an 
electronic headache diary device. 
For the purpose of this study, a CH attack will be endorsed when the following situations occur: 
1. Severe or very severe unilateral orbital, supraorbital, and/or temporal pain lasting 15 to 
180 minutes
2. Either or both of the following:

at least 1 of the following symptoms or signs, ipsilateral to the headache:

conjunctival injection and/or lacrimation

nasal congestion and/or rhinorrhea

eyelid edema

forehead and facial sweating

forehead and facial flushing

sensation of fullness in the ear

miosis and/or ptosis

a sense of restlessness or agitation
Analysis of Secondary Endpoints: Secondary efficacy endpoints will be derived from CH 
attack data (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) collected daily using an electronic 
headache diary device. In addition, oxygen and acute treatment use will be derived from the 
concomitant medications inquiries and patient perception of improvement will be evaluated at 
time points specified in Table 2 using the PPSI.


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Primary Efficacy Analysis: The primary efficacy endpoint, the mean change from baseline 
(run-in period) in the weekly average number of CH attacks during the 4-week period after 
administration of the first dose of the IMP, will be analyzed using an analysis of covariance 
(ANCOVA). The model will include treatment, baseline number of CH attacks, baseline 
preventive medication use (yes or no), gender, and region (US or other).
Sensitivity Analysis: A sensitivity analysis will be conducted to explore the impact of missing 
data in the primary efficacy analysis. Details will be provided in the statistical analysis plan.
Secondary and Exploratory Efficacy Analysis: The continuous secondary efficacy endpoints 
will be analyzed using an ANCOVA method or a mixed model for repeated measures. For the 
proportion of responders, defined as 50% or more reduction from baseline in the weekly average 
number of CH attacks, data will be analyzed using a Cochran-Mantel-Haenszel test stratified by 
baseline preventive medication use (yes/no).
Multiple Comparisons and Multiplicity: Hochberg’s step-up method will be implemented to 
test primary and secondary endpoints while controlling the overall type 1 error rate at 0.05.
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. 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 the test IMP.
Changes in laboratory, ECG, and vital signs measurements data will be summarized 
descriptively. All values will be compared with prespecified 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.
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: Pharmacokinetics plasma concentration results (fremanezumab) 
will be tabulated descriptively at each planned sampling time point by treatment group.


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In addition, the most appropriate population pharmacokinetics 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
Pharmacokinetics/Pharmacodynamics Analysis: The pharmacokinetics/pharmacodynamics
relationship may be estimated by compartmental techniques. The pharmacokinetics parameters 
will be based on fremanezumab measurements. The pharmacodynamics parameters will be the 
efficacy 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 relationship 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 
pharmacokinetics profile, IMP efficacy, and clinical safety will be evaluated. This ADA-impact 
analysis will be reported separately.
Exploratory Biomarker Analysis: Biomarker analysis will include logistic regression, receiver 
operating characteristic curves, and summary statistics. Analysis will be reported separately. 
Measurements will be made using validated assays.
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 Studies 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: An interim analysis for futility will be performed once 50% of 
patients (the first 150 patients) have completed 4-week assessments during the double-blind 
study period or have withdrawn from the study early. An independent statistician from a third 
party will perform the analysis.


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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........................................................................................................27
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...................................................................................34
1.2.2.2.
Clinical Safety and Efficacy Studies ..........................................................................35
1.3.
Known and Potential Benefits and Risks to Patients..................................................36
1.3.1.
Known and Potential Benefits and Risks of the Test Investigational 
Medicinal Product(s) ..................................................................................................36
1.3.2.
Overall Benefit and Risk Assessment for This Study ................................................37
2.
STUDY OBJECTIVES AND ENDPOINTS..............................................................38
2.1.
Primary and Secondary Study Objectives and Endpoints ..........................................38
2.1.1.
Justification of Primary Endpoint...............................................................................39
2.2.
Exploratory Objectives and Endpoints.......................................................................40
2.2.1.
Exploratory Objectives and Endpoints.......................................................................40
2.2.2.
Wearable Sensor Substudy Exploratory Objectives and Endpoints...........................41
3.
STUDY DESIGN .......................................................................................................43
3.1.
General Design and Study Schematic Diagram..........................................................43
3.2.
Planned Number of Patients and Countries................................................................46
3.3.
Justification for Study Design and Selection of Population.......................................46
3.4.
Stopping Rules for the Study......................................................................................46


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3.5.
Schedule of Study Procedures and Assessments........................................................47
4.
SELECTION AND WITHDRAWAL OF PATIENTS..............................................53
4.1.
Patient Inclusion Criteria ............................................................................................53
4.2.
Patient Exclusion Criteria...........................................................................................54
4.3.
Withdrawal Criteria and Procedures...........................................................................56
4.4.
Replacement of Patients .............................................................................................57
4.5.
Rescreening.................................................................................................................57
4.6.
Screening Failure........................................................................................................57
5.
TREATMENTS..........................................................................................................58
5.1.
Investigational Medicinal Products Used in the Study...............................................58
5.1.1.
Test Investigational Medicinal Product......................................................................59
5.1.1.1.
Starting Dose and Dose Levels...................................................................................59
5.1.2.
Placebo Investigational Medicinal Product ................................................................59
5.2.
Preparation, Handling, Labeling, Storage, and Accountability for 
Investigational Medicinal Products ............................................................................59
5.3.
Justification for Investigational Medicinal Products..................................................59
5.3.1.
Justification for Dose of Test Investigational Medicinal Product ..............................59
5.3.2.
Justification for Use of Placebo Investigational Medicinal Product ..........................60
5.4.
Treatment after the End of the Study..........................................................................60
5.5.
Restrictions .................................................................................................................60
5.5.1.
Activity .......................................................................................................................60
5.5.2.
Blood Donation...........................................................................................................60
5.5.3.
Pregnancy ...................................................................................................................61
5.6.
Prior and Concomitant Medication or Therapy..........................................................61
5.7.
Procedures for Monitoring Patient Compliance .........................................................61
5.8.
Randomization and Blinding......................................................................................61
5.9.
Maintenance of Randomization and Blinding............................................................62
5.9.1.
Maintenance of Randomization..................................................................................62
5.9.2.
Blinding and Unblinding ............................................................................................62
5.9.3.
Data Monitoring Committee.......................................................................................63
5.10.
Total Blood Volume ...................................................................................................63
6.
ASSESSMENT OF EFFICACY ................................................................................64
6.1.
Electronic Diary Device .............................................................................................64


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6.2.
Hospital Anxiety and Depression Scale .....................................................................64
6.3.
EuroQol-5 Dimension Questionnaire .........................................................................65
6.4.
Twelve-Item Short-Form Health Survey....................................................................65
6.5.
Work Productivity and Activity Impairment Questionnaire ......................................65
6.6.
Impact on Partner and Family Questionnaire .............................................................65
6.7.
Patient-Perceived Satisfactory Improvement .............................................................66
6.8.
Patient Global Impression of Change Scale ...............................................................66
7.
ASSESSMENT OF SAFETY.....................................................................................67
7.1.
Adverse Events ...........................................................................................................67
7.1.1.
Definition of an Adverse Event..................................................................................67
7.1.2.
Recording and Reporting of Adverse Events .............................................................68
7.1.3.
Severity of an Adverse Event .....................................................................................68
7.1.4.
Relationship of an Adverse Event to the Test Investigational Medicinal 
Product........................................................................................................................69
7.1.5.
Serious Adverse Events..............................................................................................69
7.1.5.1.
Definition of a Serious Adverse Event .......................................................................70
7.1.5.2.
Expectedness...............................................................................................................71
7.1.5.3.
Reporting a Serious Adverse Event............................................................................71
7.1.6.
Protocol-Defined Adverse Events not for Expedited Reporting ................................73
7.1.7.
Protocol-Defined Adverse Events of Special Interest ................................................73
7.1.8.
Protocol Deviations Because of an Adverse Event ....................................................73
7.2.
Pregnancy ...................................................................................................................73
7.3.
Medication Error and Special Situations Related to the Investigational 
Medicinal Products.....................................................................................................74
7.4.
Clinical Laboratory Tests ...........................................................................................75
7.4.1.
Serum Chemistry, Hematology, and Urinalysis .........................................................75
7.4.1.1.
Human Chorionic Gonadotropin Tests.......................................................................75
7.4.1.2.
Follicle-Stimulating Hormone Tests...........................................................................76
7.5.
Physical Examinations................................................................................................76
7.6.
Vital Signs ..................................................................................................................76
7.7.
Electrocardiography....................................................................................................76
7.8.
Immunogenicity..........................................................................................................77
7.9.
Assessment of Suicidality...........................................................................................77


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7.10.
Concomitant Therapy or Medication..........................................................................78
7.11.
Injection Site Assessments .........................................................................................78
8.
ASSESSMENT OF PHARMACOKINETICS/BIOMARKERS/ 
PHARMACOGENOMICS/IMMUNOGENICITY/ANCILLARY STUDIES..........80
8.1.
Pharmacokinetics Assessment....................................................................................80
8.2.
Pharmacodynamics Assessment.................................................................................80
8.3.
Immunogenicity Testing.............................................................................................80
8.4.
Assessment of Exploratory Biomarkers .....................................................................80
8.5.
Pharmacogenomics.....................................................................................................81
8.6.
Ancillary Studies – Wearable Sensor Substudy .........................................................81
9.
STATISTICS ..............................................................................................................83
9.1.
Sample Size and Power Considerations .....................................................................83
9.2.
Analysis Sets...............................................................................................................83
9.2.1.
Intent-to-Treat Analysis Set........................................................................................83
9.2.2.
Safety Analysis Set.....................................................................................................83
9.2.3.
Full Analysis Set.........................................................................................................83
9.2.4.
Per-Protocol Analysis Set...........................................................................................83
9.3.
Data Handling Conventions........................................................................................83
9.3.1.
Handling Withdrawals and Missing Data...................................................................84
9.4.
Study Population.........................................................................................................84
9.4.1.
Patient Disposition......................................................................................................84
9.4.2.
Demographic and Baseline Characteristics ................................................................84
9.5.
Efficacy Analysis........................................................................................................84
9.5.1.
Primary Endpoint........................................................................................................85
9.5.2.
Secondary Endpoints ..................................................................................................85
9.5.3.
Exploratory Endpoints................................................................................................85
9.5.4.
Planned Method of Analysis.......................................................................................87
9.5.4.1.
Primary Efficacy Analysis..........................................................................................87
9.5.4.2.
Sensitivity Analysis ....................................................................................................88
9.5.4.3.
Secondary and Exploratory Efficacy Analysis...........................................................88
9.6.
Multiple Comparisons and Multiplicity......................................................................88
9.7.
Safety Analysis ...........................................................................................................88
9.8.
Tolerability Analysis ..................................................................................................89


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9.9.
Pharmacokinetics Analysis.........................................................................................89
9.10.
Pharmacokinetics/Pharmacodynamics Analysis ........................................................89
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 ..........................................................90
10.
QUALITY CONTROL AND QUALITY ASSURANCE .........................................91
11.
COMPLIANCE STATEMENT..................................................................................92
12.
DATA MANAGEMENT AND RECORD KEEPING ..............................................93
13.
FINANCING AND INSURANCE.............................................................................94
14.
PUBLICATION POLICY ..........................................................................................95
15.
REFERENCES ...........................................................................................................96
16.
SUMMARY OF CHANGES TO THE PROTOCOL ................................................98
16.1.
Amendment 02 Dated 01 May 2017...........................................................................98
16.2.
Amendment 01 Dated 30 November 2016 ...............................................................118
16.3.
Letter of Clarification 04 Dated 04 December 2016 ................................................138
APPENDIX A.
CLINICAL LABORATORIES AND OTHER DEPARTMENTS AND 
INSTITUTIONS.......................................................................................................141
APPENDIX B.
STUDY PROCEDURES AND ASSESSMENTS BY VISIT.........................144
APPENDIX C.
QUALITY CONTROL AND QUALITY ASSURANCE ..............................150
APPENDIX D.
ETHICS ...........................................................................................................152
APPENDIX E.
WOMEN OF CHILDBEARING POTENTIAL AND BIRTH 
CONTROL METHODS ...........................................................................................153
APPENDIX F.
LOST TO FOLLOW-UP .................................................................................155
APPENDIX G.
HANDLING, LABELING, STORAGE, AND ACCOUNTABILITY 
FOR INVESTIGATIONAL MEDICINAL PRODUCT(S) .....................................156
APPENDIX H.
PREVENTIVE CLUSTER HEADACHE MEDICATIONS AND 
DISALLOWED MEDICATIONS............................................................................158
APPENDIX I.
ICHD 3-BETA DIAGNOSTIC CRITERIA .....................................................159
APPENDIX J.
GUIDANCE ON SAFETY MONITORING....................................................160
APPENDIX K.
CLINICAL CRITERIA FOR DIAGNOSING ANAPHYLAXIS...................163
APPENDIX L.
TOTAL BLOOD VOLUME............................................................................164


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APPENDIX M.
CLINICAL LABORATORY TESTS.............................................................165
APPENDIX N.
PHARMACOKINETICS SAMPLES .............................................................166
APPENDIX O.
IMMUNOGENICITY SAMPLES ..................................................................167
APPENDIX P.
EXPLORATORY BIOMARKERS SAMPLES ..............................................168
APPENDIX Q.
PHARMACOGENOMIC ASSESSMENTS...................................................169
APPENDIX R.
PRODUCT COMPLAINTS ............................................................................170
APPENDIX S.
DATA MANAGEMENT AND RECORD KEEPING....................................172
APPENDIX T.
PUBLICATION POLICY................................................................................175
APPENDIX U.
NATIONAL INSTITUTES OF HEALTH PATIENT EDUCATION 
GUIDELINES OF SEPTEMBER 2015 ...................................................................176


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LIST OF TABLES
Table 1:
Investigational Medicinal Products Used in the Study...............................................12
Table 2:
Study Procedures and Assessments............................................................................48
Table 3:
Investigational Medicinal Products Used in the Study...............................................58
Table 4:
The Relationship of an Adverse Event to the Test Investigational Medicinal 
Product........................................................................................................................69
Table 5:
Severity of Pain Scale for Injection Site Assessments ...............................................78
LIST OF FIGURES
Figure 1:
Overall Study Schematic Diagram .............................................................................45


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LIST OF ABBREVIATIONS
Abbreviation
Term
β-HCG
beta-human chorionic gonadotropin
λz
apparent plasma terminal elimination rate constant
ADA
antidrug antibody
ADL
activities of daily living
ALT
alanine aminotransferase (SGPT)
ALP
alkaline phosphatase
ANCOVA
analysis of covariance
ANOVA
analysis of variance
AST
aspartate aminotransferase (SGOT)
ATC
Anatomical Therapeutic Chemical
AUC
area under the plasma concentration-time curve
AUC0-t
area under the plasma concentration-time curve from time 0 to the time of the last 
measurable IMP concentration
AUC0-∞
area under the plasma concentration-time curve from time 0 to infinity
BLA
Biological License Application
BMI
body mass index
BP
blood pressure
CCH
chronic cluster headache
CDMS
clinical data management system
CFR
Code of Federal Regulations (USA)
CGI-C
Clinical Global Impression of Change
CGRP
calcitonin gene-related peptide
CH
cluster headache
CIOMS
Council for International Organizations of Medical Sciences
CL/F
apparent total plasma clearance
CM
chronic migraine
Cmax
maximum observed concentration
CONSORT
Consolidated Standards of Reporting Trials
CRF
case report form (refers to any media used to collect study data [ie, paper or 
electronic])


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Abbreviation
Term
CRO
contract research organization
CSR
clinical study report
CTA
Clinical Trial Application
CTFG
Clinical Trial Facilitation Group
CTIMP
Clinical Trial of an Investigational Medicinal Product
DEA
Drug Enforcement Administration
DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid
DSMB
Data and Safety Monitoring Board
EC
Ethics Committee
ECG
Electrocardiogram
ECH
episodic cluster headache
eC-SSRS
electronic Columbia Suicide Severity Rating Scale
EFD
embryo/fetal developmental toxicity
EM
episodic migraine
EMA
European Medicines Agency
EOT
end of treatment (visit)
EQ-5D
EuroQol-5 Dimension
ERA
European Regulatory Affairs
EU
European Union
EudraCT
European Clinical Trials
EV
EudraVigilance 
FDA
Food and Drug Administration
FEV1
forced expiratory volume in 1 second
GCP
Good Clinical Practice
GCO
Global Clinical Operations
GLP
Good Laboratory Practice
GQA
Global Quality Assurance
GRA
Global Regulatory Affairs
HBsAg
hepatitis B surface antigen
IB
Investigator’s Brochure
ICF
informed consent form


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Abbreviation
Term
ICH
The International Council for Harmonisation
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
IHS
International Headache Society
IMP
investigational medicinal product
IND
Investigational New Drug
INN
international nonproprietary name
IRB
Institutional Review Board
IRT
interactive response technology
ITT
intent-to-treat
LSO
local safety officer
MAA
Marketing Authorisation Application
mAb
monoclonal antibody
mITT
modified intent to treat
MTD
maximum tolerated dose
n
Number
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NDA
New Drug Application
NIMP
Non-Investigational Medicinal Products
OTC
over-the-counter
PEF
peak expiratory flow
PGIC
Patients’ Global Impression of Change
PP
per-protocol
PPSI
Patient-Perceived Satisfactory Improvement
PPM-BDA
Personalized & Predictive Medicine and Big Data Analytics
PRN
as needed
RA
Regulatory Affairs
RNA
ribonucleic acid
RSI
reference safety information
RTSM
Randomization and Trial Supply Management
sc
subcutaneous(ly)
SD
standard deviation


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Abbreviation
Term
SF-12
12-Item Short-Form Health Survey
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
SmPC
Summary of Product Characteristics
SOP
Standard Operating Procedure
SpO2
saturation of peripheral oxygen
SUSAR
suspected unexpected serious adverse reaction
t½
elimination half-life
tmax
time to maximum observed concentration
TMF
trial master file
TSH
thyroid stimulating hormone
ULN
upper limit of normal
US
United States (of America)
USA
United States of America
V
Visit
Vz/F
apparent total volume of distribution during the terminal phase
W
Week
WHO
The World Health Organization
WHO Drug
World Health Organization Drug Dictionary
WOCBP
women of childbearing potential
WPAI
Work Productivity and Activity Impairment
XML
Extensible Markup Language


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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 efficacy and safety of fremanezumab,
administered via the intravenous (iv) and/or subcutaneous (sc) routes, in the prevention of ECH 
in adult patients.


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1.2.
Findings from Nonclinical and Clinical Studies
Brief summaries of nonclinical pharmacology, pharmacokinetics, and toxicology studies and 
clinical studies are provided in the following sections. More detailed information is provided in 
the Investigator’s Brochure (IB).
1.2.1.
Nonclinical Studies
Fremanezumab was evaluated in nonclinical pharmacology, pharmacokinetics, and toxicology 
studies. Pivotal studies were conducted under Good Laboratory Practice (GLP).
In in-vitro studies, fremanezumab demonstrated no potential for Fcγ receptor binding, cytokine 
release, or hemolysis, up to tested concentrations of 25.5 mg/mL. The concentrations tested in 
these in vitro assays are relevant to the predicted range of concentrations for administration in 
human subjects. Fremanezumab prevents in vitro cyclic adenosine monophosphate production 
induced by CGRP while not binding to similar peptides such as amylin, calcitonin, or 
adrenomedullin. In vivo pharmacology studies of fremanezumab in animal models indicate that 
fremanezumab prevented an increase in blood flow in rat paw skin and the middle meningeal 
artery after electrical stimulation and produced a dose-dependent inhibition of the 
capsaicin-induced skin flare response in cynomolgus monkey.
Safety pharmacology studies to evaluate potential cardiovascular effect were performed. The 
data suggest no treatment-related findings after single and repeated administration up to 
6 months via once weekly administration at high dose levels (up to 300 mg/kg/week).
Fremanezumab was tested in a series of nonclinical in vivo studies in Sprague Dawley rats and 
cynomolgus monkeys. Fremanezumab was administered to rats and monkeys by the iv or sc 
route for up to 3 months in duration and by sc route in the 6-month chronic toxicity study in 
monkeys, and no toxicological concerns were identified following chronic dosing to 
experimental animals at dose levels up to 300 mg/kg/week. 
 
 
 
 
 
 
 
 
 
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.


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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.
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 
(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
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


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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 using the current validated 
bioanalytical method, and the pharmacokinetic results are described below. 
The pharmacokinetics (non-compartmental analysis) of fremanezumab demonstrated an increase 
in Cmax and 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- 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. 


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No clinically relevant changes in clinical laboratory values, vital signs measurements, or 
electrocardiogram (ECG) findings have been observed in any of the studies to date. 
1.3.
Known and Potential Benefits and Risks to Patients
Information regarding the risks and benefits of fremanezumab in patients is summarized in the 
following sections. Additional information regarding benefits and risks to patients may be found 
in the IB.
1.3.1.
Known and Potential Benefits and Risks of the Test Investigational Medicinal 
Product(s)
Results from Phase 2b clinical studies have demonstrated statistically significant reductions in 
mean headache hours after 1, 2, and 3 months of sc fremanezumab treatment in patients with 
chronic migraine and statistically significant reductions in monthly migraine days after 1, 2, and 
3 months of fremanezumab treatment in patients with episodic migraine. Results for several 
secondary/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 bruising, injection site swelling, administration site pain, injection site pain, injection site 
pruritus, injection site dermatitis, injection site rash, injection site edema, injection site 
discomfort, injection site hemorrhage, injection site irritation, injection site mass, and injection 
site hematoma, have occurred with sc administration. In addition, reports of mild and transient 
infusion site pain and swelling following iv administration have occurred. Among these events, 
the following have been identified as adverse drug reactions (identified risks): injection site 
erythema, administration site pain, injection site pain, injection site pruritus, and injection site 
dermatitis. None of these identified risks are considered important risks.
Infusion-related reaction and drug hypersensitivity were also identified as adverse drug reactions. 
To date, 1 subject who received fremanezumab iv had a non-serious infusion-related reaction, 
and 1 patient who received fremanezumab via the sc route had a non-serious event of drug 
hypersensitivity. Both events resolved following IMP discontinuation and treatment with 
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. 


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1.3.2.
Overall Benefit and Risk Assessment for This Study
In summary, the benefit and risk assessment for fremanezumab is favorable following review of 
the outlined data.


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2.
STUDY OBJECTIVES AND ENDPOINTS
2.1.
Primary and Secondary Study Objectives and Endpoints
The primary and secondary study objectives and endpoints are as follows:
Objectives
Endpoints
The primary objective of this 
study is to demonstrate the efficacy 
of fremanezumab in the prevention 
of episodic cluster headache (ECH) 
in adult patients. 
The primary efficacy endpoint of this study is the mean change 
from baseline (run-in period) in the weekly average number of 
cluster headache (CH) attacks during the 4-week period after 
administration of the first dose of the investigational medicinal 
product (IMP), ie, based on week 0 to 4 data.
A secondary objective of this 
study is to further demonstrate the 
efficacy of fremanezumab in the 
prevention of ECH in adult patients.
The secondary efficacy endpoints to further demonstrate 
efficacy are:
the proportion of patients with a ≥50% reduction from 
baseline (run-in period) in the weekly average number 
of CH attacks during the 4-week period after the first 
dose of the IMP, ie, based on week 0 to 4 data
the mean change from baseline (run-in period) in the 
number of CH attacks during the 12-week period after 
administration of the first dose of the IMP, ie, based on 
week 0 to 12 data
the mean change from baseline (run-in period) in the 
number of CH attacks during the 4-week period after 
administration of the third dose of the IMP, ie, based on 
week 8 to 12 data
the mean change from baseline (run-in period) in the 
weekly average number of days with use of cluster-
specific acute headache medications (triptans and ergot 
compounds) during the 12-week period after 
administration of the first dose of the IMP, ie, based on 
week 0 to 12 data
the mean change from baseline (run-in period) in the 
weekly average number of days oxygen is used to treat 
ECH during the 12-week period after administration of 
the first dose of the IMP, ie, based on week 0 to 12 data
assessment of patient’s perceived improvement, as 
measured by the Patient-Perceived Satisfactory 
Improvement (PPSI) at 1, 4, 8, and 12 weeks after 
administration of the first dose of the IMP relative to 


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Objectives
Endpoints
baseline (day 0)
A secondary objective of this 
study is to evaluate the safety of 
fremanezumab in adult patients 
with ECH. 
The secondary safety endpoints are as follows:
occurrence of adverse events throughout the study
clinical laboratory (serum chemistry, hematology, 
coagulation, and urinalysis) test results at each visit
vital signs (systolic and diastolic blood pressure, oral 
temperature, and pulse rate) measurements at each visit. 
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.
12-lead electrocardiogram (ECG) findings at screening, 
baseline, and week 12
use of concomitant medication during the study
clinically significant changes in physical examinations, 
including body weight 
injection site reaction (ie, erythema, induration, and 
ecchymosis) and injection site pain assessments 
occurrence of hypersensitivity/anaphylaxis reactions
suicidal ideation and behavior as measured by the 
electronic Columbia Suicide Severity Rating Scale (eC-
SSRS)
The immunogenicity objective is 
to evaluate the immunogenicity of 
fremanezumab and the impact of 
antidrug antibodies (ADAs) on 
clinical outcomes in patients 
exposed to iv and sc fremanezumab
The immunogenicity endpoints are ADA incidence and 
characteristics (eg, titer, kinetics, and neutralizing activities)
2.1.1.
Justification of Primary Endpoint
For patients with ECH, headache attacks may happen in distinct periods of time, often seasonally 
(occur daily for some weeks [7 days to a year [if not treated]) followed by a period of remission 
with distinct pain-free periods lasting at least 1 month (often last for months to years). On 
average, a cluster period lasts 6 to 12 weeks, and remissions can last up to 12 months. The 
duration of pain in these patients supports the need to evaluate time point of the primary endpoint 
of 4 weeks. This short duration of assessment at 4 weeks in patients with ECH should capture the 
seasonality nature and the possibility of prolonged remission.


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2.2.
Exploratory Objectives and Endpoints
2.2.1.
Exploratory Objectives and Endpoints
The exploratory objectives are as follows:

 
 
 
 
The exploratory endpoints are as follows:

 
 
 
 
 
 
 
 
 
 
 
 
 

 
 


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


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Wearable sensor substudy exploratory endpoints are the following:



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3.
STUDY DESIGN
3.1.
General Design and Study Schematic Diagram
This is a 13-week, multicenter, randomized, double-blind, double-dummy, placebo-controlled, 
parallel-group study to compare the safety, and efficacy of 2 dose regimens of fremanezumab
versus placebo in adult patients for the prevention of ECH. The study will consist of a screening 
visit, a run-in period lasting at least 1 week (+3 days), and a 12-week double-blind treatment 
period. During the course of any CH attack, patients will be allowed to use acute medications to 
treat acute headaches, as needed (PRN).
Patients will complete a screening visit (visit 1) after providing written informed consent, and 
eligible patients will enter a run-in period lasting at least 1 week (+3 days) during which they 
will enter baseline CH attack information into an electronic diary device daily. Patients will 
return to the study center after completing the run-in period (visit 2 [week 0]). Patients who had 
at least 7 CH attacks during the run-in period and who continue to meet eligibility criteria 
(including entry of CH attack information in an electronic diary demonstrating compliance for 
85% of days during the run-in period) will be randomly assigned at visit 2 (week 0) in a 
1:1:1 ratio to 1 of 3 treatment groups as follows:

fremanezumab 900-mg iv loading dose group: fremanezumab at 900 mg administered 
via an approximately 1-hour iv infusion at visit 2 (week 0) followed by 
fremanezumab at 225 mg administered as single sc injections (225 mg/1.5 mL) at 
visits 3 and 4 (weeks 4 and 8, respectively)

fremanezumab 675-mg sc quarterly group: fremanezumab at 675 mg administered as 
3 sc injections (225 mg/1.5 mL) at visit 2 (week 0) followed by placebo administered 
as single sc injections at visits 3 and 4 (weeks 4 and 8, respectively)

placebo group: placebo administered via an approximately 1-hour iv infusion and as 
3 sc injections at visit 2 (week 0) followed by placebo administered as single sc 
injections at visits 3 and 4 (weeks 4 and 8, respectively)
In order to maintain blinding throughout the study, the number of infusions and injections at each 
visit will be the same for all patients regardless of the treatment group to which they are 
randomized. Thus, all patients will receive an iv infusion of test IMP or placebo IMP followed 
by 3 sc injections of test IMP or placebo IMP at visit 2 (week 0), and all patients will receive 
single sc injections of test IMP or placebo IMP at visits 3 and 4 (weeks 4 and 8, respectively).
Randomization will be performed using electronic interactive response technology (IRT).
Patients will be randomly assigned with stratification based on sex, country, and baseline 
concomitant preventive medications (yes/no) to the fremanezumab 900-mg iv loading dose 
group, the fremanezumab 675 mg sc quarterly group, or the placebo group in a 1:1:1 ratio. 
Blinded treatment will be administered once monthly (ie, approximately every 4 weeks) for a 
total of 3 months. Final study assessments will be performed at the final visit for this study 
(visit 5), approximately 12 weeks after administration of the first dose of the IMP. 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 


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(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 TV48125-CNC-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. A separate protocol was issued for the long-term safety study.
CH attack information will be captured daily during the double-blind treatment period 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 PPSI and Patients’ Global Impression of Change [PGIC] scale); safety evaluations
(including eC-SSRS); blood collection for pharmacokinetic, immunogenicity, biomarker, and 
pharmacogenomic (unless not allowed per local regulation) analyses; and urine sampling for 
biomarker analysis will be performed at prespecified time points.
The end of study is defined as the last visit of the last patient.
The study duration will be 21 months from Q4/2016 to Q2/2018.
The study schematic diagram is presented in Figure 1.


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Figure 1:
Overall Study Schematic Diagram
ECH=episodic chronic headache; IV=intravenous; PBO=placebo; SC=subcutaneous; V=visit.
Note: Patients randomized to the 900-mg iv loading dose group will receive 900 mg of fremanezumab administered 
via an approximately 1-hour iv infusion followed by placebo as 3 sc injections at visit 2 (week 0) and fremanezumab
at 225 mg administered as single sc injections (225 mg/1.5 mL) at visits 3 and 4 (weeks 4 and 8, respectively). 
Patients randomized to the fremanezumab 675-mg sc quarterly group will receive placebo administered via an 
approximately 1-hour iv infusion followed by fremanezumab at 675 mg administered as 3 sc injections 
(225 mg/1.5 mL) at visit 2 (week 0) and placebo administered as single sc injections at visits 3 and 4 (weeks 4 and 8, 
respectively). Patients in the placebo group will receive placebo administered via an approximately 1-hour iv 
infusion followed by placebo administered as 3 sc injections at visit 2 (week 0) and placebo administered as single 
sc injections at visits 3 and 4 (weeks 4 and 8, respectively).
Wearable Sensor Substudy: A subset of patients in selected investigational sites will be offered
the opportunity to participate in a substudy
 
 
 Refer to Section 8.6 for 
additional details.


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3.2.
Planned Number of Patients and Countries
A total of approximately 300 patients (approximately 100 patients per treatment group) are 
planned to be enrolled in this study. Details on definition of evaluable patients and sample size 
are given in Section 9.
The study is planned to be conducted in approximately 12 countries in approximately 
80 investigational centers. The study is expected to start in Q4/2016 and last until approximately 
Q2/2018.
3.3.
Justification for Study Design and Selection of Population
The study design follows the recommendations of the IHS guidelines for controlled trials of 
drugs in CH (Lipton et al 1995), which specify that clinical trials of prophylactic drugs for CH 
should be parallel-group, placebo-controlled studies in patients meeting the diagnostic criteria set 
forth by the International Classification of Headache Disorders, third revision beta (ICHD 3-
beta) for CCH (Headache Classification Committee of the IHS 2013). Also consistent with the 
IHS guidelines, patients will be randomized with stratification based on gender (Lipton et al 
1995).
The study population will be composed of male and female patients, aged 18 to 70 years, 
inclusive, with a history of ECH (as defined by ICHD 3-beta criteria [Headache Classification 
Committee of the IHS 2013]) for at least 12 months prior to screening.
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
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 the following conditions happen:

New toxicological or pharmacological findings or safety issues invalidate the earlier 
positive benefit-risk assessment.

Development of the IMP is discontinued.

The interim analysis (performed when 50% of patients have completed 4-week 
assessments during the double-blind study period or have withdrawn from the study 
early) supports stopping early for futility.
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 Section 10, 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.


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Patients who are discontinued early for any reason will be offered the option to enroll in 
Study TV48125-CNS-30058 for the purpose of evaluating ADAs and safety (adverse events and 
concomitant medications).
3.5.
Schedule of Study Procedures and Assessments
Study procedures and assessments with their time points are presented in Table 2. 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 2:
Study Procedures and Assessments
Study period
Pretreatment period 
(including screening 
visit and run-in period)
Double-blind treatment perioda
Visit number
V1
V2
V3
V4
V5
Week number
Week -1
Week 0
Week 4
Week 8
Week 12
Procedures and assessments (completed 
before dosing, when applicable, unless 
otherwise noted)
Screeningb
Baseline 
dose 1
day 0 (+3 days)
Visit 3
day 28 (±3 days)
Visit 4
day 56 (±3 days)
EOT or early 
withdrawal
day 84 (±3 days)
Informed consent
Xc
Medical and psychiatric history
X
Prior medication history
X
Record demographic characteristics
X
Inclusion and exclusion criteria
X
X
Randomization
X
Review study compliance
X
X
X
X
Physical examination, including weight and 
heightd
X
X
X
Triplicate 12-lead ECGe
X
X
X
Vital signs measurement
X
X
X
X
X
Adverse eventsf
X
Xg
X
X
X
Concomitant medication inquiry
X
X
X
X
Clinical laboratory testsh
Xi
X
X
X
X
Serum β-HCG testj
X
X
Urine β-HCG test
X
X
X
FSHk
X
Provide electronic diary devicel
X


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Study period
Pretreatment period 
(including screening 
visit and run-in period)
Double-blind treatment perioda
Visit number
V1
V2
V3
V4
V5
Week number
Week -1
Week 0
Week 4
Week 8
Week 12
Procedures and assessments (completed 
before dosing, when applicable, unless 
otherwise noted)
Screeningb
Baseline 
dose 1
day 0 (+3 days)
Visit 3
day 28 (±3 days)
Visit 4
day 56 (±3 days)
EOT or early 
withdrawal
day 84 (±3 days)
Enter cluster headache attack information in 
the electronic diary devicem
X
X
Review electronic diary data
X
X
X
X
Return electronic diary devicen
X
Blood samples for pharmacokinetics 
analysiso
X
X
X
X
Blood samples for ADA analysisp
X
X
X
Blood sample for pharmacogenomic 
analysisq
X
Blood collection for serum, plasma, and 
RNA biomarker analysisr
X
X
Urine collection for biomarker analysis
X
X
HADSs
X
X
X
EQ-5D questionnaires
X
X
X
SF-12s
X
X
X
WPAI questionnaires
X
X
X
Impact on Partner and Family 
questionnaires,t
X
X
X
PPSIu
X
X
X
X
PGIC scaleu
X
X
X


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Study period
Pretreatment period 
(including screening 
visit and run-in period)
Double-blind treatment perioda
Visit number
V1
V2
V3
V4
V5
Week number
Week -1
Week 0
Week 4
Week 8
Week 12
Procedures and assessments (completed 
before dosing, when applicable, unless 
otherwise noted)
Screeningb
Baseline 
dose 1
day 0 (+3 days)
Visit 3
day 28 (±3 days)
Visit 4
day 56 (±3 days)
EOT or early 
withdrawal
day 84 (±3 days)
Provide wearable substudy sensor device 
and accessories
X
Wearable sensor substudy data capture
X
X
Wearable sensor device check and 
compliance check
X
X
X
X
Return wearable sensor device
Xv
eC-SSRSw
X
X
X
X
X
Administration of IMPx
X
X
X
Hypersensitivity/anaphylaxis reaction 
assessmenty
X
X
X
Injection site assessmentsz
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 Patients will complete a screening visit and a run-in period lasting at least 1 week (+3 days).
c The partner or family member who will complete the Impact on Partner and Family questionnaire 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. Patients involved in the wearable sensor substudy
will also provide consent to participate in this substudy.
d Height will only be obtained at screening.
e ECGs will be performed in triplicate, with approximately 1 to 5 minutes between recordings and will be performed before blood draws and administration of 
questionnaires.
f Adverse events will be recorded from the time informed consent is obtained through the end of study participation.
g Inquiries about adverse events will be made before and after IMP administration. Postdose inquiries will be made before the patient leaves the investigational 
center.


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h Serum chemistry, hematology, coagulation, and urinalysis. Currently menstruating information (yes, no) will be collected prior to blood and urine collection for 
laboratory tests for all females.
i In case of abnormal coagulation during screening (run-in period) or if other specific urgent tests are required, a local retest can be authorized by the sponsor or 
designee on a case-by-case basis.
j Women of childbearing potential only.
k Postmenopausal women only.
l Eligible patients will be given an electronic diary device and will be trained in its use and compliance requirements on the day of screening. 
m 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) into the electronic diary device beginning on the day after the screening visit through the EOT/early withdrawal visit. The last day 
of the run-in period should be reported in the morning of the visit day.
n Unless the patient begins participation in the long-term safety study (Study TV48125-CNS-30058) on the same day (ie, after completing all 
assessments/procedures for this visit).
o The blood sample for pharmacokinetics analysis collected at visit 2 (week 0) prior to dosing (from either arm) and at the end of the infusion (+10 minutes) from 
the arm that is not used for the IMP infusion. All other blood samples for pharmacokinetics analysis will be collected prior to dosing (where applicable) and 
may be collected from either arm.
p Blood samples for serum ADA assessment (5 mL) will also be collected upon observation of any severe hypersensitivity reaction and anaphylaxis. Patients 
who are discontinued early for any reason or do not enroll in the double-blind, long-term safety study for treatment will be offered the option to enter the long-
term safety 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 IMP in this study.
q A blood sample for pharmacogenomic analysis will be collected at visit 2 (week 0) or any visit thereafter, unless the patient declines testing or local regulations 
prohibit testing.
r Blood for further biomarkers analyses will be collected after blood collection for pharmacokinetic and immunogenicity analyses as follows
 
s Responses will be recorded in the investigational site tablet.
t 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.
u Responses at week 1 will be recorded in the electronic diary device at home, and responses at all other time points will be entered into the investigational site 
tablet.
v Patients will return the wearable sensor if they do not rollover into the long-term safety study (Study TV-48125-CNS-30058) or if they rollover into the 
long-term safety study but do not wish to continue participating in the wearable sensor substudy.
w The eC-SSRS Baseline/Screening version will be completed at visit 1, and the eC-SSRS Since Last Visit version will be completed at all other visits, including 
unscheduled visits. Results from both versions will be entered into the investigational site tablet.
x Patients randomized to the 900-mg iv loading dose group will receive 900 mg of fremanezumab administered via an approximately 1-hour iv infusion followed 
by placebo as 3 sc injections at visit 2 (week 0) and fremanezumab at 225 mg administered as single sc injections (225 mg/1.5 mL) at visits 3 and 4 (weeks 4 
and 8, respectively). Patients randomized to the fremanezumab 675-mg sc quarterly group will receive placebo administered via an approximately 1-hour iv 
infusion followed by fremanezumab at 675 mg administered as 3 sc injections (225 mg/1.5 mL) at visit 2 (week 0) and placebo administered as single sc 
injections at visits 3 and 4 (weeks 4 and 8, respectively). Patients in the placebo group will receive placebo administered via an approximately 1-hour iv 


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infusion followed by placebo administered as 3 sc injections at visit 2 (week 0) and placebo administered as single sc injections at visits 3 and 4 (weeks 4 and 
8, respectively). 
y Patients will be assessed for hypersensitivity reactions and anaphylaxis during and after administration of the IMP (through 1 hour postdose).
z Injection site 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 completion of IMP administration and hourly (±15 minutes) thereafter until the reaction is of moderate or less severity.
ADA=antidrug antibody; β-HCG=beta-human chorionic gonadotropin; CH=cluster headache; CRF=case report form; ECG=electrocardiogram; 
eC-SSRS=electronic Columbia-Suicide Severity Rating Scale; EOT=end of treatment; EQ-5D=EuroQol-5 Dimension; FSH=follicle-stimulating hormone; 
HADS=Hospital Anxiety and Depression Scale; IMP=investigational medicinal product; iv=intravenous; PGIC=Patients’ Global Impression of Change; 
PPSI=Patient-Perceived Satisfactory Improvement; RNA=ribonucleic acid; sc=subcutaneous; SF-12=12-Item Short Form Health Survey; V=visit; WPAI=Work 
Performance and Activity Impairment.


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4.
SELECTION AND WITHDRAWAL OF PATIENTS
Prospective waivers (exceptions) from study inclusion and exclusion criteria to allow patients to 
be randomized/enrolled are not granted by 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.
4.1.
Patient Inclusion Criteria
Patients may be randomized/enrolled in this study only if they meet all of the following criteria:
a.
Patients are capable of giving signed informed consent as described in Appendix D which 
includes compliance with the requirements and restrictions listed in the informed consent 
form (ICF) and in this protocol.
b. The patient is a man or woman 18 to 70 years of age, inclusive.
c.
The patient has a history of ECH according to ICHD-3 beta criteria (Headache 
Classification Committee of the IHS 2013) for ≥12 months prior to screening including 
the following:

Attacks of severe, strictly unilateral pain which is orbital, supraorbital, temporal or in 
any combination of these sites, lasting 15 to 180 minutes and occurring from once 
daily every other day to 8 times a day for more than half of the time when the 
disorder is active.

The pain is associated with at least 1 of the following symptoms or signs: ipsilateral 
conjunctival injection, lacrimation, nasal congestion, rhinorrhea, forehead and facial 
sweating, miosis and/or ptosis and/or eyelid edema, and/or sense of restlessness or 
agitation.

CH attacks occurring in periods lasting from 7 days to 1 year, separated by pain-free 
periods lasting at least 1 month.
d. CH attacks of a new cluster cycle have started within ≤2 weeks (14 days, inclusive) prior 
to screening and, based on the patient’s previous medical history, it is expected that the 
patient’s CH attacks will continue for ≥6 weeks after the screening visit.
e.
The patient has a total body weight of ≥45 kg 
f.
The patient is not using or using ≤2 concomitant medications that are commonly 
prescribed as preventive treatments for CH (Appendix H), regardless of the indication for 
which the medication was prescribed. Patients must be on a stable dose and regimen for 
at least 2 weeks prior to screening and throughout the study. 
g. If a patient is receiving Botox, it should be in a stable dose regimen, considered as having 
≥2 cycles of Botox prior to screening. The patient should not receive Botox during the 
run-in period up to the evaluation period (4 weeks) where the primary endpoint is 
evaluated.
h. The patient has demonstrated compliance with the electronic headache diary during the 
run-in period by entry of headache data on 85% of days during the run-in period.


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i.
The patient has at least 7 CH attacks during the run-in period.
j.
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. 
k. Women may be included only if they have a negative serum beta-human chorionic 
gonadotropin (β-HCG) test at screening, are sterile or postmenopausal, and are not 
lactating. Definitions of sterile and postmenopausal are given in Appendix E.
l.
Women of childbearing potential (WOCBP) whose male partners are potentially fertile 
(ie, no vasectomy) must use highly effective birth control methods for the duration of the 
study (ie, starting at screening) and for 7.5 months after discontinuation of IMP.
m. 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 
discontinuation of the IMP. Definitions of women of non-childbearing potential, sterile
women, and postmenopausal women; male contraception; and highly effective and 
acceptable birth control methods including examples are given in Appendix E.
n. The patient must be willing and able to comply with study restrictions, to remain at the 
clinic for the required duration during the study period and to return to the clinic for the 
follow-up evaluations, as specified in this protocol.
4.2.
Patient Exclusion Criteria
Patients will not be randomized/enrolled in this study if they meet any of the following criteria:
a.
The patient has used systemic steroids for any medical reason (including treatment of the 
current CH cycle) within ≤7 days prior to screening.
b. The patient reports using butalbital on more than 7 days during the 4 weeks prior to 
screening or using butalbital on more than 3 days during the screening/run-in period. 
c.
The patient reports using opioids on more than 15 days during the 4 weeks prior to 
screening or using opioids on more than 4 days during the screening/run-in period.
d. The patient has used an intervention/device (eg, scheduled nerve blocks) for headache 
during the 4 weeks prior to screening.
e.
The patient has clinically significant hematological, renal, endocrine, immunologic, 
pulmonary, gastrointestinal, genitourinary, cardiovascular, neurologic, hepatic, or ocular 
disease at the discretion of the investigator.
f.
The patient has evidence or medical history of clinically significant psychiatric issues 
determined at the discretion of the investigator.
g. The patient has a history of any suicide attempt in the past or current active suicidal 
ideation, as measured by the eC-SSRS.
h. The patient has a history of clinically significant cardiovascular disease or vascular 
ischemia (such as myocardial, neurological [eg, cerebral ischemia], peripheral extremity 


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ischemia, or other ischemic event) or thromboembolic events (arterial or venous 
thrombotic or embolic events), such as cerebrovascular accident (including transient 
ischemic attacks), deep vein thrombosis, or pulmonary embolism. 
i.
The patient has a past or current history of cancer or malignant tumor in the past 5 years, 
except for appropriately treated non-melanoma skin carcinoma. 
j.
The patient is pregnant or lactating.
k. The patient has a history of hypersensitivity reactions to injected proteins, including 
monoclonal antibodies.
l.
The patient has participated in a clinical study of a new chemical entity or a prescription 
medicine within 2 months or 5 half-lives before administration of the first dose of the 
IMP, whichever is longer.
m. The patient has participated in a clinical study of a monoclonal antibody within 3 months
or 5 half-lives before administration of the first dose of the IMP, whichever is longer, 
unless it is known that the patient received placebo during the study.
n. The patient has a history of prior exposure to a monoclonal antibody targeting the CGRP 
pathway (AMG 334, ALD304, LY2951742, or fremanezumab). If patient has participated 
in a clinical study with any of these monoclonal antibodies, it has to be confirmed that the 
patient received placebo in order to be eligible for this study.
o. The patient has any finding in the baseline 12-lead ECG considered clinically significant 
in the judgment of the investigator.
p. The patient has 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).
q. The patient has hepatic enzymes (ALT and AST) >1.5 × the upper limit of normal (ULN) 
range after confirmation in a repeat test, or the patient has suspected hepatocellular 
damage that fulfills criteria for Hy’s law at screening.
r.
The patient has serum creatinine >1.5 × the ULN or evidence of clinically significant 
renal disease in the judgement of the investigator.
s.
The patient cannot participate or successfully complete the study, in the opinion of their 
healthcare provider or the investigator, for any of the following reasons:

mentally or legally incapacitated or unable to give consent for any reason

in custody due to an administrative or a legal decision, under tutelage, or being 
admitted to a sanitarium or social institution

unable to be contacted in case of emergency

has any other condition, which, in the opinion of the investigator, makes the patient 
inappropriate for inclusion in the study
t.
The patient is an employee of the sponsor/participating study center who is directly 
involved in the study or is the relative of such an employee.


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u. The patient has an active implant for neurostimulation used in the treatment of CH.
v. The patient is a member of a vulnerable population (eg, people kept in detention).
w. The patient has a history of alcohol and/or drug abuse that in the investigator’s opinion 
could interfere with the study evaluations or the patient’s safety.
4.3.
Withdrawal Criteria and Procedures
Each patient is free to withdraw from the IMP and/or study at any time, without prejudice to their 
continued care. Patients must be withdrawn from the IMP and/or study if any of the following 
events occur:
1. Patient withdraws consent or requests discontinuation from the IMP and/or study for any 
reason.
2. Patient develops an illness that would interfere with his/her continued participation.
3. Patient is noncompliant with the study procedures and assessments or administration of 
IMPs in the opinion of the investigator.
4. Patient takes prohibited concomitant medications as defined.
5. A female patient has a confirmation of pregnancy during the study from a positive 
pregnancy test.
6. The sponsor requests withdrawal of the patient.
7. Patient experiences an adverse event or other medical condition which indicates to the 
investigator that continued participation is not in the best interest of the patient.
8. 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 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.
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. 


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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. 
All protocol-specified procedures/assessments should be performed at the early withdrawal visit 
(see Appendix B). Patients who withdraw from the study will not be replaced. Patients who 
discontinue early for any reason will be offered the opportunity to enter in the long-term safety 
study (Study TV48125-CNS-30058) for the purpose of evaluation of ADAs and safety (adverse 
events and concomitant medications) approximately 7.5 months after administration of the last 
dose of IMP in this study. These patients will not receive any doses of fremanezumab after 
completing participation in the current study and should be treated with standard of care as 
appropriate.
A patient should only be designated as lost to follow up 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). 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 randomized/enrolled but does not complete the treatment period will not be 
replaced with another eligible patient.
4.5.
Rescreening
A patient who is screened and does not meet study inclusion and exclusion criteria will not be 
considered for screening again, except for patients who do not meet study inclusion criterion “h” 
of the required number of cluster attacks during run-in period. These patients may be eligible for 
one additional rescreening if approved by the sponsor on a case-by-case basis.
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 the placebo IMP. Details of the test and placebo IMPs are 
presented in Table 3.
Table 3:
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/mL
900 mg iv loading dose followed 
by 225 mg sc monthly
or
675 mg sc quarterly
n/a
Route of Administration
Fremanezumab will be 
administered as iv infusions and 
sc injections by qualified study 
personnel at the study center.
Placebo will be administered as iv 
infusions and sc injections 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) 
on site. Prefilled syringes 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) on site. 
Prefilled syringes 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; iv=intravenous; n/a=not applicable; sc=subcutaneous.
Administration of IMP will be via the iv and sc routes. At visit 2, IMP (test or placebo) will be 
administered via an approximately 1-hour iv infusion followed by 3 sc injections of IMP (test or 
placebo). At visits 3 and 4, IMP (test or placebo) will be administered as single sc injections. 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 


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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 IMP sc injections and their locations will be 
recorded for each dosing visit (visits 2 through 4, test or placebo). A 1.5-mL volume from each 
prefilled syringe must be injected sc for dosing to be considered complete.
5.1.1.
Test Investigational Medicinal Product
Fremanezumab is a fully humanized IgG2a/kappa monoclonal antibody derived from a murine 
precursor. Fremanezumab for CH is being developed for iv and sc administration.
Additional details may be found in Table 3 and in the IB for fremanezumab. 
5.1.1.1.
Starting Dose and Dose Levels
Patients randomized to receive fremanezumab will receive either 900 mg or 675 mg. At visit 2
(week 0), iv administration of treatment (IMP or placebo) will precede sc administration (IMP or 
placebo). Patients randomized to the 900-mg iv loading dose group will receive 900 mg of 
fremanezumab administered via an approximately 1-hour iv infusion followed by placebo as 3 sc 
injections at visit 2 (week 0) and fremanezumab at 225 mg administered as single sc injections 
(225 mg/1.5 mL) at visits 3 and 4 (weeks 4 and 8, respectively). Patients randomized to the 
fremanezumab 675-mg sc quarterly group will receive placebo administered via an 
approximately 1-hour iv infusion followed by fremanezumab at 675 mg administered as 3 sc 
injections (225 mg/1.5 mL) at visit 2 (week 0) and placebo administered as single sc injections at 
visits 3 and 4 (weeks 4 and 8, respectively).
5.1.2.
Placebo Investigational Medicinal Product
The placebo will be the same vehicle and excipients as those for fremanezumab. See Table 3 for 
additional details. Patients randomized to the placebo group will receive placebo administered 
via an approximately 1-hour iv infusion followed by placebo as 3 sc injections at visit 2 (week 0) 
and placebo administered as single sc injections at visits 3 and 4 (weeks 4 and 8, respectively).
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
The fremanezumab doses, regimens, and routes of administration to be evaluated in this 
double-blind, double-dummy, placebo-controlled study were selected on the basis of 3 key 
factors. First, simulations suggest that Cmax is the most significant pharmacokinetic parameter in 
the efficacy of fremanezumab (in migraine). As CH is considered one of the most severe forms 
of pain a person can experience, treatments that provide quick and lasting relief (ie, for the 
duration of the cluster period) are a priority for this patient population. Second, the biological 
nature of the disease mandates the need for any treatment to desensitize the third order neuron, 
not the second (as is the case in migraine), suggesting that high levels of blockade at the first 


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neuron would be necessary. Third, the favorable safety profile of the drug, as well as clinical and 
nonclinical safety data on exposure, suggest that the proposed doses, regimens, and routes of 
administration will not present any safety concerns.
In the current study, high doses are planned for the first dose (900 mg iv or 675 mg sc) in order 
to provide a rapid response, especially following iv infusion where higher peak plasma Cmax
generally occur at or shortly after the end of infusion compared with 5 to 7 days postdose for sc 
injections. The 2 forms of loading dose will provide data to confirm the benefit of either the iv or 
sc as loading dose. Monthly doses of fremanezumab at 225 mg sc were added to the initial dose 
of 900 mg iv for maintenance of efficacy. Based on modelling, the inclusion of a loading dose 
should allow patients to reach steady state faster. The dose of 675 mg sc quarterly in this ECH 
population will allow for the evaluation of a single treatment dose taking into account the periods 
of remission seen with this CH form.
5.3.2.
Justification for Use of Placebo Investigational Medicinal Product
A placebo-controlled design is appropriate given the purpose and objectives of this clinical 
study. Inclusion of a placebo-control group is consistent with the IHS guidelines for controlled 
trials of drugs in CH, first edition (Lipton et al 1995).
5.4.
Treatment after the End of the Study
Patients who successfully complete the final visit of this study may be offered the opportunity to 
enroll in a long-term safety extension study (Study TV48125-CNS-30058), which includes a 
treatment period lasting approximately 40 weeks. 
Patients who are discontinued early for any reason or who do not enroll in this long-term study 
for treatment, for any reason, will be offered the option to enter the study for the purpose of 
evaluating ADAs and safety (adverse events and concomitant medications) at approximately 
7.5 months after administration of the last dose of the IMP. These patients will not receive any 
doses of fremanezumab after completing participation in the current study and should be treated 
with standard of care as appropriate.
5.5.
Restrictions
Patients will be required to comply with the following restrictions:
5.5.1.
Activity
Patients must remain at the site, for safety observation, at least 60 minutes after infusion or 
according to medical judgment. 
5.5.2.
Blood Donation
Patients may not donate blood while taking the IMP and for 5 half-lives (7.5 months) after the 
last dose of the IMP.


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5.5.3.
Pregnancy
Restrictions in regard to pregnancy and required laboratory values (ie, serum and urine β-HCG 
tests) are provided in the inclusion and exclusion criteria (Section 4.1 and Section 4.2,
respectively). Restrictions in regard to contraception methods are reviewed in Appendix E.
5.6.
Prior and Concomitant Medication or Therapy
Any prior or concomitant medication, treatment, or procedure a patient has had 3 months before 
screening visit (visit 1) and up to the end of study, including follow-up, will be recorded on the 
CRF. Trade name and INN (if available), indication, dose, and start and end dates of the 
administered medication will be recorded. The sponsor will encode all medication and treatment 
according to the World Health Organization (WHO) drug dictionary (WHO Drug).
A maximum of 2 concomitant preventive medications for ECH are allowed. Patients must be on 
a stable dose and regimen for at least 2 weeks prior to screening and throughout the study. A list 
of permissible preventive medications is provided in Appendix H.
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.
5.7.
Procedures for Monitoring Patient Compliance
The investigator will be responsible for monitoring patient compliance. A check of compliance 
with IMP intake will be performed during each visit after the IMP has been administered, and 
IMP accountability records will be completed. If the investigator or the sponsor determines that 
the patient is not in compliance with the study protocol, the investigator and the sponsor should 
determine whether the patient should be withdrawn from the study. Exposure to IMP will be 
assessed as required.
5.8.
Randomization and Blinding
This is a randomized, double-blind, double-dummy, placebo-controlled study. Patients and 
investigators will remain blinded to IMP assignment during the study. A computer-generated 
master randomization list will be provided to drug packaging facilities. Packaging vendor(s) will 
package active drug and placebo into single-visit kits according to Good Manufacturing Practice 
procedures. Kits will be identical in appearance and prefilled syringes with test IMP or placebo 
IMP. Adequate kit supply for upcoming study visits will be managed by IRT and kept 
(refrigerated at 2°C to 8°C) on site. 
Patients will be randomly assigned with stratification based on gender, country, and baseline 
concomitant preventive medication use (yes/no) to the fremanezumab at 900 mg iv loading dose 
group, the fremanezumab 675-mg sc quarterly group, or the placebo group in a 1:1:1 ratio. The 
sponsor, investigators, study staff (except for staff involved in bioanalytical analyses and interim 
analyses [by a third-party, unblinded statistician]), and patients will be blinded to treatment 
assignment throughout the study.


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The IRT will manage initial drug supply, maintenance of adequate IMP supplies on site, and 
study randomization centrally.
5.9.
Maintenance of Randomization and Blinding
5.9.1.
Maintenance of Randomization
The randomization code will be generated by the IRT third-party vendor, following 
specifications from the Biostatistics Department. A Teva statistician will be responsible for 
reviewing the dummy randomization codes, and the final randomization code will be maintained 
by the third-party vendor in a secure location.
At the time of analysis (after the end of the study), after receiving an unblinding request from the 
Teva statistician, the service provider will provide the unblinded IMP assignments according to 
the processes defined in the relevant Standard Operating Procedure (SOP).
5.9.2.
Blinding and Unblinding
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).
The planned interim analysis (Section 9.15) will be conducted by a third-party, unblinded 
statistician. Results from the interim analysis will be reported in a manner that does not unblind 
any blinded individuals (ie, the sponsor, investigators, blinded study staff, and patients).
For information about personnel who may be aware of IMP assignments, see Section 5.8. These 
individuals will not be involved in conduct of any study procedures or assessment of any adverse 
events.
In case of a serious adverse event, pregnancy, or in cases when knowledge of the IMP 
assignment is needed to make treatment decisions, the investigator may unblind the patient’s 
IMP assignment as deemed necessary, mainly in emergency situations, through specialized 
access in the IRT system. If possible, the sponsor should be notified of the event before breaking 
of the code. If this is not possible, the sponsor should be notified immediately afterwards, and the 
patient’s randomization code should not be revealed. In emergency cases, breaking of the 
randomization code can be performed by the investigational center without prior approval by the 
sponsor.
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. 
When a blind is broken, the patient will be withdrawn from the study, and the event will be 
recorded on the CRF. The circumstances leading to the breaking of the code should be fully 
documented in the investigator’s study files and in the patient’s source documentation. 
Assignment of IMP should not be recorded in any study documents or source document.


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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 blind code be broken (on a case-by-case 
basis) to comply with regulatory requirements. The report will be provided in an unblinded 
manner for regulatory submission. If this occurs, blinding will be maintained for the investigator 
and for other personnel involved in the conduct of the study, and analysis and reporting of the 
data.
5.9.3.
Data Monitoring Committee
There will be no Data Monitoring Committee used for this study.
5.10.
Total Blood Volume
The total blood volume to be collected for each patient enrolling in this study is approximately 
131.5 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.
Details are provided in Appendix L.


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6.
ASSESSMENT OF EFFICACY
Data from any efficacy assessments performed after the specified time will not be collected on 
the CRF. However, in the event that such data are collected, these data will not be analyzed.
6.1.
Electronic Diary 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). The last day of the run-in period should be reported in the morning 
of the visit day.
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
6.2.
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 in the investigational site tablet at the time points detailed in 
Table 2.


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6.3.
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 in the investigational site tablet at the time points detailed 
in Table 2.
6.4.
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 in the investigational site tablet at the time points detailed in 
Table 2.
6.5.
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 in the investigational site tablet at the time points 
detailed in Table 2.
6.6.
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 2. Responses 
will be recorded in the investigational 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 


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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. 
6.7.
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 in the electronic diary device at home at week 1 and in the 
investigational site tablet at the time points detailed in Table 2.
6.8.
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 well-being
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.”
Patients will record responses to the PGIC scale in the electronic diary device at home at week 1
and in the investigational site tablet at the time points detailed in at the time points detailed in
Table 2.


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7.
ASSESSMENT OF SAFETY
In this study, safety will be assessed by qualified study personnel by evaluating reported adverse 
events, clinical laboratory test results, vital signs measurements, ECG findings, physical 
examination findings (including body weight measurements), injection site reaction/pain 
assessments, eC-SSRS scores, and use of concomitant medication.
7.1.
Adverse Events
7.1.1.
Definition of an Adverse Event
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have to have a causal relationship with 
this treatment.
An adverse event can, therefore, be any unfavorable and unintended physical sign, symptom, or 
laboratory parameter that develops or worsens in severity during the course of this study, or 
significant worsening of the disease under study, or of any concurrent disease, whether or not 
considered related to 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 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 dosing of the 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 ICF through the EOT/early withdrawal visit. Adverse events occurring after the 
EOT/early withdrawal visit for patients who enroll in the long-term safety study 
(Study TV48125-CNS-30058) will be recorded as part of the long-term safety study database.
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 4):
Table 4:
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.
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 EOT/early withdrawal visit. Serious adverse events 
occurring in a patient after the EOT/early withdrawal visit 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
(Appendix J):

ALT or AST increase of ≥3 × the ULN

total bilirubin increase of ≥2 × the 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.
For double-blind studies, blinding will be maintained for all study personnel. Therefore, in case 
of a SUSAR, only the LSO/CRO will receive the unblinded report for regulatory submission; the 
others will receive a blinded report.
Note: Although pregnancy is not a serious adverse event, the process for reporting a pregnancy is 
the same as that for reporting a serious adverse event, but using the pregnancy form 
(see Section 7.2).
7.1.5.3.2. Sponsor Responsibility
If a serious unexpected adverse event is believed to be related to the test IMP or study 
procedures, the sponsor will take appropriate steps to notify all investigators participating in 
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


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
modifying the existing consent form and informing all study participants of new 
findings

modifying listings of expected toxicities to include adverse events newly identified as 
related to fremanezumab
7.1.6.
Protocol-Defined Adverse Events not for Expedited Reporting
Not applicable.
7.1.7.
Protocol-Defined Adverse Events of Special Interest
For purposes of this protocol, the following are considered protocol-defined adverse events of 
special interest to be sent to the sponsor’s Global Patient Safety and Pharmacovigilance 
Department for evaluation: ophthalmic related adverse events of at least moderate severity, 
events of possible drug-induced liver injury (AST or ALT ≥3 × 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 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 and severe 
hypersensitivity, vital signs, including oxygen saturation and respiration rate, will be measured. 
Other assessments will be performed at the discretion of the investigator. As a precaution, each 
site 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 to be reported to the 
Global Patient Safety and Pharmacovigilance 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 last dose of the 


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IMP, are to be reported immediately to the individual identified in the Clinical Study Personnel 
Contact Information section of this protocol, and the investigator must provide the sponsor 
(LSO/CRO) with the completed pregnancy form. The process for reporting a pregnancy is the 
same as that for reporting a serious adverse event but using the pregnancy form (Section 7.1.5.3). 
The investigator is not required to report 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 Informed Consent Form (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 noncompliant 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 


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sponsor. When the identification of the IMP is required, the investigator must follow the 
procedures for unblinding outlined in Section 5.9.2.
3. Misuse: Situations where the IMP is intentionally and inappropriately used not in 
accordance with the authorized product information.
4. Abuse: Persistent or sporadic, intentional excessive use of IMP which is accompanied by 
harmful physical or psychological effects.
5. Off-label use: Situations where an IMP is intentionally used for a medical purpose not in 
accordance with the authorized product information.
6. Occupational exposure: Exposure to an IMP, as a result of one’s professional or non-
professional occupation.
7. Breastfeeding: Suspected adverse reactions 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 and the CRF as an adverse event, and monitored as described in 
Section 7.1.2. An event may include a laboratory or diagnostic test abnormality (once confirmed 
by repeated testing) that results in the withdrawal of the patient from the study, the temporary or 
permanent withdrawal of IMP or medical treatment, or further diagnostic work-up. (Note: 
abnormal laboratory or diagnostic test results at the screening visit that preclude a patient from 
entering the study or receiving IMP are not considered adverse events.)
In addition, potentially clinically significant values 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 2. Clinical laboratory tests will be performed using the central 
laboratory. However, in case of abnormal coagulation during screening (run-in period) or 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
A serum β-HCG test will be performed for all WOCBP at screening (visit 1) and EOT (visit 5), 
and urine β-HCG tests will be performed for WOCBP at all other time points as specified in
Table 2. 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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7.4.1.2.
Follicle-Stimulating Hormone Tests
Postmenopausal women will have a follicle-stimulating hormone test at screening (visit 1).
7.5.
Physical Examinations
Physical examinations, including height (to be obtained at the screening visit only) and weight, 
will be performed at the time points detailed in Table 2. 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, body temperature, and pulse) will be measured before other 
assessments (eg, blood draws and administration of questionnaires) at the time points detailed in 
Table 2. 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 2. 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 clinical sites. 
Although the ECG interpretation will be performed centrally, the clinical evaluation remains the 
investigator’s responsibility.


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The ECG will be evaluated by the investigator at the time of recording (signed and dated), and 
the printout should be kept in the source documentation file. When potentially clinically 
significant findings are detected by the investigator, a cardiologist should be consulted for a 
definitive interpretation. All communications and diagnoses should be filed in the source 
documentation file. The investigator’s interpretation will be recorded in the CRF regardless of 
the central reading interpretation. Any abnormal findings assessed by the investigator as 
clinically significant should be recorded in the relevant CRF modules (eg, adverse event, medical 
history).
Objective alerts are predefined as described in the central ECG reading manual. In these cases, 
the site and the sponsor will be informed immediately. 
Any unscheduled ECGs must also be submitted for central ECG reading.
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 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.
7.8.
Immunogenicity
Blood samples for serum ADA assessment will be collected at the time points detailed in
Table 2. 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. 
Patients who are discontinued early for any reason or do not enroll in the double-blind, long-term 
safety study for treatment, for any reason, will be offered the option to enter the long-term safety 
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 IMP.
Samples from placebo-treated patients will not be analyzed unless the patient elects to enroll into 
the extension study where the patient will receive fremanezumab treatment. In this case the 
pre-dose (baseline) sample from the rolled-over placebo patient will be analyzed along with 
post-treatment samples collected in the extension study and reported in the extension 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 


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of suicidal ideation and behavior, and to report such symptoms immediately to the study 
investigator.
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 Baseline/Screening version will be completed by the 
patient at visit 1, and the eC-SSRS Since Last Visit version will be completed by the patient at 
every visit thereafter, 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 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 use will be monitored throughout the study. Details of 
prohibited medications are found in Section 5.6. 
7.11.
Injection Site Assessments
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 5.
Table 5:
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,has severe injection site 
induration, erythema, ecchymosis, or pain at 1 hour after completion of IMP administration, the 


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patient will be reassessed at 3 hours (±15 minutes) after completion of IMP administration and 
hourly (±15 minutes) thereafter until the reaction is of moderate or less severity.
Appropriate treatment may be provided if necessary, in which case it must be recorded as 
concomitant medication.
Injection-site reactions (injection site erythema, induration, ecchymosis, and pain) should be 
recorded as adverse events.


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8.
ASSESSMENT OF PHARMACOKINETICS/BIOMARKERS/ 
PHARMACOGENOMICS/IMMUNOGENICITY/ANCILLARY 
STUDIES
8.1.
Pharmacokinetics Assessment
Sampling for pharmacokinetics will be sparse. Thus, the fremanezumab pharmacokinetics
samples will be analyzed using a population pharmacokinetics approach and will be reported 
separately to the clinical study report. 
Blood samples 
 will be collected via venipuncture/indwelling catheter at the time points 
detailed in Table 2 for plasma concentration measurements of fremanezumab. 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 patients who receive active IMP will be analyzed for concentration of 
fremanezumab using a validated method. Samples from patients who were randomized to receive 
placebo will not be analyzed. Details on sample handling, storage, shipment, and analysis are 
given in Appendix N.
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 2 for immunogenicity testing.
Samples from patients who receive active IMP will be analyzed for ADA using a validated 
method. Samples from patients who receive placebo will not be analyzed unless the patient elects 
to enroll into an available extension study where the patient will receive fremanezumab
treatment. In this case, the predose (baseline) sample from the rolled-over placebo patient will be 
analyzed along with posttreatment samples collected in the extension study and values will be 
reported in the extension study. 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
 


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In preclinical models, CGRP can promote angiogenesis in ischemia, capsaicin-induced synovitis, 
and neovascularization of tumors.
 
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. Exploratory analysis will be 
conducted 
 
 
 
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 pharmacogenomic 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 (6 mL) will be collected from each patient (unless the 
patient declines testing or local regulations prohibit testing) for pharmacogenomic assessment 
during this study. Pharmacogenomic assessment potentially includes the association analysis of 
both known and unknown DNA and RNA genetic variations.
8.6.
Ancillary Studies – Wearable Sensor Substudy
At selected sites, a subset of patients (n=45, approximately 15 patients from each treatment 
group) will be asked to wear a sensor monitoring system (digital wearable device) on the wrist to 
track sleep patterns and activity patterns.
 
 
These changes will be evaluated during days when patients experience CH attacks relative to 
days free of attacks, and will be evaluated for use as predictors of seasonal onset of new CH 
epoch.
 
 
Patients with CH describe their attacks to exhibit remarkable circadian and annual periodicity. 
The attacks are described to strike at predictable times of the day, mostly related to nocturnal 
sleep, and the clusters of these at specific times of the year (Barloese 2012, 2015, Rozen and 
Fishman 2012). CH attacks are also accompanied by systemic manifestations such as agitation 
and restlessness (Barloese 2015).


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It is anticipated that risks to patients beyond those listed in Section 1.3 are unlikely. 
Patients who are able to demonstrate appropriate use of the wearable device and are willing to 
comply with the requirements for use of the digital wearable device will be given the device and 
accessories at the baseline visit. The device will be worn continuously throughout the 12-week 
treatment period, and for patients who continue into the long-term safety study (Study TV48125-
CNS-30058), the device will be worn continuously throughout the 40-week treatment period of 
that study. Device checks and compliance checks will be done at the study center as described in 
the schedule of events shown in Table 2. The device will be collected at the time the patient 
discontinues from the study (ie, at the EOT visit if the patient will not continue participating in 
the substudy during the long-term safety study or at the early withdrawal visit). 
The digital wearable device is provided by Philips and will monitor activity during wake periods, 
which will be used to quantify relative activity. It will also monitor activity during sleep periods, 
which will be used to quantify sleep-wake parameters. Data will be obtained with an actigraphy 
device worn on the wrist. Motion data will be analyzed with either standard analysis techniques 
and/or advanced signal processing algorithms to extract the maximum amount of information 
from the data. Further information on the device and its use is provided in the substudy manual.


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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
A sample size of 258 patients (86 evaluable patients completing the study per treatment group) 
will provide at least 90% power to detect a treatment difference of 1 CH attack in the weekly 
average (assuming a common standard deviation [SD] of 2 CH attacks) at a 2-sided alpha level 
of 0.05. Assuming a 14% discontinuation rate, approximately 300 patients will be randomized in 
the trial.
9.2.
Analysis Sets
9.2.1.
Intent-to-Treat Analysis Set
The intent-to-treat (ITT) analysis set will include all randomized patients.
In the ITT analysis set, treatment will be assigned based on the treatment to which patients were 
randomized, regardless of which treatment they actually received.
9.2.2.
Safety Analysis Set
The safety analysis set will include all randomized patients who receive at least 1 dose of IMP.
In the safety analysis set, treatment will be assigned based on the treatment patients actually 
received, regardless of the treatment to which they were randomized, unless otherwise specified.
9.2.3.
Full Analysis Set
The full analysis set will include all patients in the ITT analysis set who receive at least 1 dose of 
IMP and have at least 1 postbaseline efficacy assessment on the primary endpoint. 
9.2.4.
Per-Protocol Analysis Set
The per-protocol (PP) analysis set is a subset of the ITT analysis set including only patients 
without any important protocol deviations. Important protocol deviations will be determined 
before unblinding/database lock.
In the PP analysis set, treatment will be assigned based on the treatment patients actually 
received, regardless of the treatment to which they were randomized. 
9.3.
Data Handling Conventions
Efficacy variables from patients who do not have diary entries completed for the entire study 
period will be imputed. Detailed data imputation rules will be described in the statistical analysis 
plan.


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9.3.1.
Handling Withdrawals and Missing Data
Efficacy variables from patients who do not have diary data completed for the entire study period 
will be imputed. For the analyses based on the proportion of responders, patients who are 
terminated from the study early will considered as non-responders. For patients who complete 
the study and have intermittent missing days in the e-diary, data will be prorated to 7 days. 
Details will be provided in 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 by treatment group and for all patients.
9.4.1.
Patient Disposition
Data from patients screened; patients screened but not randomized and reason for not 
randomized; patients who are randomized; patients randomized but not treated; patients in the 
ITT, safety, and other analysis sets; patients who complete the study; and patients who withdraw 
from the study will be summarized using descriptive statistics. Data from patients who withdraw 
from the study will also be summarized by reason for withdrawal using descriptive statistics.
9.4.2.
Demographic and Baseline Characteristics
Patient demographic and baseline characteristics, including medical history, prior medications
and therapies, and ECG findings will be summarized using descriptive statistics. For continuous 
variables, descriptive statistics (number [n], mean, SD, median, minimum, and maximum) will 
be provided. For categorical variables, patient counts and percentages will be provided. 
Categories for missing data will be presented if necessary.
Treatment groups will be compared for all continuous variables, using an analysis of variance 
(ANOVA) with treatment group as a factor. The categorical variables of patient sex and race will 
be summarized using descriptive statistics for each variable category. Missing categories will be 
presented if necessary. Treatment groups will be compared for all categorical variables using a 
Pearson’s chi-square (or Fisher’s exact test if cell sizes are too small).
9.5.
Efficacy Analysis
For the purpose of this study, a CH attack will be endorsed when the following situations occur: 
1. Severe or very severe unilateral orbital, supraorbital, and/or temporal pain lasting 15 to 
180 minutes
2. Either or both of the following:

at least 1 of the following symptoms or signs, ipsilateral to the headache:

conjunctival injection and/or lacrimation

nasal congestion and/or rhinorrhea

eyelid edema

forehead and facial sweating


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
forehead and facial flushing

sensation of fullness in the ear

miosis and/or ptosis

a sense of restlessness or agitation
9.5.1.
Primary Endpoint
The primary efficacy endpoint of this study is the mean change from baseline (run-in period) in 
the weekly average number of CH attacks during the 4-week period after administration of the 
first dose of the IMP, ie, based on week 0 to 4 data.
9.5.2.
Secondary Endpoints
The secondary efficacy endpoints to further demonstrate efficacy are as follows:

the proportion of patients with a ≥50% reduction from baseline (run-in period) in the 
weekly average number of CH attacks during the 4-week period after the first dose of 
the IMP, ie, based on week 0 to 4 data

the mean change from baseline (run-in period) in the number of CH attacks during the 
12-week period after administration of the first dose of the IMP, ie, based on week 0 
to 12 data

the mean change from baseline (run-in period) in the number of CH attacks during the 
4-week period after administration of the third dose of the IMP, ie, based on week 8 
to 12 data

the mean change from baseline (run-in period) in the weekly average number of days 
with use of cluster-specific acute headache medications (triptans and ergot 
compounds) during the 12-week period after administration of the first dose of the 
IMP, ie, based on week 0 to 12 data

the mean change from baseline (run-in period) in the weekly average number of days
oxygen is used to treat ECH during the 12-week period after administration of the 
first dose of the IMP, ie, based on week 0 to 12 data

assessment of patient’s perceived improvement, as measured by the PPSI at 1, 4, 8, 
and 12 weeks after administration of the first dose of the IMP relative to baseline 
(day 0)
9.5.3.
Exploratory Endpoints
The exploratory efficacy endpoints of this study are as follows: 

 
 
 
 


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
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Wearable sensor substudy exploratory endpoints are the following:

 


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9.5.4.
Planned Method of Analysis
The full analysis set (see Section 9.2.3) will be used for all efficacy analyses. Summaries will be 
presented by treatment group.
9.5.4.1.
Primary Efficacy Analysis
The primary efficacy endpoint, the mean change from baseline (run-in period) in the weekly 
average number of CH attacks during the 4-week period after administration of the first dose of 
the IMP, will be analyzed using an analysis of covariance (ANCOVA). The model will include 
treatment, baseline number of CH attacks, baseline preventive medication use (yes or no), 
gender, and region (US or other).


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9.5.4.2.
Sensitivity Analysis
Sensitivity analysis will be conducted to explore the impact of missing data in the primary 
efficacy analysis. Details will be provided in the statistical analysis plan.
9.5.4.3.
Secondary and Exploratory Efficacy Analysis
The continuous endpoints will be analyzed using an ANCOVA or a mixed model for repeated 
measures. For the proportion of responders, defined as 50% or more reduction from baseline in 
the weekly average number of CH attacks, data will be analyzed using a 
Cochran-Mantel-Haenszel test stratified by baseline preventive medication use (yes/no).
9.6.
Multiple Comparisons and Multiplicity
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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 2.
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 


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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. 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 prespecified 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.
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
9.9.
Pharmacokinetics Analysis
Pharmacokinetics plasma concentration results (fremanezumab) will be tabulated descriptively at 
each planned sampling time point by treatment group.
In addition, the most appropriate population pharmacokinetics 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 relationship may be estimated by compartmental 
techniques. The pharmacokinetics parameters will be based on fremanezumab measurements. 
The pharmacodynamics parameters will be the efficacy 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 relationship will be tested for inclusion 
in the model. If performed, this analysis will be reported separately.


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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. Results 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 pharmacokinetics 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
An interim analysis for futility will be performed once 50% of patients (the first 150 patients) 
have completed 4-week assessments during the double-blind study period or have withdrawn 
from the study early. An independent statistician from a third party will perform evaluations.
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 CSR, or any combination of these, as 
appropriate, and in accordance with applicable national, local, and regional requirements and 
regulations.


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10.
QUALITY CONTROL AND QUALITY ASSURANCE
Refer to Appendix C for information regarding quality control and quality assurance. This 
includes information about protocol amendments, deviations, responsibilities of the investigator 
to study personnel, study monitoring, and audit and inspection.
Refer to Appendix 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 ICH Harmonised Tripartite Guideline 
for GCP E6 and any applicable national and local laws and regulations (eg, Title 21 Code of 
Federal Regulations [21CFR] Parts 11, 50, 54, 56, 312, and 314, Directive 2001/20/EC of the 
European Parliament and of the Council on the approximation of the laws, regulations and 
administrative provisions of the Member States relating to the implementation of 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 or assent, competent authorities 
and IEC and IRB, confidentiality regarding study patients, and requirements for registration of 
the clinical study.


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12.
DATA MANAGEMENT AND RECORD KEEPING
See Appendix 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 (FDA) 3454 form. 
Each investigator will notify the sponsor of any relevant changes during the conduct of the study 
and for 1 year after the study has been completed.


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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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Japanese Headache Society. Clinical practice guideline for chronic headache 2013. 
www.neurology-jp.org/guidelinem/ch/documents/guideline2013.pdf
Kudrow L. The cyclic relationship of natural illumination to cluster period frequency. 
Cepahalalgia 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 three 
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. Pharmaco Economics 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 02 Dated 01 May 2017
The primary reason for this amendment is to provide clarification based on feedback from 
participating investigators and regulatory agencies. This amendment is considered to be 
substantial (ie, requires approval by competent authorities, IEC, and/or IRB) by the sponsor’s 
Authorized Representative. 
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 2 (Study Procedures and Assessments) has been revised to reflect changes described 
below.


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Original text with changes shown
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Reason/justification 
for change
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.
It is relevant to note that due to the higher exposure observed in
the recent clinical Study TV48125-PK-10078 (Japanese bridging 
study), a re-evaluation of the safety margins was performed. An 
internal investigation indicates that the original assay 
underestimated fremanezumab measured plasma concentrations. 
Comparison of the exposure parameters of maximum observed 
concentration (Cmax) and area under the plasma concentration-
time curve from time 0 to infinity (AUC0-∞) from Study LBR-
101-011 (including iv dosing), which were analyzed by the 
original bioassay, with the exposure parameters from Study 
TV48125-PK-10078, which were analyzed using the newer 
validated assay for the 225-mg and 900-mg sc dose levels, 
indicates an apparent exposure difference between 2.9- and 3.5-
fold in Study TV48125-PK-10078 relative to Study LBR-101-
011. Thus, the most conservative factor of 3.5 was used to 
recalculate the safety margins, meaning that LBR-101-011 
exposure was assumed to be 3.5-fold higher than originally 
reported, and as such, safety margins decreased by 3.5-fold.
It is relevant to note that due to the higher exposure 
observed in the recent clinical Study TV48125-PK-10078 
(Japanese bridging study), a re-evaluation of the safety 
margins was performed. An internal investigation 
indicates that the original assay underestimated 
fremanezumab measured plasma concentrations. 
Comparison of the exposure parameters of maximum 
observed concentration (Cmax) and area under the plasma 
concentration-time curve from time 0 to infinity (AUC0-∞) 
from Study LBR-101-011 (including iv dosing), which 
were analyzed by the original bioassay, with the exposure 
parameters from Study TV48125-PK-10078, which were 
analyzed using the newer validated assay for the 225-mg 
and 900-mg sc dose levels, indicates an apparent 
exposure difference between 2.9- and 3.5-fold in Study 
TV48125-PK-10078 relative to Study LBR-101-011. 
Thus, the most conservative factor of 3.5 was used to 
recalculate the safety margins, meaning that LBR-101-
011 exposure was assumed to be 3.5-fold higher than 
originally reported, and as such, safety margins decreased 
by 3.5-fold.
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 
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 
Added updated 
information for 
nonclinical studies.


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Reason/justification 
for change
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.
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.
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 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.).
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.
Added updated 
information for clinical 
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 
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 
Added updated 
information for 
pharmacology studies.


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Reason/justification 
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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 using the current validated bioanalytical method, and 
the pharmacokinetic results are described below. 
The pharmacokinetics (non-compartmental analysis) of 
fremanezumab demonstrated an increase in Cmax and AUC 
values slightly greater than dose proportionality over the sc dose 
range of 225 to 900 mg. Median time to
 
 
aximum observed concentration (tmax) values 
was generally of 1.0 to 5 to 7 days post sc
 
 
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 6.49 to 13 L at 225- to 900-mg sc doses of 30 to 
2000 mg. The mean apparent total plasma clearance (CL/F)
ranged from 0.0777141 to 0.0895 mL/min276 L/day at this dose 
range. The mean t½ ranged from 32.2 26.8 to 53.4 days within 
the dose range of 30 to 36.2 days. Fremanezumab exposure 
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 using 
the current validated bioanalytical method, and the 
pharmacokinetic results are described below. 
The pharmacokinetics (non-compartmental analysis) of 
fremanezumab demonstrated an increase in Cmax and 
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 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
 
 
 
 


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parameters and overall pharmacokinetic profile were 2000 mg. 
Absolute bioavailability of the sc dose was similar for healthy 
Japanese and Caucasian subjects. 
 
 
 
 
 
 
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 TV48125-CNS-30049 and TV48125 
CNS-30050, as of 23 April 2016).
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-CNS-30049 and TV48125 CNS-30050, as of 
23 April 2016).
Updated for 
clarification.
Section 2.2.1, Exploratory Objectives and Endpoints (other section affected by this change: Section 3.1 Study Design, 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: Section 3.4, Stopping Rules for the Study; 
Section 3.5, Table 2: Schedule of Study Procedures and Assessments [footnote p]; Section 4.3, Withdrawal Criteria and Procedures; Section 
5.4, Treatment after the End of the Study; and Section 7.8, Immunogenicity)
Blinded treatment will be administered once monthly (ie, 
approximately every 4 weeks) for a total of 3 months. Final 
study assessments will be performed at the final visit for this 
study (visit 5), approximately 12 weeks after administration of 
Blinded treatment will be administered once monthly (ie, 
approximately every 4 weeks) for a total of 3 months. 
Final study assessments will be performed at the final 
visit for this study (visit 5), approximately 12 weeks after 
Added clarification that 
all patients will be 
offered opportunity to 
participate in the long-


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the first dose of the IMP. Upon satisfactory completion of the 
final study assessments, early withdrawal from the study or 
discontinuation for any reason, patients willmay be offered the 
opportunity to enter a 32 68 week long-term safety study (as
described in Study TV48125-CNS-30058) for safety), consisting 
of a 40 week long term treatment period and ADA evaluation 
without additional dosing.a final follow up visit approximately 
7.5 months after the last dose of the IMP. A separate protocol 
will be issued for the long term safety study. Patients who do 
not enroll in the long term safety study for any reason may be 
offered the opportunity to enter the study for the purpose of 
evaluating ADAs, fremanezumab concentrations, and safety 
(adverse events and concomitant medications) at approximately 
7.5 months after receiving the last dose of the IMP. 
Patients who satisfactorily complete the study may be offered to 
enroll the song-term safety study TV 48125-CNC-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. A separate protocol 
was issued for the long-term safety study.
CH attack information will be captured daily during the double-
blind treatment period using an electronic diary device. 
Assessments of CH related disability, 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 PPSI and Patients’ Global Impression of Change 
[PGIC] scale); safety evaluations (including eC-SSRS); blood 
collection for pharmacokinetics, immunogenicity, biomarker, 
administration of the first dose of the IMP. 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 TV48125-
CNC-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. A separate 
protocol was issued for the long-term safety study.
CH attack information will be captured daily during the 
double-blind treatment period 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 
PPSI and Patients’ Global Impression of Change [PGIC] 
scale); safety evaluations (including eC-SSRS); blood 
collection for pharmacokinetic, immunogenicity, 
biomarker, and pharmacogenomic (unless not allowed per 
local regulation) analyses; and urine sampling for 
biomarker analysis will be performed at prespecified time 
points.
term safety study either 
for treatment and 
long-term safety 
assessment or for long-
term safety assessment 
alone.


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Reason/justification 
for change
and pharmacogenomics (unless not allowed per local regulation) 
analyses; and urine sampling for biomarker analysis will be 
performed at prespecified time points.
Section 3.4, Stopping Rules for the Study (other section affected by this change: Section 4.3, Withdrawal Criteria and Procedures)
•
Tthe interim analysis (performed when 50% of patients have 
completed 4-week assessments during the double-blind study 
period or have withdrawn from the study early) supports 
stopping early for futility.
•
The interim analysis (performed when 50% of 
patients have completed 4-week assessments during the 
double-blind study period or have withdrawn from the 
study early) supports stopping early for futility.
Added clarification 
regarding the timing of 
the interim analysis
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 Section 10, noncompliance, or adverse 
event).
The investigator and/or sponsor can withdraw a patient 
from the study at any time for any reason (eg, lack of 
efficacy, protocol deviation as defined in Section 10, 
noncompliance, or adverse event).
Added clarification that 
lack of efficacy may 
result in withdrawal 
from the study.
Section 3.5, Table 2: Study Procedures and Assessments (other section affected by this change: Appendix B, Study Procedures and 
Assessments by Visit)
Week 12 - EOT or early withdrawal
day 84 (±3 days)
Removed “Hypersensitivity/anaphylaxis reaction assessment” 
time point from the table
Hypersensitivity/anaphy
laxis reaction 
assessment removed 
because there is no IMP 
administration at this 
visit.
Section 4, Selection and Withdrawal of Patients
Prospective waivers (exceptions) from study inclusion and 
exclusion criteria to allow patients to be randomized/enrolled are 
not granted by 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: Appendix H, Preventive Cluster Headache Medications and 
Disallowed Medications)
CH attacks of a new cluster cycle have started no more than 
within ≤2 weeks (1514 days, inclusive) prior to screening and, 
based on the patient’s previous medical history, it is expected 
that the patient’s CH attacks will continue for ≥6 weeks after the 
screening visit.
d.
CH attacks of a new cluster cycle have started within 
≤2 weeks (14 days, inclusive) prior to screening and, 
based on the patient’s previous medical history, it is 
expected that the patient’s CH attacks will continue for 
≥6 weeks after the screening visit.
Updated for 
clarification.


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e.
The patient is not using or using ≤a maximum of 2 
concomitant medications that are commonly prescribed as 
preventive treatments for CH (Appendix H), regardless of the 
indication for which the medication was prescribed. Patients 
must be on a stable dose and regimen for at least 2 weeks prior 
to screening and throughout the study
f.
The patient is not using or using ≤2 concomitant 
medications that are commonly prescribed as preventive 
treatments for CH (Appendix H), regardless of the 
indication for which the medication was prescribed. 
Patients must be on a stable dose and regimen for at least 
2 weeks prior to screening and throughout the study.
Updated for 
clarification.
g.
If a patient is receiving Botox, it should be in a stable dose 
regimen, considered as having ≥2 cycles of Botox prior to 
screening. The patient should not receive Botox during the run-
in period up to the evaluation period (12 weeks) where the 
primary endpoint is evaluated.
g.
If a patient is receiving Botox, it should be in a stable 
dose regimen, considered as having ≥2 cycles of Botox 
prior to screening. The patient should not receive Botox 
during the run-in period up to the evaluation period (4
weeks) where the primary endpoint is evaluated.
Added inclusion 
criterion to specify 
treatment window for 
patients that have been 
treated with Botox for 
the prevention of 
migraine.
j.
Women may be included only if they have a negative serum 
beta-human chorionic gonadotropin (β-HCG) test at screening, 
are sterile, or postmenopausal, and are not lactating.
k.
Women may be included only if they have a negative 
serum beta-human chorionic gonadotropin (β-HCG) test 
at screening, are sterile or postmenopausal, and are not 
lactating.
Updated for 
clarification. 
l.
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 discontinuation of 
the IMP. Definitions of WOCBPwomen of non-childbearing 
potential, sterile women, and postmenopausal women; male 
contraception; and highly effective and acceptable birth control 
methods including examples are given in Appendix E.
m. 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 discontinuation of the IMP. Definitions of 
women of non-childbearing potential, sterile women, and 
postmenopausal women; male contraception; and highly 
effective and acceptable birth control methods including 
examples are given in Appendix E.
Updated for 
clarification.
Section 4.2, Patient Exclusion Criteria (other section affected by this change: Appendix H, Preventive Cluster Headache Medications and 
Disallowed Medications)
a.
The patient has used systemic steroids for any medical 
reason (including treatment of short corticosteroid cycle to treat
the current CH cycle) within ≤7 days prior to screening.
a.
The patient has used systemic steroids for any 
medical reason (including treatment of short 
corticosteroid cycle to treat the current CH cycle) within 
≤7 days prior to screening.
Updated for 
clarification.


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Reason/justification 
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e.
The patient has clinically significant hematological, renal, 
endocrine, immunologic, pulmonary, gastrointestinal, 
genitourinary, cardiovascularcardiac, neurologic, hepatic, or 
ocular disease at the discretion of the investigator.
e.
The patient has clinically significant hematological, 
renal, endocrine, immunologic, pulmonary, 
gastrointestinal, genitourinary, cardiovascular, 
neurologic, hepatic, or ocular disease at the discretion of 
the investigator.
Updated for 
clarification.
i.
The patient has known infection or history of human 
immunodeficiency virus, tuberculosis, or chronic hepatitis B or 
C infection.
Exclusion criterion 
deleted.
j.
The patient has a past or current history of cancer or 
malignant tumor in the past 5 years, except for appropriately 
treated non-melanoma skin carcinoma. 
i.
The patient has a past or current history of cancer or 
malignant tumor in the past 5 years, except for 
appropriately treated non-melanoma skin carcinoma.
Updated for 
clarification.
k.
The patient is pregnant or lactatingnursing.
j.
The patient is pregnant or lactating.
Updated for 
clarification.
n.
The patient has participated in a clinical study of a 
monoclonal antibody within 3 months or 5 half-lives before 
administration of the first dose of the IMP, whichever is longer,
unless it is known that the patient received placebo during the 
study.
m. The patient has participated in a clinical study of a 
monoclonal antibody within 3 months or 5 half-lives 
before administration of the first dose of the IMP, 
whichever is longer, unless it is known that the patient 
received placebo during the study.
Updated for 
clarification.
o.
The patient has a history of prior exposure to a monoclonal 
antibody targeting the CGRP pathway (AMG 334, ALD304, 
LY2951742, or fremanezumab). If the patient has participated in 
a clinical study with any of these monoclonal antibodies, it has 
to be confirmed that the patient received placebo in order to be 
eligible for this study.
n.
The patient has a history of prior exposure to a 
monoclonal antibody targeting the CGRP pathway (AMG 
334, ALD304, LY2951742, or fremanezumab). If the 
patient has participated in a clinical study with any of 
these monoclonal antibodies, it has to be confirmed that 
the patient received placebo in order to be eligible for this 
study.
Updated for 
clarification.
v.
The patient has an active implant for neurostimulation used 
in the treatment of CH.
u.
The patient has an active implant for 
neurostimulation used in the treatment of CH.
Updated for 
clarification.
x.
The patient has a history of alcohol and/or drug abuse that in 
the investigator’s opinion could interfere with the study 
evaluations or the patient’s safetyabuse prior to screening.
w. The patient has a history of alcohol and/or drug abuse 
that in the investigator’s opinion could interfere with the 
study evaluations or the patient’s safety.
Updated for 
clarification.
Section 4.3,Withdrawal Criteria and Procedures (other sections affected by this change: Section 5.4, Treatment after the End of the Study, 
Section 7.8 Immunogenicity, and Appendix C, Quality Control and Quality Assurance)
8.
The investigator and/or sponsor may withdraw an individual 
patient from the study at any time for any reason (eg, lack of 
8.
The investigator and/or sponsor may withdraw an 
individual patient from the study at any time for any 
Added text for 
clarification for reasons 


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efficacy, protocol deviation as defined in Section 10, 
noncompliance, or adverse event). In additon, 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.
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.
for withdrawal.
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.
All protocol-specified procedures/assessments should be 
performed at the early withdrawal visit (see Appendix B). 
Patients who withdraw from the study will not be replaced. 
Patients who discontinue early for any reason willHowever, they 
may be offered the opportunityoption to enterenroll in the long-
term safety study (Study TV48125-CNS-30058) for the purpose 
of evaluation of ADAs, fremanezumab concentrations, and 
safety (adverse events and concomitant medications) 
approximately 7.5 months (approximately 5 half lives of the 
active IMP) after administration of the last dose of IMP in this 
study. These patients will not receive any doses of 
fremanezumab after completing participation in the current 
study and should be treated with standard of care as appropriate.
All protocol-specified procedures/assessments should be 
performed at the early withdrawal visit (see Appendix B). 
Patients who withdraw from the study will not be 
replaced. Patients who discontinue early for any reason 
willHowever, they may be offered the opportunityoption 
to enterenroll in the long-term safety study (Study 
TV48125-CNS-30058) for the purpose of evaluation of 
ADAs, fremanezumab concentrations, and safety (adverse 
events and concomitant medications) approximately 7.5 
months (approximately 5 half-lives of the active IMP) 
after administration of the last dose of IMP in this study. 
These patients will not receive any doses of 
fremanezumab after completing participation in the 
current study and should be treated with standard of care 
as appropriate.
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, 
except for patients who do not meet study inclusion criterion “h” 
of the required number of cluster attacks during run-in period. 
These patients may be eligible for one additional rescreening if 
approved by the sponsor on a case-by-case basis. 
A patient who is screened and does not meet study 
inclusion and exclusion criteria will not be considered for 
screening again, except for patients who do not meet 
study inclusion criterion “h” of the required number of 
cluster attacks during run-in period. These patients may 
be eligible for one additional rescreening if approved by 
Added text for 
clarification.


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Reason/justification 
for change
the sponsor on a case-by-case basis.
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 5.3.1 Justification for Dose of Test Investigational Medicinal Product
 
 
 
 
 
 
 
 
 
Revised for 
clarification.
Section 5.4,Treatment after the End of the Study (other sections affected by this change: Section 7.8 Immunogenicity)
Patients who successfully complete the final visit of this study 
may be offered the opportunity to enroll in athe long-term safety 
extension study (Study TV48125-CNS-30058), which includes a 
treatment period lasting approximately 40 weeks. 
Patients who successfully complete the final visit of this 
study may be offered the opportunity to enroll in a long-
term safety extension study (Study TV48125-CNS-
30058), which includes a treatment period lasting 
approximately 40 weeks. 
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 6.1, Electronic Diary Device (other section affected by this change: Section 3.5, Table 2: Study Procedure and Assessments [footnote 
m])
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 
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 
Revised for 
clarification.


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Original text with changes shown
New wording
Reason/justification 
for change
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.
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.
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 48 hours 2 days have elapsed since completion of that 
day. If more than 48 hours 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 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. 
Revised for 
clarification.
Section 7.1.8, Protocol Deviations Because of an Adverse Event (other sections affected by this change: Section 7.3, Medication Error and 
Special Situations Related to the Investigational Medicinal Products; Appendix C, Quality Control and Quality Assurance)
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 
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 
Revised for 
clarification.


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Reason/justification 
for change
noncompliances should be reported to the Regulatory Authority 
as a serious breach of Good Clinical Practice (GCP) and the 
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.
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. When meeting important protocol deviation criteria, 
all instances of incorrect IMP administration should be reported 
in the clinical trial management system. A noncompliant 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. When meeting 
important protocol deviation criteria, all instances of 
incorrect IMP administration should be reported in the 
clinical trial management system. A noncompliant 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 (other sections affected by the change: Section 3.5, Table 2: Study Procedure 
and Assessments footnote i; Appendix B, Study Procedures and Assessments by Visit)
Clinical laboratory tests (serum chemistry, hematology, and
urinalysis) will be performed at the time points detailed in Table 
2. Clinical laboratory tests will be performed using the central 
laboratory. However, in case of abnormal coagulation during 
screening (run-in period) or 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 2. Clinical laboratory tests will be 
performed using the central laboratory. However, in case 
of abnormal coagulation during screening (run-in period) 
or 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 2. Only the samples from 
fremanezumab treated patients will be analyzed for ADAs. 
Blood samples for serum ADA assessment will be 
collected at the time points detailed in Table 2. 
Revised for 
clarification.
Section 7.11, Injection Site Assessments (other sections affected by this change: Section 3.5, Table 2: Study Procedure and Assessments 
footnote z; Appendix B, Study Procedures and Assessments by Visit)
Injection site assessments will be performed immediately (+10 
Injection site assessments will be performed immediately Added clarification for 


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for change
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 5.
(+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 5.
injection site assessment 
windows.
Revised the “Assessment” column in Table 5 Severity of Pain 
Scale for Injection Site Assessments
Severity grade 1 (mild) = Painful on touch revised to Severity 
grade 1 = Mild
Severity grade 2 (moderate) = Pain on ambulation revised to 
Severity grade 2 = Moderate
Severity grade 3 (severe) = Spontaneously painful revised to 
Severity grade 3 = Severe
Severity grade 1 = Mild
Severity grade 2 = Moderate
Severity grade 3 = Severe
Revised for 
clarification.
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
Assuming a 14% discontinuation rate, approximately
300 patients will be randomized in the trial.
Assuming a 14% discontinuation rate, approximately
300 patients will be randomized in the trial.
Revised for consistency 
with other sections.


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Section 9.6, Multiple Comparisons and Multiplicity
Hochberg’s step-up method will be implemented to test primary 
and secondary endpoints while controlling the overall type 1 
error rate at 0.05. The treatment comparisons will be for the 
fremanezumab 900-mg iv loading dose group versus placebo 
[H01] and the fremanezumab 675-mg sc quarterly group versus 
placebo [H02]. According to Hochberg step-up method, the rules 
of multiple comparisons for 2 null hypotheses for the primary 
endpoint are as follows:. Details will be provided in the 
statistical analysis plan.
If the resulting 2-sided p-values from both comparisons are 
≤0.05 (reject both null hypotheses), then the next comparison of 
interest will be interpreted inferentially at the alpha level of 0.05 
and statistical significance will be claimed for both active dose 
groups. Testing of secondary efficacy measures will be 
continued.
If the resulting 2-sided p-value from 1 of comparisons is >0.05 
(fail to reject the null hypothesis) and the other resulting 2-sided 
p-value is ≤0.025 (/2=0.025; reject the null hypothesis), then 
the result from the comparison with p-value ≤0.025 will be 
interpreted inferentially at the alpha level of 0.05 and statistical 
significance will be claimed for this active dose group. No other 
comparison(s) will be interpreted inferentially.
If the resulting 2-sided p-values from both comparisons are 
>0.05 (fail to reject both null hypotheses), then no statistical 
significance will be claimed and no comparisons will be 
interpreted inferentially.
If the resulting 2-sided p-values from both comparisons for the 
primary endpoint are ≤0.05 (reject both hypotheses; case 1 as 
described above), testing of secondary efficacy measures will 
proceed at an error rate of 0.05 in the sequential manner as 
specified in Section 2.1. The same testing rules as described 
above will be followed. This process will continue either until 
all comparisons of interest for secondary endpoints are 
Hochberg’s step-up method will be implemented to test 
primary and secondary endpoints while controlling the 
overall type 1 error rate at 0.05. The treatment 
comparisons will be for the fremanezumab 900-mg iv 
loading dose group versus placebo [H01] and the 
fremanezumab 675-mg sc quarterly group versus placebo 
[H02]. According to Hochberg step-up method, the rules 
of multiple comparisons for 2 null hypotheses for the 
primary endpoint are as follows:
If the resulting 2-sided p-values from both comparisons 
are ≤0.05 (reject both null hypotheses), then the next 
comparison of interest will be interpreted inferentially at 
the alpha level of 0.05 and statistical significance will be 
claimed for both active dose groups. Testing of secondary 
efficacy measures will be continued.
If the resulting 2-sided p-value from 1 of comparisons is 
>0.05 (fail to reject the null hypothesis) and the other 
resulting 2-sided p-value is ≤0.025 (/2=0.025; reject the 
null hypothesis), then the result from the comparison with 
p-value ≤0.025 will be interpreted inferentially at the 
alpha level of 0.05 and statistical significance will be 
claimed for this active dose group. No other 
comparison(s) will be interpreted inferentially.
If the resulting 2-sided p-values from both comparisons 
are >0.05 (fail to reject both null hypotheses), then no 
statistical significance will be claimed and no 
comparisons will be interpreted inferentially.
If the resulting 2-sided p-values from both comparisons 
for the primary endpoint are ≤0.05 (reject both 
hypotheses; case 1 as described above), testing of 
secondary efficacy measures will proceed at an error rate 
of 0.05 in the sequential manner as specified in Section 
2.1. The same testing rules as described above will be 
Details about multiple 
comparisons and 
multiplicity added for 
clarification.


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interpreted inferentially or until the point at which the resulting 
2-sided p-value for a comparison of interest is >0.05. At the 
point where a 2-sided p-value is >0.05, the testing process stops. 
No further comparisons will be interpreted inferentially.
followed. This process will continue either until all 
comparisons of interest for secondary endpoints are 
interpreted inferentially or until the point at which the 
resulting 2-sided p-value for a comparison of interest is 
>0.05. At the point where a 2-sided p-value is >0.05, the 
testing process stops. No further comparisons will be 
interpreted inferentially.
Section 9.15, Planned Interim Analysis 
An interim analysis for futility will be performed once 50% of 
patients (the first 150 patients) have completed 4-week 
assessments during the double-blind study period or have 
withdrawn from the study early. An independent statistician 
from a third party will perform evaluations.
An interim analysis for futility will be performed once 
50% of patients (the first 150 patients) have completed 4-
week assessments during the double-blind study period or 
have withdrawn from the study early. An independent 
statistician from a third party will perform evaluations.
Revised for 
clarification.
Section 11, Compliance Statement
See Appendix D for the ethics expectations of informed consent 
or assent, competent authorities and IEC and IRVIRB, 
confidentiality regarding study patients, and requirements for 
registration of the clinical study.
See Appendix D for the ethics expectations of informed 
consent or assent, competent authorities and IEC and 
IRB, confidentiality regarding study patients, and 
requirements for registration of the clinical study.
Revised for correctness.
APPENDIX C, QUALITY CONTROL AND QUALITY ASSURANCE
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 randomized has 
already started taking the study drug, a risk/benefit evaluation 
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 randomized has already 
Revised for 
clarification.


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has to take place and a strong clinical justification must be 
provided in case the patient is not withdrawn from the study 
drug.
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.
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 high an 
increased concentration of follicle-stimulating hormone (FSH)
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) 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 iv infusions: Investigational 
medicinal product (IMP) syringes should be allowed to 
equilibrate at room temperature for 45 to 60 minutes before 
administration into the iv bag. The contents of 4 prefilled 
syringes, each containing fremanezumab (225 mg/1.5 mL) or 1.5 
Preparation instructions for iv infusions: Investigational 
medicinal product (IMP) syringes should be allowed to 
equilibrate at room temperature for 45 to 60 minutes 
before administration into the iv bag. The contents of 
4 prefilled syringes, each containing fremanezumab (225 
Revised for correctness.


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mL of placebo, will be added to 500 mL of normal saline 
solution. The iv infusion will be administered over 
approximately 1 hour.
Preparation instructions for sc injections: IMP should be allowed 
to equilibrate at room temperature for 4515 to 6030 minutes 
before sc administration.
mg/1.5 mL) or 1.5 mL of placebo, will be added to 500 
mL of normal saline solution. The iv infusion will be 
administered over approximately 1 hour.
Preparation instructions for sc injections: 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
2. Concomitant Medications Allowed and Disallowed
Steroids:
The only allowed steroids are intra-articular injection or ocular, 
ear drops, intranasal, inhaled, and creams for topical use.
Butalbital:
Screening/run-in period: Disallowed if used more than 3 days 
during the screening/run-in period. Patients can use butalbital as 
needed (PRN) after randomization into the study.
Opioids:
Screening/run-in period: Disallowed if used more than 4 days 
during the screening/run-in period. Patients can use opioids PRN 
after randomization into the study.
Steroids:
The only allowed steroids are intra-articular injection or 
ocular, ear drops, intranasal, inhaled, and creams for 
topical use.
Butalbital:
Screening/run-in period: Disallowed if used more than 3 
days during the screening/run-in period. Patients can use 
butalbital as needed (PRN) after randomization into the 
study.
Opioids:
Screening/run-in period: Disallowed if used more than 4 
days during the screening/run-in period. Patients can use 
opioids PRN after randomization into the study.
Revised for 
clarification.
Appendix L, TOTAL BLOOD VOLUME (other sections affected by this change: (Section 3.5, Table 2: Study Procedure and Assessments 
[footnote r]; Section 5.10, Total Blood Volume; Appendix B, Study Procedures and Assessments by Visit; Appendix P)
The total blood volume to be collected for each patient in this 
study is approximately 131.5118 mL (at maximum) for 
scheduled tests.
The total blood volume to be collected for each patient in 
this study is approximately 131.5 mL (at maximum) for 
scheduled tests.
Revised for clarification
Serum chemistry sample volume was revised from 3 to 3.5 mL 
(5 samples in total) with a total volume of 17.5 mL.
Serum pregnancy sample volume was revised from 3 mL (5 
samples in total) to 3.5 mL (2 samples in total).
Hematology sample volume was revised from 3 mL to 2 mL, 
and the total volume was changed from 15 mL to 10 mL.
Coagulation sample of 4.5 mL (5 samples in total) with a total 
volume of 22.5 mL was added.
Serum chemistry: 3.5 mL at 5 total number of samples
and 17.5 mL total volume
Serum pregnancy: 3.5 mL at 2 total number of samples
and 7 mL total volume
Hematology: 2 mL at 5 total number of samples and 10 
mL total volume
Coagulation: 4.5 mL at 5 total number of samples and 22 
mL total volume
Revised for clarification


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FSH sample volume was revised from 3 mL to 3.5 mL, and the 
total volume was changed from 3 mL to 3.5 mL.
The number of pharmacokinetic samples was decreased from 5 
to 4, and the total volume was changed from 20 mL to 16 mL.
Biomarker serum sample volume was revised from 14.5 mL to 
8.5 mL, and the total volume was changed from 29 mL to 17 
mL.
Biomarker plasma sample of 6 mL (2 samples in total) with a 
total volume of 12 mL was added.
Biomarker RNA sample was adjusted from 14.5 mL to 2.5 mL, 
and the total volume was changed from 29 mL to 5 mL.
The total volume of sample is thus changed from 118 mL to 
131.5 mL, and the total number of samples was changed from 22 
to 32.
FSH: 3.5 mL at 1 total number of samples and 3.5 mL 
total volume
Pharmacokinetics: 4 mL at 4 total number of samples and 
16 mL total volume
Biomarker serum: 8.5 mL at 2 total number of samples
and 17 mL total volume
Biomarker plasma: 6 mL at 2 total number of samples
and 12 mL total volume
Biomarker RNA: 2.5 mL at 2 total number of samples
and 5 mL total volume
Total: 32 samples at 131.5 mL total volume
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 
 (Sets A and B).
Separated plasma will be transferred in approximately 
equal portions in 2 labeled 
 
(Sets A and B).
Revised for 
clarification.
Set A samples will be transported frozen, with a temperature 
data logger and frozen with 
 sufficient for 4 days, on a 
monthly basis by next day courier to the central laboratory. 
Central laboratory will ship the Set A samples on a monthly 
basis to the or bioanalytical laboratory with 
 sufficient for 
4 days and with a temperature data logger. 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.
Set A samples will be transported frozen, with a 
temperature data logger and with 
 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 or bioanalytical laboratory with 
 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.
Revised for 
clarification.
ADA=antidrug antibody; ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; AUC=area under the plasma 
concentration-time curve; AUC0-∞=area under the plasma concentration-time curve from 0 to infinity; CH=cluster headache; CGRP= calcitonin gene related 
peptide; CL/F=mean apparent total plasma clearance (except for metabolites); Cmax=maximum observed concentration; CSR=clinical study report; 
ECH=episodic cluster headache; EOT=end of treatment; FSH=follicle-stimulating hormone; GCP=Good Clinical Practice; GGT=gamma-glutamyl 
transpeptidase; IMP=investigational medicinal product; INR=international normalized ratio; IRT=interactive response technology; iv=intravenous; PRN=as 


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needed; sc=subcutaneous; RNA=ribonucleic acid; tmax=time to maximum observed drug concentration; Vz/F=apparent total volume of distribution (except for 
metabolites); WOCBP=women of childbearing potential.


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16.2.
Amendment 01 Dated 30 November 2016
The primary reason for this amendment is to update the primary endpoint based on feedback 
from regulatory agencies and the sample size for this study based on the new primary endpoint. 
This amendment is considered to be substantial (ie, requires approval by competent authorities, 
IEC, and/or IRB) by the sponsor’s Authorized Representative. This amendment also incorporates 
changes detailed in the letter of clarification 01 (Section 16.4), letter of clarification 02 (Section
16.3), and letter of clarification 03 (Section 16.2) and other nonsubstantial changes. 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 2 (Study Procedures and Assessments) has been revised to reflect 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.
Investigator Agreement
Principal Investigator
Principal Investigator
Typo correction
Section 2.1, Primary and Secondary Study Objectives and Endpoints (other sections affected by this change: Section 9.5.1, Primary 
Endpoint; Section 9.5.2, Secondary Endpoints)
The primary efficacy endpoint of this study is the 
mean change from baseline (run-in period) in the 
weekly average number of cluster headache (CH) 
attacks during the 4-week period after administration 
of the first dose of the investigational medicinal 
product (IMP), ie, based on week 0 to 4 
dataproportion of patients with a ≥50% reduction 
from baseline (run in period) in the weekly average 
number of cluster headache (CH) attacks during the 4 
week period after the first dose of the investigational 
medicinal product (IMP), ie, based on week 0 to 4 
data.
The primary efficacy endpoint of this study is the 
mean change from baseline (run-in period) in the 
weekly average number of cluster headache (CH) 
attacks during the 4-week period after 
administration of the first dose of the investigational 
medicinal product (IMP), ie, based on week 0 to 4 
data.
The primary endpoint was updated 
based on feedback from regulatory 
agencies.
The secondary efficacy endpoints to further 
demonstrate efficacy are:

the proportion of patients with a ≥50% 
reduction from baseline (run-in period) in the 
weekly average number of CH attacks during 
the 4 week period after the first dose of the 
IMP, ie, based on week 0 to 4 datathe mean 
change from baseline (run in period) in the 
number of CH attacks during the 4 week 
period after administration of the first dose of 
the IMP, ie, based on week 0 to 4 data
The secondary efficacy endpoints to further 
demonstrate efficacy are:

the proportion of patients with a 
≥50% reduction from baseline (run-in 
period) in the weekly average number of 
CH attacks during the 4 week period after 
the first dose of the IMP, ie, based on 
week 0 to 4 data
The first secondary endpoint is 
now the primary endpoint. The 
endpoint that was previously the 
primary endpoint is now a 
secondary endpoint.


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Section 2.2.1 Exploratory Objectives and Endpoints (other section affected by this change: Section 9.5.3, Exploratory Endpoints):

 
 
 

 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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4 data
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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Reason/Justification for change

 
Section 3.1, General Design and Study Schematic Diagram
The study will consist of a screening visit, a run-in 
period lasting at least 1 week (+3 days), and a 
12-week double-blind treatment period. During the 
course of any CH attack, patients will be allowed to 
use acute medications to treat acute headaches, as 
needed.
The study will consist of a screening visit, a run-in 
period lasting at least 1 week (+3 days), and a 
12-week double-blind treatment period. 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.
Blinded treatment will be administered once monthly 
(ie, approximately every 4 weeks) for a total of 3 
months. Final study assessments will be performed at 
the final visit for this study (visit 5), approximately 
12 weeks after administration of the first dose of the 
IMP. Upon satisfactory completion of the final study 
assessments, patients maywill be offered the 
opportunity to enter a 68 week long-term safety study 
(Study TV48125-CNS-30058), consisting of a 
40-week long-term treatment period and a final 
follow-up visit approximately 7.5 months after the 
last dose of the IMP. A separate protocol will be 
issued for the long-term safety study. Patients who do 
not enroll in the long-term safety study for any reason 
maywill be offered the option to enter the study for 
the purpose of evaluating ADAs, fremanezumabTEV 
48125 concentrations, and safety (adverse events and 
concomitant medications) at approximately 7.5 
months after receiving the last dose of the IMP.
Blinded treatment will be administered once 
monthly (ie, approximately every 4 weeks) for a 
total of 3 months. Final study assessments will be 
performed at the final visit for this study (visit 5), 
approximately 12 weeks after administration of the 
first dose of the IMP. Upon satisfactory completion 
of the final study assessments, patients may be 
offered the opportunity to enter a 68 week 
long-term safety study (Study TV48125-CNS-
30058), consisting of a 40-week long-term 
treatment period and a final follow-up visit 
approximately 7.5 months after the last dose of the 
IMP. A separate protocol will be issued for the 
long-term safety study. Patients who do not enroll in 
the long-term safety study for any reason may be 
offered the option to enter the study for the purpose 
of evaluating ADAs, fremanezumab concentrations, 
and safety (adverse events and concomitant 
medications) at approximately 7.5 months after 
receiving the last dose of the IMP.
Edited to allow flexibility 
regarding enrollment in the 
long-term safety study.
Figure 1 was updated to show PBO SC and PBO IV
PBO SC
Update made to clarify how 


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at the first dosing visit (visit 2) for each of the active 
treatment groups.
PBO IV
blinding will be maintained.
A subset of patients in US basedselected 
investigational sites will be offered the opportunity to 
participate in a substudy 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).
A subset of patients in selected investigational sites 
will be offered the opportunity to participate in a 
substudy 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).
There is a possibility that patients 
at non-US sites may be offered the 
opportunity to participate in the 
wearable sensor substudy. The text 
has been revised to reflect this 
possibility.
Section 3.2, Planned Number of Patients and Countries
A total of approximately 216300 patients 
(approximately 72100 patients per treatment group) 
are planned to be enrolled in 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 Q4/2016 and last until approximately 
Q2/2018.
A total of approximately 300 patients 
(approximately 100 patients per treatment group) 
are planned to be enrolled 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 Q4/2016 and last until approximately 
Q2/2018.
The sample size was increased 
based on the new primary 
endpoint and decision not to re-
estimate the sample size as part of 
the interim analysis.
The number of investigational 
centers was increased based on the 
increased sample size, and the 
number of countries has been 
reduced based on feasibility 
assessments.
Section 3.4, Stopping Rules for the Study
The investigator and/or sponsor can withdraw a 
patient from the study at any time for any reason (eg, 
protocol violation or deviation as defined in 
Section 10, noncompliance, or adverse event).
The investigator and/or sponsor can withdraw a 
patient from the study at any time for any reason 
(eg, protocol deviation as defined in Section 10, 
noncompliance, or adverse event).
Change to terminology (violation 
changed to deviation) to align with 
guidance from the ICH.
Patients who are discontinued early for any reason 
willmay be offered the option to enroll in 
Study TV48125-CNS-30058 for the purpose of 
evaluating ADAs, fremanezumabTEV 48125
concentrations, and safety (adverse events and 
Patients who are discontinued early for any reason 
may be offered the option to enroll in 
Study TV48125-CNS-30058 for the purpose of 
evaluating ADAs, fremanezumab concentrations, 
and safety (adverse events and concomitant 
Edited to allow flexibility 
regarding enrollment in the 
long-term safety study.


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concomitant medications).
medications).
Section 3.5, Schedule of Procedures and Assessments
o.
The blood sample for pharmacokinetics analysis 
collected immediately before the end of the 
infusion at visit 2 (week 0) should be collected 
from the arm that is not used for the IMP 
infusion. Blood samples for pharmacokinetics 
analysis will be collected from the arm that is not 
used for the IMP infusion prior to dosing and 
immediately before the end of the infusion at 
visit 2 (week 0). All otherAt each visit thereafter, 
a single blood samples for pharmacokinetics 
analysis will be collected prior to dosing (where 
applicable) and may be collected from either arm.
o.
The blood sample for pharmacokinetics 
analysis collected immediately before the end 
of the infusion at visit 2 (week 0) should be 
collected from the arm that is not used for the 
IMP infusion. All other blood samples for 
pharmacokinetics analysis will be collected 
prior to dosing (where applicable) and may be 
collected from either arm.
With the exception of the blood 
sample collected immediately 
before the end of the IMP infusion 
(must be collected from the arm 
that is not used for the IMP 
infusion), blood samples for 
pharmacokinetics analysis may be 
collected from either arm.
Section 4.2, Patient Exclusion Criteria
h.
The patient has a history of clinically significant 
cardiovascular disease or vascular ischemia (such 
as myocardial, neurological [eg, cerebral 
ischemia], peripheral extremity ischemia, or other 
ischemic event) or thromboembolic events 
(arterial or venous thrombotic or embolic events), 
such as cerebrovascular accident (including 
transient ischemic attacks), deep vein thrombosis, 
or pulmonary embolism in the last 2 years. 
h. The patient has a history of clinically significant 
cardiovascular disease or vascular ischemia 
(such as myocardial, neurological [eg, cerebral 
ischemia], peripheral extremity ischemia, or 
other ischemic event) or thromboembolic events 
(arterial or venous thrombotic or embolic 
events), such as cerebrovascular accident 
(including transient ischemic attacks), deep vein 
thrombosis, or pulmonary embolism.
Time period expanded as it is 
important to include patients with 
CH who are otherwise healthy.
Section 4.3, Withdrawal Criteria and Procedures
Patients who withdraw from the study will not be 
replaced. However, they maywill be offered the 
option to enroll in Study TV48125-CNS-30058 for 
the purpose of evaluation of ADAs, 
fremanezumabTEV 48125 concentrations, and safety 
(adverse events and concomitant medications) 
approximately 7.5 months (approximately 5 half-lives 
Patients who withdraw from the study will not be 
replaced. However, they may be offered the option 
to enroll in Study TV48125-CNS-30058 for the 
purpose of evaluation of ADAs, fremanezumab
concentrations, and safety (adverse events and 
concomitant medications) approximately 
7.5 months (approximately 5 half-lives of the active 
Edited to allow flexibility 
regarding enrollment in the
long-term safety study.


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of the active IMP) after administration of the last 
dose of IMP in this study.
IMP) after administration of the last dose of IMP in 
this study.
Section 5.4, Treatment after the End of the Study (other section affected by this change: Section 3.5, Schedule of Procedures and 
Assessments)
Patients who successfully complete this study 
maywill be offered the opportunity to enroll in the 
long-term safety extension study (Study TV48125-
CNS-30058), which includes a treatment period 
lasting approximately 40 weeks. These patients will, 
therefore have continued access to TEV 48125 for up 
to 40 additional weeks after completing the final visit 
of this study. Patients who do not enroll in this long-
term study for any reason maywill be offered the 
option to enter the study for the purpose of evaluating 
ADAs, fremanezumabTEV 48125 concentrations, 
and safety (adverse events and concomitant 
medications) at approximately 7.5 months after 
administration of the last dose of the IMP.
Patients who successfully complete this study may 
be offered the opportunity to enroll in the long-term 
safety extension study (Study TV48125-CNS-
30058), which includes a treatment period lasting 
approximately 40 weeks. Patients who do not enroll 
in this long-term study for any reason may be 
offered the option to enter the study for the purpose 
of evaluating ADAs, fremanezumab concentrations, 
and safety (adverse events and concomitant 
medications) at approximately 7.5 months after 
administration of the last dose of the IMP.
Edited to allow flexibility 
regarding enrollment in the 
long-term safety study.
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)(other section affected by this change: Appendix L, Total Blood Volume)
The total blood volume to be collected for each 
patient enrolling in this study for treatment with 
TEV 48125 is approximately 11826 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 is approximately 
118 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 2 PAXGene 
RNA samples are to be collected, 
the total blood volume is reduced 
by 8 mL.
This text was also updated to 
clarify that blood will be collected 
from all patients regardless of 
treatment and additional blood 


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may be collected in the case of 
elevated liver function tests as 
detailed in Appendix J.
Section 6.1, Electronic Diary Device
If a patient fails to complete the diary for the 
preceding day within the allowed timeframe (until 
00:00 hours of 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 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 
daythe missed 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 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.
If a CH is reported, then CH intensity will be 
subjectively rated by the patient as follows:using 
NRS 11 rating scale.

Mild

Moderate

Severe

Very severe
If a CH is reported, then CH intensity will be 
subjectively rated by the patient as follows:

Mild

Moderate

Severe

Very severe
Removed the NRS scale to meet 
the definition of the IHS for CH 
attack.
Section 6.2, Numeric Rating Scale (other section affected by this change: Section 3.5, Schedule of Procedures and Assessments)
6.2.Numeric Rating Scale
The NRS 11 is an 11 point scale for patient self
reporting of pain. The numeric scale ranges from '0' 
representing “no pain” to '10' representing “pain as 
bad as you can imagine” or “worst pain imaginable”.
Patients will complete the NRS 11 questionnaire in 
the electronic diary for each attack throughout the 
run in and treatment periods (ie, through the end of 
Removed the NRS scale to meet 
the definition of the IHS for CH 
attack.


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treatment [EOT]; visit 5).
Section 6.7, Patient-Perceived Satisfactory Improvement (other section affected by this change: Section 3.5, Schedule of Procedures and 
Assessments)
New section number due to removal of Section 6.2: 
Section 6.78, Patient-Perceived Satisfactory 
Improvement
The PPSI was developed by ten Klooster et al (2006)
and is composed of an unmarked 100 mm visual 
analog scalefor pain intensity (VAS PI)and was 
adjusted for CH symptoms improvementwith “no 
pain” and “unbearable pain” as anchors and a 
question regarding change in pain intensity. Patients 
will mark the level of CH-associated pain 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])4 weeks ago. PPSI will be defined as the 
change in pain on the VAS PIthat corresponds with a 
minimal rating of “satisfactoryslightly improved.”
Section 6.7, 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.”
In the e-diary, a VAS cannot be 
used. Understanding that CH 
causes pain, the report to measure 
improvement or not is adapted for 
CH.
Section 6.8, Patient Global Impression of Change Scale
New section number due to removal of Section 6.2: 
Section 6.89, 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 
during assigned time points 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 
New section number due to removal of Section 6.2: 
Section 6.8, 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,” 
Updated the text to align with the 
e-diary.


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7 point scale where 1 is as “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.”
“slightly worse,” “stayed the same,” “a little better,” 
“moderately better,” or “much better.”
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.
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 reported 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 7.4.1, Serum Chemistry, Hematology, and Urinalysis (other section affected by this change: Section 3.5, Schedule of Procedures 
and Assessments)
Clinical laboratory tests will be performed using the 
central laboratory. However, in case of abnormal 
coagulation during screening (run-in period), a retest 
to be performed locally can be authorized by the 
Clinical laboratory tests will be performed using the 
central laboratory. However, in case of abnormal 
coagulation during screening (run-in period), a local 
retest can be authorized by the sponsor on a case-
Added to allow for additional 
assessment if necessary.


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Sponsor on a case-by-case basis.
by-case basis.
Section 7.8, Immunogenicity (other section affected by this change: Section 3.5, Schedule of Procedures and Assessments)
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. 
Bioanalytical personnel should be made aware of 
anaphylaxis occurrence as soon as possible in case an 
anti-fremanezumabTEV 48125 IgE assay is needed. 
Patients who will not enroll in the double-blind, long-
term safety study, for any reason, willmay be offered 
the option to enter the long-term safety study for the 
purpose of evaluating ADAs, fremanezumabTEV 
48125 concentrations, and safety (adverse events and 
concomitant medications) approximately 7.5 months 
(approximately 5 half-lives of the active IMP) after 
administration of the last dose of IMP in this study.
Bioanalytical personnel should be made aware of 
anaphylaxis occurrence as soon as possible in case 
an anti-fremanezumab IgE assay is needed. Patients 
who will not enroll in the double-blind, long-term 
safety study, for any reason, may be offered the 
option to enter the long-term safety study for the 
purpose of evaluating ADAs, fremanezumab
concentrations, and safety (adverse events and 
concomitant medications) approximately 
7.5 months (approximately 5 half-lives of the active 
IMP) after administration of the last dose of IMP in 
this study.
Edited to allow flexibility 
regarding enrollment in the 
long-term safety study.
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 a patient 
reports current suicide ideation with specific plan and 
intentIf the patient scores 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 
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 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 
Adapted text to the eC-SSRS 
electronic questionnaire format.


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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.
actions) should be excluded and/or discontinued 
from the study.
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 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 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. 

…
Symp om
Severity
grade
Assessment
Pain
0
AbsentNo pain
1 (mild)
Painful on touchMild
2
(moderate)
Pain on 
ambulationModerate
3 (severe)
Spontaneously 
painfulSevere
4
Worst possible
Injection site assessments will be performed 
immediately 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:

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
Assessme t
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, 
Deleted grade 4 to align severity 
grading with severity scale for 
adverse events.


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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.
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, 
At selected sites in the US, a subset of patients (n=45, 
approximately 15 patients from each treatment group) 
will be asked to wear a sensor monitoring system 
(digital wearable device) on the wrist to track sleep 
patterns and physical movementactivity patterns
 
 
These changes will be evaluated during 
days when patients experience CH attacks relative to 
days free of attacks, and will be evaluated for use as 
predictors of seasonal onset of new CH epoch.
 
 
 
…
At selected sites, a subset of patients (n=45, 
approximately 15 patients from each treatment 
group) will be asked to wear a sensor monitoring 
system (digital wearable device) on the wrist to 
track sleep patterns and activity patterns.
 
 
 
 These 
changes will be evaluated during days when patients 
experience CH attacks relative to days free of 
attacks, and will be evaluated for use as predictors 
of seasonal onset of new CH epoch.
 
 
…
 
Changed to align with how the 
Phillips device reports activity.


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New wording
Reason/Justification for change
 
 
 
It is anticipated that risks to patients beyond 
those listed in Section 1.3 are unlikely.
 
 
It is anticipated that risks to patients beyond those 
listed in Section 1.3 are unlikely.
Section 9.1, Sample Size and Power Considerations
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
.
Section 9.2.4, Per-Protocol Analysis Set
The per-protocol (PP) analysis set is a subset of the 
ITT analysis set including only patients without any 
major important protocol violationsdeviations. 
MajorImportant protocol deviationsviolations will be 
determined before unblinding/database lock.
The per-protocol (PP) analysis set is a subset of the 
ITT analysis set including only patients without any 
important protocol deviations. Important protocol 
deviations will be determined before 
unblinding/database lock.
Change to terminology (violation 
to deviation) to align with 
guidance from the ICH.
Section 9.3.1, Handling Withdrawals and Missing Data
Efficacy variables from patients who do not have 
diary data completed for the entire study period will 
be imputed. For the primary analysisanalyses based 
on the proportion of responders, patients who are 
terminated from the study early will considered as 
non-responders. For patients who complete the study 
and have intermittent missing days in the e-diary, 
Efficacy variables from patients who do not have 
diary data completed for the entire study period will 
be imputed. For the analyses based on the 
proportion of responders, patients who are
terminated from the study early will considered as 
non-responders. For patients who complete the 
study and have intermittent missing days in the 
Added to clarify that imputation 
will be used.


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data will be prorated to 7 days. Details will be 
provided in statistical analysis plan.
e-diary, data will be prorated to 7 days. Details will 
be provided in statistical analysis plan.
Section 9.5.4.1, Primary Efficacy Analysis
The primary efficacy endpoint, the mean change from 
baseline (run-in period) in the weekly average 
number of CH attacks during the 4-week period after 
administration of the first dose of the IMP, the 
proportion of patients with ≥50% reduction from 
baseline (run in period) in the weekly average 
number of CH attacks during the 4 week period after 
administration of the first dose of IMP, will be 
analyzed using an analysis of covariance 
(ANCOVA)Cochran Mantel Haenszel test stratified 
by baseline preventive medication use (yes/no). The 
model will include treatment, baseline number of CH 
attacks, baseline preventive medication use (yes or 
no), gender, and region (US or other).
The primary efficacy endpoint the mean change 
from baseline (run-in period) in the weekly average 
number of CH attacks during the 4-week period 
after administration of the first dose of the IMP, will 
be analyzed using an analysis of covariance 
(ANCOVA). The model will include treatment, 
baseline number of CH attacks, baseline preventive 
medication use (yes or no), gender, and region (US 
or other).
Update made due to new primary 
endpoint.
Section 9.5.4.3, Secondary and Exploratory Efficacy Analysis
The continuous endpoints will be analyzed using an 
ANCOVA or a mixed model for repeated measures
(MMRM). For the proportion of responders, defined 
as 50% or more reduction from baseline in the 
weekly average number of CH attacks, data will be 
analyzed using a Cochran-Mantel-Haenszel test 
stratified by baseline preventive medication use 
(yes/no)in a manner analogous to the primary 
endpoint.
The continuous endpoints will be analyzed using an 
ANCOVA or mixed model for repeated measures. 
For the proportion of responders, defined as 50% or 
more reduction from baseline in the weekly average 
number of CH attacks, data will be analyzed using a 
Cochran-Mantel-Haenszel test stratified by baseline 
preventive medication use (yes/no).
Update made due to new primary 
endpoint.
Section 9.15, Planned Interim Analysis
An interim analysis for futility and sample size re
estimation will be performed once 50% of patients 
have completed 4-week assessments during the 
double-blind study period. 
An interim analysis for futility will be performed 
once 50% of patients have completed 4-week 
assessments during the double-blind study period.
Sample size re-estimation will no 
longer be performed.


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Reason/Justification for change
Section 10, Quality Control and Quality Assurance (other section affected by this change: Appendix C, 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
Procedures for Screening:

In case of abnormal coagulation during screening 
(run-in period), a local retest can be authorized 
by the sponsor on a case-by-case basis.

In case of abnormal coagulation during 
screening (run-in period), a local retest can be 
authorized by the sponsor on a case-by-case 
basis.
To align with Section 7.4.1.
Edit in each instance of the following:

Complete the numeric rating scale (NRS 11) 
questionnaire. Note: this will be completed by the 
patient after receiving the electronic diary device 
at home and not during the investigational site 
visit.
Removed the NRS scale to meet 
the definition of the IHS for CH 
attack.
Visit 2, procedures before administration of the IMP

Obtain a 4-mL blood sample for 
pharmacokinetics analysis from theeither arm
that will not be used for dosing with IMP.

Obtain a 4-mL blood sample for 
pharmacokinetics analysis from either arm.
With the exception of the blood 
sample collected immediately 
before the end of the IMP infusion 
(must be collected from the arm 
that is not used for IMP infusion), 
blood samples for 
pharmacokinetics analysis may be 
collected from either arm.
Visit 2 (Week 0 [Day 0+3 Days])
After completing predose assessments, patients will 
be treated with IMP. Refer to Section 5.1.1.1 for 
details regarding IMP administration. A 4-mL blood 
sample for pharmacokinetics analysis will be 
collected immediately before the end of the IMP 
Visit 2 (Week 0 [Day 0+3 Days])

After completing predose assessments, patients 
will be treated with IMP. Refer to 
Section 5.1.1.1 for details regarding IMP 
administration. A 4-mL blood sample for 
pharmacokinetics analysis will be collected 
The blood sample collected 
immediately before the end of the 
IMP infusion must be collected 
from the arm that is not used for 
the IMP infusion.


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infusion from the arm that is not used for the IMP 
infusion.
immediately before the end of the IMP infusion 
from the arm that is not used for the IMP 
infusion.
Edit in each instance of the following:

Obtain a 4-mL blood sample for 
pharmacokinetics analysis from either arm.

Obtain a 4-mL blood sample for 
pharmacokinetics analysis from either arm.
With the exception of the blood 
sample collected immediately 
before the end of the IMP infusion 
(must be collected from the arm 
that is not used for IMP infusion), 
blood samples for 
pharmacokinetics analysis may be 
collected from either arm.
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.

Complete the visual analog scale for pain 
intensity (VAS PI) of the PPSI using the 
electronic diary device. Note: this will be 
completed by the patient at home, not during the 
investigational site visit.

Complete the PPSI.
To align with changes in 
Section 6.7.
Edit in each instance of the following:

Perform local injection site assessment 
immediately and at 1 hour 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 and at 1 hour 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 PGIC scale and the PPSI 
(complete the VAS PI and respond to question about 
Week 1 (Day 7)
Patients will complete the PGIC scale and the PPSI 
at 1 week after receiving IMP using the electronic 
To align with changes in 
Section 6.7.


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change in pain intensity) at 1 week after receiving 
IMP using the electronic diary device. 
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).
Complete the PPSI.
To align with changes in 
Section 6.7.
Appendix N, Pharmacokinetics Samples (other section affected by this change: Appendix O, Immunogenicity Samples)
Samples will be stored at a temperature of 
 
 (inclusive) in an upright position until they 
are shipped to the central laboratory.
Samples will be stored at a temperature of 
 
 (inclusive) in an upright position until they 
are shipped to the central laboratory.
Pharmacokinetic and ADA 
samples can be stored in a
 
 at the clinical 
sites before shipping.
Appendix P, Exploratory Biomarkers Samples
 
 
.
 
 
 
 
 
 
 
ADA=antidrug antibody; ANCOVA=analysis of covariance; CH=cluster headache; CRF=case report form; eC-SSRS= electronic Columbia-Suicide Severity 
Rating Scale; ECH=episodic cluster headache; EOT=end of treatment; ICH=International Council for Harmonisation; IHS=International Headache Society; 
IMP=investigational medicinal product; ITT=intent to treat; MMRM=mixed model for repeated measures; NRS=numeric pain rating scale; PGIC=Patient Global 
Impression of Change; PP=per protocol; PPSI=Patient Perceived Satisfactory Improvement; SD=standard deviation; RNA=ribonucleic acid; VAS=visual analog 
scale; VAS-PI-visual analog scale for pain intensity.


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16.3.
Letter of Clarification 04 Dated 04 December 2016


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APPENDIX A. CLINICAL LABORATORIES AND OTHER 
DEPARTMENTS AND INSTITUTIONS
Sponsor’s Authorized Representative
Teva Branded Pharmaceutical Products R&D, Inc.
Tel: 
Fax:
Cel: 
Legal Representative of the sponsor in the EU
Teva GmbH
Graf-Arco-Str.3
89079 Ulm
Germany
Tel: 
Email address:
Sponsor’s Medical Expert/Contact Point 
designated by the sponsor for Further 
Information on the Study
Study Director
Tel: 
Fax: 
Cel: 
Sponsor’s Contact Point designated by the 
sponsor for Further Information on the Study
Teva Branded Pharmaceuticals R&D, Inc.
Tel: 
Fax:
Cel: 
 
Teva Branded Pharmaceuticals R&D, Inc.
Tel: 
Cel: 


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Study Principal Investigator
 
Tel: 
Sponsor’s Representative of Global Patient 
Safety and Pharmacovigilance
For serious adverse events:
Send by email to the local safety officer/contract 
research organization (LSO/CRO). The email 
address will be provided in the serious adverse 
event report form. In the event of difficulty 
transmitting the form, contact the sponsor’s study 
personnel identified above for further instruction.
Safety Physician
 
Tel: 
Cel
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
 
 
Teva Branded Pharmaceuticals R&D, Inc.
Tel:
Email
 
 
Teva Branded Pharmaceuticals R&D, Inc.
Tel:
Email


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Bioanalytical Immunogenicity Evaluation
 
Teva Branded Pharmaceuticals R&D, Inc.
Tel: 
Email
Pharmacogenomics/Biomarker Evaluation
 
Teva Branded Pharmaceuticals R&D, Inc.
Tel:
Cel
Email: 
 
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
1. Procedures for Screening (Visit 1, 7 to 10 Days Before Visit 2)
The screening visit (visit 1) will take place during a run-in period lasting at least 1 week
(+3 days) before visit 2 (week 0). The following procedures will be performed at visit 1:

Obtain written informed consent before any other study-related procedures are 
performed.

Review medical and psychiatric history.

Review medication history.

Record demographic and baseline characteristics.

Review inclusion and exclusion criteria.

Perform a physical examination, including height and weight. Body mass index will 
be calculated from the screening height and weight. 

Perform triplicate 12-lead ECGs.

Perform vital signs measurements (includes systolic and diastolic blood pressure, 
pulse, and body temperature).

Inquire about adverse events.

Perform clinical laboratory tests (serum chemistry, hematology, coagulation, and 
urinalysis).

In case of abnormal coagulation during screening (run-in period) or if other specific 
urgent tests are required, a local retest can be authorized by the sponsor or designee
on a case-by-case basis.

Perform serum β-HCG pregnancy test (for women of childbearing potential only).

Perform serum follicle-stimulating hormone test (postmenopausal women only).

Record cluster headache (CH) attack information in the electronic diary device. Note: 
this will be completed by the patient at home, not during the investigational site visit.

Complete the eC-SSRS Baseline/Screening version. 
Patients who meet inclusion and none of the exclusion criteria will be given an electronic 
diary device and trained on its use and compliance requirements. These patients will 
complete a run-in period lasting at least 1 week (+3 days) during which they will enter CH 
attack information daily.
2. Procedures Before Administration of Investigational Medicinal Product(s) (Baseline 
[Visit 2, Day 0+3 day(s)])
Patients who meet the inclusion and exclusion criteria at visit 1 will continue to visit 2
(week 0), when baseline assessments will be conducted.


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The following procedures will be performed at visit 2 (week 0):

Review inclusion/exclusion criteria.

Review study compliance.

Review electronic diary data including compliance.

Perform triplicate 12-lead ECGs.

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 clinical laboratory tests (serum chemistry, hematology, coagulation, and 
urinalysis).

Perform urine β-HCG pregnancy test (for women of childbearing potential only).

Record CH attack information in the electronic diary device. Note: this will be 
completed by the patient at home, not during the investigational site visit.

Obtain a 4-mL blood sample for pharmacokinetics analysis from either arm.

Obtain a 5-mL blood sample for ADA analysis.

Obtain a 6-mL blood sample for pharmacogenomics analysis.

Obtain blood sample for biomarker analysis (8.5 mL for serum, 6 mL for plasma, and 
2.5 mL for ribonucleic acid [RNA]).

Obtain a 5-mL urine sample for biomarker analysis.

Administer the HADS, EQ-5D questionnaire, SF-12, and WPAI questionnaire.

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. 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.

Complete the PPSI.

Complete the eC-SSRS Since Last Visit version.
Patients who meet eligibility criteria will be randomized to 1 of the treatment groups.
Eligible patients who consented to participate in the wearable sensor substudy, who are able 
to demonstrate appropriate use of the wearable device, and who are willing to comply with 
the requirements for use of the digital wearable device will be given the wearable device and 
accessories. The device will be worn on the wrist throughout the 12-week double-blind 
treatment period.


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3. Procedures During Administration of Investigational Medicinal Product 
(Double-Blind Treatment Period [Visit(s) 2 through 5, Day(s) 0 through 
84+3 day(s)])
Eligible patients will complete entries of CH attack information (ie, occurrence, number of 
attacks, and duration of attacks) using electronic diary devices daily from visit 2 through 
visit 5 (week 12). See Section 6.1 for additional details.
Visit 2 (Week 0 [Day 0+3 Days])
After completing predose assessments, patients will be treated with IMP. Refer to 
Section 5.1.1.1 for details regarding IMP administration. A 4-mL blood sample for 
pharmacokinetics analysis will be collected at the end of the IMP infusion (+10 minutes) 
from the arm that is not used for the IMP infusion.
The following procedures and assessments will be performed at visit 2 (week 0) 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 study center.
Week 1 (Day 7)
Patients will complete the PGIC scale and the PPSI at 1 week after receiving IMP using the 
electronic diary device.
Visit 3 (Week 4 [Day 28+3 Days])
The following predose procedures and assessments will be performed at visit 3:

Review study compliance.

Review electronic diary data.

Perform vital signs measurements (includes systolic and diastolic blood pressure, 
pulse, and body temperature).

Inquire about adverse events.

Inquire about concomitant medications.

Perform clinical laboratory tests (serum chemistry, hematology, coagulation, and 
urinalysis).

Perform urine β-HCG pregnancy test (for women of childbearing potential only).

Obtain a 4-mL blood sample for pharmacokinetics analysis from either arm.

Obtain a 5-mL blood sample for ADA analysis.

Administer the HADS, EQ-5D questionnaire, SF-12, and WPAI questionnaire. 


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
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. 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.

Complete the PPSI.

Complete the PGIC scale.

Complete the eC-SSRS Since Last Visit version.

Perform wearable sensor device check and compliance check for patients enrolled in 
the wearable sensor substudy.
In addition, a 6-mL blood sample for pharmacogenomic analysis (DNA) may be obtained at 
this visit if the sample is not obtained at visit 2 (week 0), unless the patient declines or local 
regulations prohibit pharmacogenomic testing.
After completing predose assessments, patients will be treated with IMP. Refer to 
Section 5.1.1.1 for details regarding IMP administration.
The following procedures and assessments will be performed at visit 3 (week 4) 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 study center. 
Visit 4 (Week 8 [Day 56+3 Days])
The following predose procedures and 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).

Inquire about adverse events.

Inquire about concomitant medications.

Perform clinical laboratory tests (serum chemistry, hematology, coagulation, and 
urinalysis).

Perform urine β-HCG pregnancy test (for women of childbearing potential only).

Obtain a 4-mL blood sample for pharmacokinetics analysis from either arm.

Complete the PPSI.

Complete the PGIC scale.


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
Complete the eC-SSRS Since Last Visit version.

Perform wearable sensor device check and compliance check for patients enrolled in 
the wearable sensor substudy.
In addition, a 6-mL blood sample for pharmacogenomic analysis (DNA) may be obtained at 
this visit if the sample is not obtained at an earlier visit, unless the patient declines or local 
regulations prohibit pharmacogenomic testing.
After completing predose assessments, patients will be treated with IMP. Refer to 
Section 5.1.1.1 for details regarding IMP administration.
The following procedures and assessments will be performed at visit 4 (week 8) 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 study center. 
End-of-Treatment Visit (Visit 5 [Week 12 (Day 84+3 Days)])/Early Withdrawal Visit
The following procedures and assessments will be performed at the EOT visit (visit 5)/early 
withdrawal visit:

Review electronic diary data.

Review study compliance.

Perform triplicate 12-lead ECGs.

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 clinical laboratory tests (serum chemistry, hematology, coagulation, and 
urinalysis).

Perform a serum β-HCG pregnancy test (for women of childbearing potential only).

Obtain a 4-mL blood sample for pharmacokinetics analysis from either arm.

Obtain a 5-mL blood sample for ADA analysis.

Obtain blood sample for biomarker analysis (8.5 mL for serum, 6 mL for plasma, and 
2.5 mL for ribonucleic acid [RNA]). .

Obtain a 5-mL urine sample for biomarker analysis.

Administer the HADS, EQ-5D questionnaire, SF-12, and WPAI questionnaire.


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
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. 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.

Complete the PPSI.

Complete the PGIC scale.

Complete the eC-SSRS Since Last Visit version.

Perform wearable sensor device check and compliance check for patients enrolled in 
the wearable sensor substudy.
In addition, a 6-mL blood sample for pharmacogenomic analysis (DNA) will be obtained at 
this visit if the sample is not obtained at an earlier visit, unless the patient declines or local 
regulations prohibit pharmacogenomic testing.
Patients enrolling into Study TV48125-CNS-30058 for the purpose of evaluating the 
long-term safety of fremanezumab on the same day as this visit will keep the electronic diary 
device. All other patients will return the electronic diary device after completing this visit.
Patients in the wearable device substudy will return the wearable sensor if they do not 
rollover into the long-term safety study (Study TV-48125-CNS-30058) or if they rollover 
into the long-term safety study but do not wish to continue participating in the wearable 
sensor 
4. Unscheduled Visits
An unscheduled visit may be performed at any time during the study at the patient’s request 
and as deemed necessary by the investigator. The date and reason for the unscheduled visit 
will be recorded on the CRF as well as any other data obtained from procedures and 
assessments.
Procedures performed during unscheduled visits include:

Review electronic diary data.

Review study compliance.

Perform vital signs measurements (including systolic and diastolic blood pressure, 
pulse, and body temperature).

Inquire about adverse events.

Inquire about/review concomitant medications.

Complete the eC-SSRS Since Last Visit version.
Other procedures may be performed at the discretion of the investigator.


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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 GCP guidelines; noncompliance to 
IMP administration; 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 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 randomized 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 
ensure that all study personnel are qualified by education, experience, and training to perform 
their specific task. These study personnel members must be listed on the investigational center 


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authorization form, which includes a clear description of each personnel member’s 
responsibilities. This list must be updated throughout the study, as necessary.
The study monitor is responsible for explaining the protocol to all study personnel, including the 
investigator, and for ensuring they comply with the protocol.
Study Monitoring
To ensure compliance with GCP guidelines, the study monitor or representative is responsible 
for ensuring that patients have signed the informed consent form and the study is conducted 
according to applicable 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 (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 
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, which will be signed and personally dated by the 
patient and by the person who conducted the informed consent discussion. The investigator will 
keep the original informed consent forms, and copies will be given to the patients. It will also be 
explained to the patients that the patient is free to refuse participation in the study and free to 
withdraw from the study at any time without prejudice to future treatment.
Competent Authorities and Independent Ethics Committees/Institutional Review Boards
Before this study starts, the protocol will be submitted to the national competent authority and to 
the respective IEC/IRB for review. As required, the study will not start at a given investigational 
center before the IEC/IRB and competent authority (as applicable) for the investigational center 
give written approval or a favorable opinion.
Confidentiality Regarding Study Patients
The investigator must ensure that the privacy of the patients, including their identity and all 
personal medical information, will be maintained at all times. In 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 (GCA), or competent 
authorities. Personal medical information will always be treated as confidential.
Registration of the Clinical Study
In compliance with national and local regulations and in accordance with Teva standard 
procedures, this clinical study will be registered on trials registry websites.


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APPENDIX E.
WOMEN OF CHILDBEARING POTENTIAL AND BIRTH 
CONTROL METHODS
Assessment of likelihood of possible interaction between investigational medicinal product 
(IMP) or concomitant medications and hormonal contraception should be conducted. Hormonal 
contraception may be susceptible to interaction with the IMP, which may reduce the efficacy of 
the contraception method.
Drug interaction studies have not been conducted with fremanezumab. Like other therapeutic 
antibodies, fremanezumab is expected to be primarily metabolized via proteolytic catabolism. 
Therefore, interaction with and impact on drug metabolizing enzymes (eg, 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 IgG2 isotype that is directed against a non-immunologic and soluble (not 
cell bound) target. Thus, the risk of cytokine release is considered to be low in the clinical 
setting. Furthermore, fremanezumab was tested for stimulation of pro-inflammatory cytokine 
release in human whole blood (Study 111320). Fremanezumab did not elicit 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 are considered. Such methods include the 
following:

Combined estrogen and progestogen hormonal contraception (oral, intravaginal, or 
transdermal) associated with inhibition of ovulation; these should be initiated at least 
7 days before dosing of IMP.

Progestogen-only hormonal contraception (oral, injectable, or implantable) associated 
with inhibition of ovulation; these should be initiated at least 7 days before dosing of 
IMP.


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
Intrauterine device (IUD) and intrauterine hormone-releasing system (IUS) 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; cap; diaphragm; or 
sponge with spermicide. The combinations of male condom with 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, or post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and lactational amenorrhea method are not acceptable methods of 
contraception. Female condom and male condom should not be used together.
Male contraception:
Male subjects 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 and counsel the patient on the importance of 
maintaining the assigned visit schedule and ascertain whether or not the patient 
wishes to and/or should continue in the study.

In cases in which the patient is deemed lost to follow-up, the investigator or designee 
must make every effort to regain contact with the patient (where possible, 3 telephone 
calls and, if necessary, a certified letter to the patient’s last known mailing address or 
local equivalent methods). These contact attempts should be documented in the 
patient’s medical record.

Should the patient continue to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of ‘lost to follow-up’.


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APPENDIX G. HANDLING, LABELING, STORAGE, AND 
ACCOUNTABILITY FOR INVESTIGATIONAL 
MEDICINAL PRODUCT(S)
Preparation of Investigational Medicinal Products
Fremanezumab or placebo will be provided in prefilled syringes contained in uniquely numbered 
kits and stored accordingly (see above). At the time of each study visit, the IRT will be queried, 
and investigational site personnel will retrieve the appropriately numbered kit(s). Kit numbers 
will be entered into the CRF.
Preparation instructions for iv infusions:
 
 The contents of 4 prefilled syringes, each containing fremanezumab
(225 mg/1.5 mL) or 1.5 mL of placebo, will be added to 500 mL of normal saline solution. The 
iv infusion will be administered over approximately 1 hour.
Preparation instructions for sc injections: 
 
. A 1.5 mL volume from each syringe 
in each visit 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 IMP (fremanezumab) and placebo must be stored refrigerated at 2°C to 8°C (36°F to 46°F), 
protected from light; the investigational site should have a process for monitoring the drug 
storage temperature.
Diversion is considered to have occurred when the legal supply chain of prescription analgesic 
medicinal products is broken, and medicinal products are transferred from a licit to an illicit 
channel of distribution or use.
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 


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accordance with the CFR 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 site may supply or administer IMPs. All IMPs must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labeled storage conditions or appropriate instructions with access limited to the investigator and 
authorized staff at the investigational center.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for IMP accountability, reconciliation, and record maintenance (ie, receipt, 
reconciliation, and final disposition records).
A record of IMP accountability (ie, IMP and other study materials received, used, retained, 
returned, or destroyed) must be prepared and signed by the principal investigator or designee, 
with an account given for any discrepancies. Empty and partially used prefilled syringes should 
be destroyed, and the investigational site should provide a certificate of destruction. If the 
investigational site 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 syringes of IMP will 
be returned to the sponsor or designee.


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APPENDIX H. PREVENTIVE CLUSTER HEADACHE MEDICATIONS 
AND DISALLOWED MEDICATIONS
1. Medications Commonly Prescribed for Cluster Headache
The following medications will be considered as being used for the prevention of cluster 
headaches, regardless of the initial indication.

verapamil

lithium

methysergide

valproate

topiramate
Patients are allowed to take up to 2 of these medications provided that they are on a stable 
dose and regimen for at least 2 weeks prior to screening and throughout the study. 
If a patient is receiving Botox, it should be in a stable dose regimen, considered as having 
≥2 cycles of Botox prior to screening. The patient should not receive Botox during the run-in 
period up to the evaluation period (4 weeks) where the primary endpoint is evaluated.
2. Concomitant Medications Allowed and Disallowed
Steroids:
Screening/run-in period and throughout the study: Systemic steroids are not allowed to be 
used in the treatment of cluster cycles during the screening/run-in period and for the duration 
of the study.
The only allowed steroids are intra-articular injection or ocular, ear drops, intranasal, inhaled,
and creams for topical use.
Screening/run-in period: Disallowed if patient has used systemic steroids for any medical 
reason (including treatment of the current CH cycle) within ≤7 days of screening.
Butalbital:
Screening/run-in period: Disallowed if used more than 3 days during the screening/run-in 
period. Patients can use butalbital as needed (PRN) after randomization into the study.
Opioids:
Screening/run-in period: Disallowed if used more than 4 days during the screening/run-in 
period. Patients can use opioids PRN after randomization into the study.


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APPENDIX I.
ICHD 3-BETA DIAGNOSTIC CRITERIA
Refer to the ICHD 3-Beta Diagnostic Criteria (Headache Classification Committee of the IHS 
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 
B) Occurring without a remission period or with remissions lasting <1 month, for ≥1 year
                                                
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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APPENDIX J.
GUIDANCE ON SAFETY MONITORING
Guidance on Monitoring Patients with Elevated Liver Function Tests
Liver enzymes (ALT, AST, GGT, and 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 ULN (including patients 
whose baseline ALT or AST levels are ≥2 × and ≤3 × the ULN, who may be enrolled in the 
study), a thorough medical history and physical examination with a focus on liver disease should 
be undertaken.2 In addition, the patient should be instructed to refrain from alcoholic beverages.
In case of symptoms compatible with drug-induced liver injury during the study, patients will be 
instructed to return to the study center for an unscheduled visit or to go to the emergency room to 
measure liver enzymes as soon as possible. Solitary elevations of total, 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 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

the baseline value was above the ULN and ALT or AST is ≥2 × the baseline value
                                                
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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Additional Tests/Evaluations:
Upon confirmation of the abnormality as noted above, the following additional evaluations 
should be performed and results should be recorded in the CRF:

serology for hepatitis A (antibody and immunoglobulins M and G), B (core antibody 
total, core immunoglobulin M, and surface antigen), and C viruses (central 
laboratory)

serology for autoimmune hepatitis: anti-nuclear antibodies (titer), anti-smooth muscle 
antibodies, and anti-liver kidney microsomal antibodies (central laboratory); further 
testing may be required in case of a positive result for hepatitis B or C

ultrasound examination of the liver and biliary tract at the investigator’s discretion

other diagnostic tests/consultations as deemed necessary by the investigator 
(eg, serology for hepatitis E virus in case of travel to endemic geography)

observation and follow-up (to be performed after the abnormality was confirmed as 
above)
ALT or AST ≥3 × (>3.5 × the ULN if the Baseline Value is >2.5 × the ULN) but <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 site to return the IMP. Early withdrawal visit activities 
should be performed as soon as possible.

Liver enzymes should be monitored until normalization or stabilization of the 
abnormality, according to the discretion of the investigator.

In any case, following the early withdrawal visit, the minimal follow-up period will 
be 30 days and will include measurement of liver enzymes at least once weekly (may 
be performed in local laboratory, with at least 1 test being sent to the central 
laboratory).

Every effort should be made to complete the additional tests/evaluations, as described 
above.


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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], hypoxemia)
b. reduced blood pressure or associated symptoms of end-organ dysfunction 
(eg, hypotonia [collapse], syncope, incontinence)
2. Two or more of the following that occur rapidly after exposure to a likely allergen for 
that patient (minutes to several hours):
a.
involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, swollen 
lips-tongue-uvula)
b. respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia)
c.
reduced blood pressure or associated symptoms (eg, hypotonia [collapse], syncope, 
incontinence)
d. persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting)
3. Reduced blood pressure after exposure to known allergen for that patient (minutes to 
several hours):
a.
adults: systolic blood pressure of <90 mm Hg or >30% decrease from that person’s 
baseline
In the event of suspected anaphylaxis, vital signs, including oxygen saturation and respiration 
rate, will be measured. Other assessments will be performed at the discretion of the investigator. 
As a precaution, each investigational site should have a resuscitation cart nearby.


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APPENDIX L. TOTAL BLOOD VOLUME
The total blood volume to be collected for each patient in this study is approximately 131.5 mL
(at maximum) 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
5
17.5
Serum pregnancya
3.5
2
7
Hematology
2
5
10
Coagulation
4.5
5
22.5
FSHb
3.5
1
3.5
Pharmacokinetics
4
4
16
ADAc
5
3
15
Biomarker serum
8.5
2
17
Biomarker plasma
6
2
12
Biomarker RNA
2.5
2
5
Pharmacogenomicd
6
1
6
Total
--
32
131.5
a A serum pregnancy test will be performed for women of childbearing potential at screening only.
b Postmenopausal women only. 
c ADA assessment will also be collected upon observation of severe hypersensitivity or anaphylaxis or if there is a 
suspected causal relationship of an AE potentially being related to immunogenicity (eg, lack of efficacy).
d Unless the patient declines testing or local regulations prohibit testing. 
ADA=antidrug antibody; AE=adverse event; FSH=follicle-stimulating hormone; RNA=ribonucleic acid.


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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 (BUN)
Alanine aminotransferase (ALT)
Aspartate aminotransferase (AST)
Lactate dehydrogenase (LDH)
Gamma-glutamyl transpeptidase (GGT)
Alkaline phosphatase
Bicarbonate
Carbon dioxide
Protein
Albumin
Bilirubin
Direct bilirubin
Indirect bilirubin
Hemoglobin
Hematocrit
Erythrocytes
Platelets
Leucocytes
Neutrophils
Lymphocytes
Eosinophils
Monocytes
Basophils
Lymphocytes atypical
Prothrombin International Normalized 
Ratio (INR)
Color and appearance
Protein
Glucose
Albumin
Ketones
Leukocyte esterase
Nitrite
Bilirubin
Hemoglobin
pH
Specific gravity
Microscopic tests
Bacteria
Erythrocytes
Leucocytes
Crystals
Casts
ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; 
GGT=gamma-glutamyl transpeptidase; INR=international normalized ratio; RBC=red blood cell; WBC=white 
blood cell.


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APPENDIX N. PHARMACOKINETICS SAMPLES
Specimen Sampling and Handling
 
 
 
 
 
.
Labels for samples should include study number, patient randomization number, nominal 
collection time (Visit number), Set A or B, and indication that they are pharmacokinetics
samples. Samples will be stored at a temperature of
(inclusive) in an upright 
position until they are shipped to the central laboratory.
Shipment and Analysis of Samples
Plasma samples for all patients will be shipped from the investigational center to the central 
laboratory, where they will be stored until shipped to the sponsor or designee for analysis. 
Samples will be stored in an upright position at 
 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 
 
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 
 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, if any, intact.


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APPENDIX O. IMMUNOGENICITY SAMPLES
Blood Sampling and Handling
 
 
 
 
 
 
Label of samples should include study number, patient randomization number, nominal
collection time (Visit number), Set A or B, and indication that they are ADA samples. Serum 
samples will be stored at a temperature of
 (inclusive) 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 
. 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 
 
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 
 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, if any, intact.


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APPENDIX P.
EXPLORATORY BIOMARKERS SAMPLES
 
 
 
 
 
All blood and urine tubes will be labeled with the patient code number. Following DNA 
extraction from the pharmacogenomic sample, the sample will be labeled with a new code 
(ie, double coding), so that genetic data will not be recorded with a patient number. 
Samples will be stored for a period of up to 15 years from the last patient’s last visit in the main 
study and then destroyed.
Shipment and Analysis of Samples
Biomarker samples for serum, plasma, RNA, and urine will be 
 and sent to the 
central laboratory on 
 per instructions in the laboratory manual. Sample labels should 
include study number, patient randomization number, visit code, collection date and time, and 
indication that they are biomarker samples. Shipments should be made as specified in the 
laboratory manual. An electronic file containing sample demographics will be emailed to the 
respective biomarker laboratory and the sponsor’s biomarker representative for each shipment.
Following DNA extractions of whole blood, the samples will be stored at 
 and labeled 
with a new code (ie, double coding), so that genomic data will not be recorded with a patient 
number. Data will be kept confidential and stored separately.
The biomarker sample analyses will be performed if and when required. Since new techniques 
continue to be developed, the method and laboratory that will be recommended for the future 
biomarker analysis cannot be anticipated.


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APPENDIX Q. PHARMACOGENOMIC ASSESSMENTS
 
 
 
 
 
 
 
 
Pharmacogenomic assessment will be performed based on study results. Samples will be used 
only for investigations related to headache or response to test IMP or related investigational 
medicinal products.
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 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, 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 
equivalent, before they are transcribed to the CRF. Data may not be recorded directly on the CRF 
and considered as source data unless the sponsor provides written instructions specifying which 
data are permitted to be recorded directly to the CRF.
If data are processed from other institutions or by other means (eg, clinical laboratory, central 
image center, or electronic diary data) the results will be sent to the investigational center, where 
they will be retained but not transcribed to the CRF, unless otherwise noted in the protocol. 
These data may also be sent electronically to the sponsor (or organization performing data
management).
The medical experts, study monitors, auditors, IEC/IRB, and inspectors from competent 
authority (or their agents) will be given direct access to source data and documents (eg, medical 
charts/records, laboratory test results, printouts, videotapes) for source data verification, provided 
that patient confidentiality is maintained in accordance with national and local requirements.
The investigator must maintain the original records (ie, source documents) of each patient’s data 
at all times. The investigator must maintain a confidential patient identification list that allows 
the unambiguous identification of each patient.
Data Collection
Data will be collected using CRFs that are specifically designed for this study. The data collected 
on the CRFs will be captured in a 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, ePRO tablet), these data will be sent to the investigational 
center, where they will be retained but not transcribed to the CRF, unless otherwise noted in the 
protocol. These data may also be sent electronically to the sponsor (or organization performing 
data management). All patient data must have supportive original source documentation in the 
medical records, or equivalent, before they are transcribed to the CRF. Data may not be recorded 
directly on the CRF and considered as source data unless the sponsor provides written 
instructions specifying which data are permitted to be recorded directly to the CRF.
For patients who enter a study but do not meet entry criteria, at a minimum, data for screening 
failure reason, demography, and adverse events from the time of informed consent will be 
entered in the CRF.


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Data Quality Control
Data Management is responsible for the accuracy, quality, completeness, and internal 
consistency of the data from this study. Oversight will be carried out as described in the 
sponsor’s SOPs for clinical studies. Day to day data management tasks for this study are 
delegated to a contract organization, and these functions may be carried out as described in the 
SOPs for clinical studies at that organization. These SOPs will be reviewed by the sponsor before 
the start of data management activities.
Data will be verified by the study monitor using the data source, and reviewed by Data 
Management using both automated logical checks and manual review. Data identified as 
erroneous, or data that are missing, will be referred to the investigational center for resolution 
through data queries. Any necessary changes will be made in the clinical database, and data 
review and validation procedures will be repeated as needed. Data from external sources will be 
compared with the information available in the CDMS and any discrepancies will be queried.
Applicable terms will be coded according to the coding conventions for this study.
At the conclusion of the study, the CDMS and all other study data will be locked to further 
additions or corrections. Locking the study data represents the acknowledgement that all data 
have been captured and confirmed as accurate. All data collected will be approved by the 
investigator at the investigational center. This approval acknowledges the investigator’s review 
and acceptance of the data as being complete and accurate.
Archiving of Case Report Forms and Source Documents
Sponsor Responsibilities
The original CRFs will be archived by the sponsor. Investigational center-specific CRFs will be 
provided to the respective investigational centers for archiving.
Investigator Responsibilities
The investigator must maintain all written and electronic records, accounts, notes, reports, and 
data related to the study and any additional records required to be maintained under country, 
state/province, or national and local laws, including, but not limited to:

full case histories

signed informed consent forms

patient identification lists

case report forms for each patient on a per-visit basis

data from other sources (eg, central laboratory, bioanalytical laboratory, central image 
center, electronic diary)

safety reports

financial disclosure reports/forms

reports of receipt, use, and disposition of the IMPs

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 CRO 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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SAP_001.pdf: 
 
 
 
 
Statistical Analysis Plan 
 
 
A Multicenter, Randomized, Double-Blind, Double-Dummy, Placebo-
Controlled, Parallel-Group Study Comparing the Efficacy and Safety of 2 
Dose Regimens (Intravenous/Subcutaneous and Subcutaneous) of TEV-48125 
versus Placebo for the Prevention of Episodic Cluster Headache 
 
Study Number TV48125-CNS-30056 
 
 
NCT02945046 
 
 
SAP Approval Date: 19 June 2019 


Placebo-Controlled Study–Episodic Cluster Headache
Statistical Analysis Plan
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Statistical Analysis Plan
Study Number TV48125-CNS-30056
A Multicenter, Randomized, Double-Blind, Double-Dummy, Placebo-Controlled, 
Parallel-Group Study Comparing the Efficacy and Safety of 2 Dose Regimens 
(Intravenous/Subcutaneous and Subcutaneous) of TEV-48125 versus Placebo for the 
Prevention of Episodic Cluster Headache
Phase 3
IND number: 129606;
EudraCT number: 2016-003278-42
Approval Date: June 19 2019
Sponsor
Teva Branded Pharmaceutical 
Products R&D, Inc.
41 Moores Road
Frazer, Pennsylvania 19355
United States
Prepared by:
Teva Global Statistics


Placebo-Controlled Study–Episodic Cluster Headache
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STATISTICAL ANALYSIS PLAN APPROVAL


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TABLE OF CONTENTS
TITLE PAGE...................................................................................................................................1
STATISTICAL ANALYSIS PLAN APPROVAL..........................................................................2
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..................................................9
INTRODUCTION .........................................................................................................................11
1.
STUDY ENDPOINTS................................................................................................12
1.1.
Primary Efficacy Endpoints........................................................................................12
1.2.
Secondary Efficacy Endpoints....................................................................................12
1.3.
Safety Endpoints.........................................................................................................12
1.4.
Immunogenicity Assessment Endpoints.....................................................................13
1.5.
Exploratory Endpoints................................................................................................13
1.6.
Wearable Sensor Substudy Endpoints........................................................................14
2.
STUDY DESIGN .......................................................................................................16
2.1.
General Design ...........................................................................................................16
2.1.1.
Wearable Sensor Substudy .........................................................................................18
2.2.
Randomization and Blinding......................................................................................18
2.3.
Data Monitoring Committee.......................................................................................18
2.4.
Sample Size and Power Considerations .....................................................................18
2.5.
Sequence of Planned Analyses ...................................................................................19
2.5.1.
Planned Interim Analyses...........................................................................................19
2.5.2.
Final Analyses and Reporting.....................................................................................19
3.
ANALYSIS SETS ......................................................................................................20
3.1.
Intent-to-Treat Analysis Set........................................................................................20
3.2.
Safety Analysis Set.....................................................................................................20
3.3.
Full Analysis Set.........................................................................................................20
3.4.
Per-Protocol Analysis Set...........................................................................................20
3.5.
Adjudicated Population ..............................................................................................20
4.
GENERAL ISSUES FOR DATA ANALYSIS..........................................................21
4.1.
General........................................................................................................................21
4.2.
Specification of Baseline Values................................................................................21
4.3.
Region of Pooled Countries........................................................................................21
4.4.
Handling Withdrawals and Missing Data...................................................................21


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4.5.
Study Days and Visits.................................................................................................21
5.
STUDY POPULATION.............................................................................................23
5.1.
General........................................................................................................................23
5.2.
Patient Disposition......................................................................................................23
5.3.
Demographics and Baseline Characteristics...............................................................23
5.4.
Medical History ..........................................................................................................23
5.5.
Prior Therapy and Medication....................................................................................23
5.6.
Childbearing Potential and Methods of Contraception ..............................................24
5.7.
Physical Examinations................................................................................................24
5.8.
Study Protocol Deviations..........................................................................................24
6.
EFFICACY ANALYSIS ............................................................................................25
6.1.
General........................................................................................................................25
6.1.1.
Cluster Headache Attacks Data from E-diary ............................................................25
6.1.2.
Data Derivation...........................................................................................................25
6.1.3.
Analysis Windows for E-diary Data...........................................................................26
6.1.4.
Handling Missing E-diary Data..................................................................................27
6.1.4.1.
Primary Efficacy Endpoint .........................................................................................27
6.1.4.2.
Analyses Based on Monthly and 12-week Window...................................................28
6.1.4.3.
Analyses of Mean Change from Baseline Using MMRM Method Based on 
1-Week Window.........................................................................................................28
6.2.
Primary Efficacy Endpoint and Analysis ...................................................................28
6.2.1.
Definition....................................................................................................................28
6.2.2.
Primary Efficacy Analysis..........................................................................................28
6.2.3.
Sensitivity Analyses for the Primary Efficacy Endpoint............................................29
6.2.3.1.
Analysis with Multiple Imputation Method ...............................................................29
6.2.3.2.
Mixed Model for Repeated Measures Analysis..........................................................30
6.2.4.
Exploratory Analysis ..................................................................................................31
6.2.5.
Subgroup Analyses .....................................................................................................31
6.3.
Secondary Efficacy Endpoints and Analyses .............................................................32
6.3.1.
Proportion of Patients with a ≥50% Reduction from Baseline in the Weekly 
Average Number of CH Attacks During the 4-Week Period After the First 
Dose of the IMP..........................................................................................................32
6.3.2.
Mean Change from Baseline in the Number of Cluster Headache Attacks ...............32


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6.3.3.
Mean Change from Baseline in the Weekly Average Number of Days with 
Use of Cluster-Specific Acute Headache Medications (Triptans and Ergot 
Compounds) During the 12-Week Period After Administration of the First 
Dose of the IMP..........................................................................................................33
6.3.4.
Mean Change from Baseline in the Weekly Average Number of Days 
Oxygen is Used to Treat Episodic Cluster Headaches During 12-week Period 
After Administration of the First Dose of the IMP.....................................................33
6.3.5.
Patient-Perceived Satisfactory Improvement at 1, 4, 8, and 12 Weeks After 
Administration of the First Dose of the IMP Relative to Baseline.............................34
6.4.
Exploratory Efficacy Endpoints and Analysis............................................................34
6.4.1.
Proportion of Patients with ≥50%, 75%, or 100% Reduction from Baseline 
in the Weekly Average Number of CH Attacks During the 12-Week Period 
(First 3 Exploratory Efficacy Endpoints) ...................................................................34
6.4.2.
Mean Change from Baseline in the Number of CH Attacks During Weeks 1, 
2, 3, 4, 8, and 12 After Administration of the First Dose of the IMP.........................35
6.4.3.
Mean Change from Baseline in the Number of CH Attacks During the 
8-Week Period (Weeks 1 to 8) After Administration of the First Dose of the 
IMP .............................................................................................................................35
6.4.4.
Change from Baseline in the Severity of CH Attacks (Mild, Moderate, 
Severe and Very Severe) During Weeks 1, 2, 3, 4, 8, and 12 After 
Administration of the First Dose of the IMP..............................................................35
6.4.5.
Mean Change from Baseline in the Weekly Average Number of Days with 
Use of any Acute Headache Medications During the 12-Week Period After 
Administration of the First Dose of the IMP..............................................................36
6.4.6.
Cumulative Proportion of Responders Analysis.........................................................36
6.4.7.
Mean Change from Baseline in the Weekly Average Number of CH Attacks 
of at Least Severe Severity During the 4-Week Period After Administration 
of the First Dose of the IMP .......................................................................................37
6.4.8.
Changes from Baseline in Responses to Questionnaires That Measure 
Quality of Life, Satisfaction with Treatment, and Health Status................................38
6.4.8.1.
Change from Baseline in EuroQol-5 Dimension Questionnaire ................................38
6.4.8.2.
Hospital Anxiety and Depression Scale .....................................................................38
6.4.8.3.
12-Item Short-Form Health Survey............................................................................39
6.4.8.4.
Impact on Partner and Family Questionnaire .............................................................40
6.4.8.5.
Work Productivity and Activity Impairment Questionnaire: General Health 
V2.0 ............................................................................................................................40
6.4.8.6.
Patient Global Impression of Change Scale ...............................................................40
7.
MULTIPLE COMPARISONS AND MULTIPLICITY ............................................42


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8.
SAFETY ANALYSIS ................................................................................................43
8.1.
General........................................................................................................................43
8.2.
Duration of Exposure to Study Drug..........................................................................43
8.3.
Adverse Events ...........................................................................................................43
8.4.
Injection Site Assessments .........................................................................................44
8.5.
Hypersensitivity/Anaphylaxis.....................................................................................44
8.6.
Electronic Columbia Suicide Severity Rating Scale ..................................................44
8.7.
Deaths .........................................................................................................................45
8.8.
Clinical Laboratory Tests ...........................................................................................45
8.8.1.
Laboratory Values Meeting Hy’s Law Criteria..........................................................47
8.9.
Physical Examinations................................................................................................47
8.10.
Vital Signs ..................................................................................................................47
8.11.
Electrocardiography....................................................................................................48
8.12.
Concomitant Medications or Therapies......................................................................48
9.
TOLERABILITY VARIABLES AND ANALYSIS..................................................49
10.
PHARMACOKINETIC ANALYSIS.........................................................................50
11.
PHARMACOGENOMIC ANALYSIS ......................................................................51
12.
BIOMARKER ANALYSIS........................................................................................52
13.
IMMUNOGENICITY ANALYSIS............................................................................53
14.
ANCILLARY STUDY ANALYSIS – WEARABLE SENSOR SUBSTUDY .........54
15.
STATISTICAL SOFTWARE ....................................................................................55
16.
CHANGES TO ANALYSES SPECIFIED IN THE STUDY PROTOCOL..............56
17.
REFERENCES ...........................................................................................................57
APPENDIX A.
E-DIARY QUESTIONNAIRE..........................................................................58
APPENDIX B.
LOGICS FOR CLUSTER HEADACHE DERIVATION.................................61
APPENDIX C.
EUROQOL-5 DIMENSION QUESTIONNAIRE (EQ-5D).............................62
APPENDIX D.
HOSPITAL ANXIETY AND DEPRESSION SCALE (HADS)......................64
APPENDIX E.
12-ITEM SHORT-FORM HEALTH SURVEY (SF-12) ..................................66
APPENDIX F.
IMPACT ON PARTNER AND FAMILY QUESTIONNAIRE -
PATIENTS .................................................................................................................68
APPENDIX G.
IMPACT ON PARTNER AND FAMILY QUESTIONNAIRE -
PARTNERS................................................................................................................70


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APPENDIX H.
WORK PRODUCTIVITY AND ACTIVITY IMPAIRMENT 
QUESTIONNAIRE: GENERAL HEALTH V2.0(WPAI:GH)..................................72


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LIST OF TABLES
Table 1:
Study Visits.................................................................................................................22
Table 2:
Criteria for Potentially Clinically Significant Laboratory Values..............................46
Table 3:
Criteria for Potentially Clinically Significant Vital Signs..........................................47


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
ADA
antidrug antibodies
ANCOVA
analysis of covariance
ANOVA
analysis of variance
AR (1)
the first-order autoregressive structure
β-HCG
beta-human chorionic gonadotropin
CGRP
calcitonin gene-related peptide
CH
cluster headache 
CMH
Cochran-Mantel-Haenszel
CNS
central nervous system
CPRA
cumulative proportion of responder’s analysis
CRF
case report form
CS
the compound-symmetry structure
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
FAS
full analysis set
HADS
Hospital Anxiety and Depression Scale
IMP
investigational medicinal product
FCS
fully conditional specification
IRT
interactive response technology
ITT
intent-to-treat
iv
intravenous(ly)
LS
least square
MCS
Mental Health Composite Scores
MedDRA
Medical Dictionary for Regulatory Activities
MI 
multiple imputation
MMRM
mixed model for repeated measures
NSAID
non-steroidal anti-inflammatory drug


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Abbreviation
Term
PCS
Physical Composite Scores
PGIC
Global Impression of Change
PP
per-protocol
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
SI
standard international
SOC
system organ class
SOP
standard operating procedure
ULN
upper limit of normal
UN
unstructured covariance
WHO Drug
World Health Organization Drug Dictionary
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-30056, (a multicenter, 
randomized, double-blind, double-dummy, placebo-controlled, parallel-group study comparing 
the efficacy and safety of 2 dose regimens [intravenous/subcutaneous and subcutaneous] of 
TEV-48125 [fremanezumab] versus placebo for the prevention of episodic cluster headache), 
and was written in accordance with SOP GBP_RD_702.
The reader of this SAP is encouraged to read the study protocol for details on the conduct of this 
study, the operational aspects of clinical assessments, and the timing for completing the 
participation of a patient in this study.
The SAP is intended to be in agreement with the protocol, especially with regard to the primary 
and all secondary endpoints and their respective analyses. However, the SAP may contain more 
details regarding these particular points of interest, or other types of analyses (eg, other 
endpoints).When differences exist in descriptions or explanations provided in the study protocol 
and this SAP, the SAP prevails; the differences will be explained in the clinical study report.


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1.
STUDY ENDPOINTS
1.1.
Primary Efficacy Endpoints
The primary efficacy endpoint of this study is the mean change from baseline (run-in period) in 
the weekly average number of cluster headache (CH) attacks during the 4-week period after 
administration of the first dose of the investigational medicinal product (IMP), ie, based on 
week 0 to 4 data.
1.2.
Secondary Efficacy Endpoints
The secondary efficacy endpoints to further demonstrate efficacy are:

the proportion of patients with a ≥50% reduction from baseline (run-in period) in the 
weekly average number of CH attacks during the 4-week period after the first dose of 
the IMP, ie, based on week 0 to 4 data

the mean change from baseline (run-in period) in the number of CH attacks during the 
12-week period after administration of the first dose of the IMP, ie, based on week 0 
to 12 data

the mean change from baseline (run-in period) in the number of CH attacks during the 
4-week period after administration of the third dose of the IMP, ie, based on week 8 
to 12 data

the mean change from baseline (run-in period) in the weekly average number of days 
with use of cluster-specific acute headache medications (triptans and ergot 
compounds) during the 12-week period after administration of the first dose of the 
IMP, ie, based on week 0 to 12 data

the mean change from baseline (run-in period) in the weekly average number of days 
oxygen is used to treat episodic cluster headache (ECH) during the 12-week period 
after administration of the first dose of the IMP, ie, based on week 0 to 12 data

assessment of patient’s perceived improvement, as measured by the Patient-Perceived 
Satisfactory Improvement (PPSI) at 1, 4, 8, and 12 weeks after administration of the 
first dose of the IMP relative to baseline (day 0)
1.3.
Safety Endpoints
The safety endpoints are as follows:

occurrence of adverse events throughout the study

clinical laboratory (serum chemistry, hematology, coagulation, and urinalysis) test 
results at each visit

vital signs (systolic and diastolic blood pressure, oral temperature, and pulse rate) 
measurements at each visit. 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.


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
12-lead electrocardiogram (ECG) findings at screening, baseline, and week 12

use of concomitant medication during the study

clinically significant changes in physical examinations, including body weight 

injection site reaction (ie, erythema, induration, and ecchymosis) and injection site 
pain assessments 

occurrence of hypersensitivity/anaphylaxis reactions

suicidal ideation and behavior as measured by the electronic Columbia Suicide 
Severity Rating Scale (eC-SSRS)
1.4.
Immunogenicity Assessment Endpoints
The immunogenicity endpoints are the following:

antidrug antibody (ADA) incidence and characteristics (eg, titer, kinetics, and 
neutralizing activities)
1.5.
Exploratory Endpoints
The exploratory endpoints are as follows:
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1.6.
Wearable Sensor Substudy Endpoints
Wearable sensor substudy exploratory endpoints are the following:

 
 
 
 
 
 
 
 
 


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2.
STUDY DESIGN
2.1.
General Design
This is a 13-week, multicenter, randomized, double-blind, double-dummy, placebo-controlled, 
parallel-group study to compare the safety and efficacy of 2 dose regimens of fremanezumab
versus placebo in adult patients for the prevention of ECH. The study will consist of a screening 
visit, a run-in period lasting at least 1 week (+3 days), and a 12-week double-blind treatment 
period. During the course of any CH attack, patients will be allowed to use acute medications to 
treat acute headaches, as needed.
Patients will complete a screening visit (visit 1) after providing written informed consent, and 
eligible patients will enter a run-in period lasting at least 1 week (+3 days) during which they 
will enter baseline CH attack information into an electronic diary device (e-diary) daily. Patients 
will return to the study center after completing the run-in period (visit 2 [week 0]). Patients who 
had at least 7 CH attacks during the run-in period and who continue to meet eligibility criteria 
(including entry of CH attack information in an e-diary demonstrating compliance for 85% of 
days during the run-in period) will be randomly assigned at visit 2 (week 0) in a 1:1:1 ratio to 1 
of 3 treatment groups (see details in Section 2.2).
Blinded treatment will be administered once monthly (ie, approximately every 4 weeks) for a 
total of 3 months. Final study assessments will be performed at the final visit for this study 
(visit 5), approximately 12 weeks after administration of the first dose of the IMP. 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 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. A separate protocol was issued for the long-term safety study.
CH attack information will be captured daily during the double-blind treatment period 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 PPSI and Patients’ Global Impression of Change [PGIC] scale); safety evaluations 
(including eC-SSRS); blood collection for pharmacokinetics, immunogenicity, biomarker, and 
pharmacogenomics (unless not allowed per local regulation) analyses; and urine sampling for 
biomarker analysis will be performed at prespecified time points.
The end of study is defined as the date the last patient attends the end of treatment (EOT)/early 
withdrawal visit. The study duration will be 21 months from Q4/2016 to Q2/2018.


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The study schematic diagram is presented in Figure 1. Study procedures and assessments with 
their timing are summarized in Table 2 of the study protocol.
Figure 1:
Overall Study Schematic Diagram
ECH=episodic cluster headache; IV=intravenous; PBO=placebo; SC=subcutaneous; V=visit. Note: Patients 
randomized to the 900-mg iv loading dose group will receive 900 mg of fremanezumab administered via an 
approximately 1-hour iv infusion followed by placebo as 3 sc injections at visit 2 (week 0) and fremanezumab at 
225 mg administered as single sc injections (225 mg/1.5 mL) at visits 3 and 4 (weeks 4 and 8, respectively). Patients 
randomized to the fremanezumab 675-mg sc quarterly group will receive placebo administered via an approximately 
1-hour iv infusion followed by fremanezumab at 675 mg administered as 3 sc injections (225 mg/1.5 mL) at visit 2 
(week 0) and placebo administered as single sc injections at visits 3 and 4 (weeks 4 and 8, respectively). Patients in 
the placebo group will receive placebo administered via an approximately 1-hour iv infusion followed by placebo 
administered as 3 sc injections at visit 2 (week 0) and placebo administered as single sc injections at visits 3 and 4 
(weeks 4 and 8, respectively).


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2.1.1.
Wearable Sensor Substudy
A subset of patients in selected investigational sites will be offered to participate in a substudy to 
understand the 
 
Patients who are able to demonstrate appropriate use of the wearable device and are willing to 
comply with the requirements for use of the digital wearable device will be given the device and 
accessories at the baseline visit. The device will be worn continuously throughout the 12-week 
treatment period, and for patients who continue into the long-term safety study (Study TV48125-
CNS-30058), the device will be worn continuously throughout the 40-week treatment period of 
that study. Refer to Section 8.6 of the study protocol for additional details.
2.2.
Randomization and Blinding
Patients will be randomly assigned with stratification based on gender, country, and baseline 
concomitant preventive medication use (yes or no) in a 1:1:1 ratio to 1 of 3 treatment groups.

fremanezumab 900-mg intravenous (iv) loading dose group: fremanezumab at 900 
mg administered via a 1-hour iv infusion and 3 subcutaneous (sc) placebo injections 
at visit 2 followed by fremanezumab at 225 mg administered as single sc injections 
(225 mg/1.5 mL) at visits 3 and 4

fremanezumab 675-mg sc quarterly group: fremanezumab at 675 mg administered 
as 3 sc injections (225 mg/1.5 mL) and a 1-hour placebo iv infusion at visit 2 
followed by placebo administered as single sc injections at visits 3 and 4

placebo group: placebo administered via a 1-hour iv infusion and as 3 sc injections at 
visit 2 followed by placebo administered as single sc injections at visits 3 and 4
The sponsor, investigators, study staff (except for staff involved in bioanalytical analyses and 
interim analyses [by a third-party, unblinded statistician]), and patients will be blinded to 
treatment assignment throughout the study.
Randomization will be performed using electronic interactive response technology (IRT), a
third-party vendor. The randomization code will be generated by IRT following specifications 
from the Biostatistics Department. A Teva statistician will be responsible for reviewing the 
dummy randomization codes, and the final randomization code will be maintained by the 
third-party vendor in a secure location.
2.3.
Data Monitoring Committee
Not applicable.
2.4.
Sample Size and Power Considerations
 
 


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2.5.
Sequence of Planned Analyses
2.5.1.
Planned Interim Analyses
An interim analysis for futility evaluation will be performed once 50% of patients (the first 
150 patients) have completed 4-week assessments during the double-blind study period or have 
withdrawn from the study early. An independent statistician from a third party will perform 
evaluation.
Details are provided in the separate interim analysis plan.
2.5.2.
Final Analyses and Reporting
All analyses identified in this SAP will be performed after the final database lock for study 
completion or for early termination of study as result of futility evaluation at interim analysis.


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3.
ANALYSIS SETS
3.1.
Intent-to-Treat Analysis Set
The intent-to-treat (ITT) analysis set will include all randomized patients.
In the ITT analysis set, treatment will be assigned based on the treatment to which patients were 
randomized, regardless of which treatment they actually received.
3.2.
Safety Analysis Set
The safety analysis set will include all randomized patients who receive at least 1 dose of the 
IMP.
In the safety analysis set, treatment will be assigned based on the treatment patients actually 
received, regardless of the treatment to which they were randomized, unless otherwise specified.
3.3.
Full Analysis Set
The full analysis set (FAS) will include all patients in the ITT analysis set who receive at least 
1 dose of the IMP and have at least 10 days of postbaseline efficacy assessment in the first
4-week on the primary endpoint.
In the FAS, treatment will be assigned based on the treatment to which patients were
randomized, regardless of which treatment they actually received.
3.4.
Per-Protocol Analysis Set
The per-protocol (PP) analysis set will consist of all patients who have completed the study 
without any violations of the inclusion/exclusion criteria or any violations or omissions of the 
drug administration. 
In the PP anlaysis set, treatment will be assigned based on the treatment to which patients were
randomized, regardless of which treatment they actually received.
The efficacy analysis for the primary and secondary endpoints will be repeated for the 
per-protocol analysis set.
3.5.
 
 
 
 
 
 


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4.
GENERAL ISSUES FOR DATA ANALYSIS
4.1.
General
Descriptive statistics for continuous variables include count (n), mean, SD, standard error (SE),
median, minimum, and maximum. In addition, for fremanezumab concentration percentage 
coefficient of variation (%CV) and geometric mean will also be calculated. Descriptive statistics 
for categorical variables include patient counts and percentages, and a missing category will be 
displayed as appropriate.
Summaries of potentially clinically significant abnormal values for clinical laboratory tests and 
vital signs values will include all postbaseline values (including scheduled, unscheduled, and 
early withdrawal visits).
4.2.
Specification of Baseline Values
Baseline is the last observed data before the administration of the first dose of the IMP, unless 
otherwise noted. For data collected in the e-diary daily, baseline will be derived from the run-in 
period (including days from the informed consent up to the day prior to the first dose of the IMP
administration) and prorated to 7 days if the number of days in the run-in period is not equal to 7. 
Details are provided in Section 6.1.
4.3.
Region of Pooled Countries 
The study is planned to be conducted in approximately 12 countries. The countries will be 
pooled to 2 regions (US/Canada and other).
4.4.
Handling Withdrawals and Missing Data
For efficacy analyses using e-diary data, the missing data handling methods are provided in 
Section 6.1.4. For the efficacy analyses using non-e-diary data, missing data handling methods, if 
applicable, will be provided in the efficacy analysis section for that endpoint.
 
 
 
4.5.
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 


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unscheduled assessments), except for triplicate ECG assessments (see Section 8.11 for further 
details).
Study visits are detailed in Table 1.
Table 1:
Study Visits
Visit #
V1
V2
V3
V4
V5
Week #
Week -1
Week 0
Week 4
Week 8
Week 12
Visit
Screening
Baseline 
Visit 3
Visit 4
EOT/early withdrawal
(84 ±3 days)
Notes: EOT=end of treatment; V2/Week 0 is day 1, which is the day eligible patients are randomized and receive 
first dose of IMP.
‘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. The start of 
treatment (day 1) is defined as the date on which a patient takes the first dose of the IMP, as 
recorded on the case report form (CRF). Days will be numbered relative to treatment start (ie, ..., 
–2, –1, 1, 2, ...; with day 1 being the first day of the IMP administration and day –1 being the day 
before the first day of the IMP administration).
For data from the e-diary, weekly analysis windows (week 1, week 2, etc.) and 4-week analysis 
windows (weeks 1 to 4, weeks 5 to 8, and weeks 9 to 12) will be derived for the purpose of 
efficacy endpoint analyses. Details are provided in Section 6.1.3.


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5.
STUDY POPULATION
5.1.
General
The ITT analysis set (see Section 3.1) will be used for all study population summaries unless 
otherwise specified. Summaries will be presented by treatment group and for all patients.
5.2.
Patient Disposition
Data from patients screened; patients screened but not randomized and reason for not 
randomized; patients who are randomized; patients randomized but not treated; patients in the 
ITT, safety, and other analysis sets; patients who complete the study; patients who withdraw 
from the study; and patients continuing into the long-term safety 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.
Patients who consent to the wearable sensor substudy and their completion status (completed and 
reason for not-completed the substudy) will be summarized using descriptive statistics.
This summary will include all patients.
5.3.
Demographics and Baseline Characteristics
The demographic data will be collected at the screening visit after the patient signs the informed 
consent form. Patient’s demographics 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), and baseline body mass index (kg/m2) will be summarized 
using descriptive statistics for all analysis sets. 
Baseline characteristics including years since first ECH diagnosis, preventive medication use
(yes or no) at screening or baseline, use of any triptans/ergots during the run-in period (yes or 
no), and number of CH attacks during the run-in period will be summarized for the ITT analysis 
set 
using descriptive statistics. No inferential analyses will be
performed.
 
5.4.
Medical History
All medical history abnormalities will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA). The incidence of medical history abnormalities will be summarized using 
descriptive statistics by system organ class (SOC) and preferred term. Patients are counted only 
once in each SOC and only once in each preferred term.
5.5.
Prior Therapy and Medication
All prior medications or therapy will be coded using the World Health Organization Drug
Dictionary of medical codes (WHO Drug). The incidence of prior medications or therapy will be 


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summarized by therapeutic class and preferred term using descriptive statistics. Patients are 
counted only once in each therapeutic class category, and only once in each preferred term
category. Prior medications will include all medications taken prior to the administration of the 
first dose of the IMP.
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
5.6.
Childbearing Potential and Methods of Contraception
Information related to reproductive system findings will be collected at the screening visit. Data 
will be listed.
5.7.
Physical Examinations
Patients with at least 1 abnormal finding (overall) and abnormal findings for each category will 
be summarized.
5.8.
Study Protocol Deviations
Data from patients with any important protocol deviations during the study will be summarized 
overall and for each category using descriptive statistics.


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6.
EFFICACY ANALYSIS
6.1.
General
The FAS will be used for all efficacy analyses unless otherwise noted. Analyses of the primary 
and secondary endpoints will be repeated for the PP analysis set
.
For data not collected daily, baseline is the last observed data before the administration of the 
first dose of the IMP. For data collected daily in the e-diary, baseline will be derived from the 
run-in period (including days from the informed consent up to the day prior to the first dose of 
the IMP administration). Details are provided in Section 6.1.3. The efficacy baseline value 
derived from the run-in period are 

number of CH attacks

number of CH attacks of at least severe severity

number of days with use of cluster-specific acute headache medication (triptans and 
ergot compounds)

number of days with use of any acute headache medication

number of days oxygen is used

severity of CH attacks
Summaries will be presented by treatment group as randomized unless otherwise noted. In 
addition to inferential statistics, descriptive statistics will be presented by-visit or 
by-analysis-window summaries.
6.1.1.
Cluster Headache Attacks Data from E-diary
 
 
 
 
 
 
 
 
6.1.2.
Data Derivation 
The weekly average/value of an efficacy endpoint will be calculated and prorated to 7 days as 
follow:


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∑	
  		  ℎ 
  	
 ℎ	   ℎ 	
  ℎ  × 7 [1]
The “efficacy endpoint data” will be “number of CH attacks”, “days with use of cluster-specific 
acute headache medications (tripants and ergot compounds)”, “days oxygen is used to treat 
ECH”, or “days with use of any headache medication”, etc.
The period will be the run-in period ( including days from the informed consent up to the day
prior to the first dose of the IMP administration) for baseline calculation or an analysis window 
(eg. weeks 1 to 4, weeks 5 to 8, weeks 9 to 12, etc.) for post-baseline calculations.
 
.
6.1.3.
Analysis Windows for E-diary Data
Baseline window is the run-in period and includes days from the informed consent to the day
prior to the first dose of the IMP administration. The baseline weekly average value for an 
efficacy variable will be calculated based on data recorded in the run-in period and prorated to 7 
days using formula [1].
Note, per eligibility checks at visit 2, patients with more than 10 days in the run-in period will 
not be eligible and will not be randomized for the study. However, in case there are patients with 
more than 10 days of the e-diary data collected during the run-in period, all data will be used for 
the baseline calculation by prorating the data to 7 days.
 
 
 
 
 
 
 
 


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6.1.4.
Handling Missing E-diary Data
This section includes missing data handling for e-diary data. For other type of data, the missing
data handling methods are provided in the analysis section for the endpoint if applicable.
6.1.4.1.
Primary Efficacy Endpoint
The weekly average number of CH attacks during the 4-week period will be calculated based on 
data available and prorated to 7 days using formula [1]. Note, patients who have < 10 days of e-
diary data in the first 4-week will be excluded from FAS and PP analysis set (Section 3).
As sensitivity analyses, the primary endpoint will be analyzed using the following methods for 
handling missing data :

Multiple imputation (MI) method to impute missing weekly data

An mixed model for repeated measures (MMRM) method to analyze the weekly data
Detail is provided in Section 6.2.3.
 


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6.1.4.2.
Analyses Based on Monthly and 12-week Window
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.2.
Primary Efficacy Endpoint and Analysis
6.2.1.
Definition
The primary efficacy endpoint of this study is the mean change from baseline (run-in period) in 
the weekly average number of CH attacks during the 4-week period after administration of the 
first dose of the IMP.
CH attacks will be derived from the e-diary data as described in Section 6.1.1. The analysis will 
be based on the weeks 1 to 4 analysis window, which will be derived using the algorithm 
described in Section 6.1.3. Missing data handling methods are provided in Section 6.1.4.1.
6.2.2.
Primary Efficacy Analysis
The hypothesis testing for the primary analysis is:
where 
and 
are the estimates of mean change from baseline in the weekly average number 
of CH attacks for the fremanezumab treatment group and the placebo group, respectively. To 
2
1
2
1
:
:






a
o
H
vs
H
1
2



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control overall type I error rate, the comparison of each active treatment group (fremanezumab
900-mg iv loading dose group and fremanezumab 675-mg sc quarterly group) versus the placebo 
will be tested using Hochberg’s step-up method as described in Section 7.
The primary endpoint will be analyzed using an ANCOVA method. The model will include 
baseline preventive medication use (yes or no), gender, region (US/Canada or other), and 
treatment as fixed effects; the baseline number of CH attacks as a covariate. The least square
(LS) mean and SE for each treatment group, LS means and corresponding 95% confidence 
intervals for the treatment differences (fremanezumab - placebo), and associated p-values will be 
presented.
The analysis will be performed on the FAS and PP analysis set,
 
     
 
     
 
     
 
     
 
 
6.2.3.
Sensitivity Analyses for the Primary Efficacy Endpoint
Sensitivity analyses will be conducted to explore the impact of missing data in the primary 
efficacy analysis.
6.2.3.1.
 
 
 
 
 
 
 
.


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.
The analysis will be performed on the ITT analysis set.
6.2.3.2.
Mixed Model for Repeated Measures Analysis
MMRM analysis will be utilized to estimate the mean change from baseline in the weekly 
number of CH attacks during the 4-week period after administration of the first dose of the IMP. 
Postbaseline data will include data from four 1-week analysis windows derived using the 
algorithm described in Section 6.1.3. Missing data will be handled as described in Section 6.1.4.3
The MMRM will include baseline preventive medication use (yes or no), gender, region 
(US/Canada or other), treatment, week (weeks 1 to 4), and week-by-treatment interaction as 
fixed effects and baseline number of CH attacks as a covariate. The unstructured covariance 
structure (UN) will be used to model intra-subject correlation. LS mean and SE for each 
treatment group, LS means and corresponding 95% confidence intervals for the treatment 
differences (fremanezumab - placebo), and the associated p-values from the overall results for 
treatment comparisons on the average of weeks 1 to 4 will be presented to support the primary 
analysis.


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Notes: if UN dose not converge, the hierarchy uses the first-order autoregressive structure 
[AR-(1)] and the compound-symmetry structure (CS).  
      
 
      
      
      
      
 
 
The analysis will be performed on the FAS.
6.2.4.
Exploratory Analysis
As an exploratory analysis,
 
 
. The overall results will be presented.
6.2.5.
 
 
 
 
 


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6.3.
Secondary Efficacy Endpoints and Analyses
The secondary efficacy endpoints are listed in Section 1.2. Analyses will be based on the FAS
and PP analysis sets
.
As exploratory analyses, endpoints analyzed using an ANCOVA method will be also analyzed 
using MMRM method in a manner analogous to the analysis as described in Section 6.2.3.2. The 
analysis windows will be specified in the related section.
6.3.1.
Proportion of Patients with a ≥50% Reduction from Baseline in the Weekly 
Average Number of CH Attacks During the 4-Week Period After the First Dose 
of the IMP
This secondary efficacy endpoint will be analyzed using Cochran-Mantel-Haenszel (CMH) test 
stratified by baseline preventive medication use (yes or no). Descriptive statistics (count and 
percent) and p-value for Row Mean Scores difference will be presented.
CH attacks will be derived from the e-diary data as described in Section 6.1.1. The analysis will 
be based on weeks 1 to 4 analysis window which will be derived using the algorithm described 
in Section 6.1.3. The weekly average number of CH attacks will be calculated based on data 
available and prorated to 7 days using formula [1]. Missing data handling methods are provided 
in Section 6.1.4.2.
The proportion of reduction for a patient will be calculated using formula [2]. Responders will be 
those with ≥50% reduction. 
     
 
     
 
 
6.3.2.
Mean Change from Baseline in the Number of Cluster Headache Attacks
The following 2nd and 3rd secondary efficacy endpoints will be analyzed using an MMRM 
method in a manner analogous to the analysis as described in Section 6.2.3.2 with month and
month-by-treatment interaction in the model instead.


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
the mean change from baseline (run-in period) in the number of CH attacks during the 
12-week period after administration of the first dose of the IMP, ie, based on week 0 
to 12 data

the mean change from baseline (run-in period) in the number of CH attacks during the 
4-week period after administration of the third dose of the IMP, ie, based on week 8 
to 12 data
Postbaseline data will include data from three 4-week analysis windows (weeks 1 to 4, weeks
5 to 8, and weeks 9 to 12) derived using the algorithm described in Section 6.1.3. CH attacks 
within each analysis window will be derived from the e-diary data as described in Section 6.1.1. 
The weekly average of number of CH attacks for a patient in each analysis window will be 
calculated and prorated to 7 days using formula [1]. Missing data handling methods are provided 
in Section 6.1.4.2.
The analysis will be based on data from all three 4-week analysis windows. Results for each 
endpoint will be subsetted from PROC MIXED outputs. For the 2nd secondary endpoint, the 
overall results will be presented; for the 3rd secondary endpoint, the results from the weeks 9 to 
12 analysis window will be presented.
6.3.3.
Mean Change from Baseline in the Weekly Average Number of Days with Use of 
Cluster-Specific Acute Headache Medications (Triptans and Ergot Compounds) 
During the 12-Week Period After Administration of the First Dose of the IMP
Use of triptans and ergot compounds for CH will be recorded in the e-diary. The 12-week period 
is the period from administration of the first dose of the IMP to the EOT/early withdrawal visit. 
The weekly average number of days with use of triptans or/and ergots for CH for a patient during
12-week period will be calculated and prorated to 7 days using formula [1]. Missing data 
handling method is provided in Section 6.1.4.2.
Data will be analyzed using an ANCOVA method in a manner analogous to the primary 
endpoint as described in Section 6.2.2.
MMRM analysis will be based on weekly analysis windows. Data in weekly analysis windows 
will be derived.
6.3.4.
Mean Change from Baseline in the Weekly Average Number of Days Oxygen is 
Used to Treat Episodic Cluster Headaches During 12-week Period After 
Administration of the First Dose of the IMP
Use of oxygen will be recorded in the e-diary. The 12-week period is the period from
administration of the first dose of the IMP to the EOT/early withdrawal visit. The weekly
average number of days using oxygen for a patient during the 12-week period will be calculated
and prorated to 7 days using formula [1]. Missing data handling method is provided in
Section 6.1.4.2.
Data will be analyzed using an ANCOVA method in a manner analogous to the primary 
endpoint as described in Section 6.2.2.
MMRM analysis will be based on weekly analysis windows. Data in weekly analysis windows 
will be derived.


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6.3.5.
Patient-Perceived Satisfactory Improvement at 1, 4, 8, and 12 Weeks After 
Administration of the First Dose of the IMP Relative to Baseline
The PPSI scale will be completed in the e-diary at home at week 1 (day 7) and in the 
investigational site tablet at the visits 2, 3, 4, and 5. Patients will mark the level of CH-associated 
pain and indicate the level of pain using the following scale compared with 4 weeks ago:

1 = Much worse

2 = Moderately worse

3 = Slightly worse

4 = Unchanged

5 = Slightly improved

6 = Moderately improved

7 = Much improved
PPSI will be defined as change in pain that corresponds with a minimal rating of “slightly 
improved” (Protocol Section 6.7). For analysis purpose, a dichotomous scale of “Responder” 
(scales 5 to 7) or “Non-responder” (scales 1 to 4) will be derived.
The percentage of patients in dichotomous scale of “Responder” or “Non-responder” at week 1,
visit 3, 4, and 5 will be analyzed using a CMH method in a manner analogous to the first 
secondary endpoint as described in Section 6.3.1. Missing scores will not be imputed.
Modification to SAS code in Section 6.3.1: adding a ‘by’ statement for visit.
Raw scales will be summarized using descriptive statistics. A missing category will be presented 
if applicable.
6.4.
Exploratory Efficacy Endpoints and Analysis
Exploratory efficacy endpoints are listed in Section 1.5.
.
 
Section 6.2.3.2. The analysis windows will be specified in the related section.
6.4.1.
 
The following exploratory efficacy endpoints will be analyzed 
 
 
 
 


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6.4.2.
Mean Change from Baseline in the Number of CH Attacks During Weeks 1, 2, 3, 
 
 
 
      
6.4.3.
 
 
 
 
6.4.4.
 
 
 


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6.4.5.
 
 
 
 
 
 
 
 
 
 
 
 


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
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.4.7.
 
 
 
   
     
 
 
 
  
  


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The derivation of input data for this analysis is the same as the primary analysis except only 
 
6.4.8.
 
 
 
 
6.4.8.1.
 
 
 
 
 
 
 
 
6.4.8.2.
 
 
 
 


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6.4.8.3.
 
 
 
 


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6.4.8.4.
 
 
 
6.4.8.5.
 
 
 
 
 
 
 
 
 
 
 
6.4.8.6.
 


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7.
MULTIPLE COMPARISONS AND MULTIPLICITY
 
 
 
 
 
 
 
 
.
 
 
 
 
 
 
 


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8.
SAFETY ANALYSIS
8.1.
General
The safety analysis set will be used for all safety analyses. Summaries will be presented using 
descriptive statistics by treatment group and all fremanezumab as actually received unless 
otherwise stated.
8.2.
Duration of Exposure to Study Drug
At the visit 2, each patient will receive a 1-hour iv infusion and 3 sc injections of fremanezumab
or placebo. At visits 3 and 4, patients will receive 1 sc injection of fremanezumab or placebo.
 
 
 
 
Duration of the treatment period (days), duration of iv infusion (minutes), dosing visit interval 
(days), the number of doses received, total number of injections received (placebo or 
fremanezumab), and reasons for IMP not administrated will be summarized using descriptive 
statistics. Summary will be presented by treatment group.
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 
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.


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Summaries for injection site and infusion-related 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 and infusion-related 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.
8.4.
Injection Site Assessments
Injection site assessments will be performed immediately (+10 minute) and 1 hour (±15 minutes)
after receiving each dose of the IMP at visits 2, 3 and 4. The injection site(s) 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 summary 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 2, 3, and 4. 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.
Data will be listed.
8.6.
Electronic Columbia Suicide Severity Rating Scale
The eC-SSRS Baseline/Screening version will be completed at visit 1, and the eC-SSRS Since 
Last Visit version will be completed at all other visits (visits 2, 3, 4, and 5), including 
unscheduled visits. Any positive findings on the eC-SSRS Since Last Visit version require 
evaluation by a physician or doctoral-level psychologist.
Data for patients with positive findings (having suicidal ideation or suicidal behavior) will be 
listed.


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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 all visits (visit 1 [screening] through visit 5 [EOT]) 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 (also see Section 4.2).
The potentially clinically significant abnormal values will be derived using criteria specified in 
Table 2 based on all postbaseline values (including scheduled, unscheduled, and withdrawal
visits). The overall incidence of potentially clinically significant abnormal values will be 
summarized for laboratory variables using descriptive statistics by treatment group. Listings for 
patients who have potentially clinically significant abnormal laboratory data will be presented.


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Table 2:
Criteria for Potentially Clinically Significant Laboratory Values
Test
Criterion value
Serum chemistry
ALT
3x ULN
AST
3x ULN
ALP
3x ULN
GGT
3x ULN
LDH
3x ULN
BUN
10.71 mmol/L
Creatinine
177 mol/L
Bilirubin (total)
34.2 mol/L
Hematology
Hematocrit
Men
<0.37 L/L
Women
<0.32 L/L
Hemoglobin
Men
115 g/L
Women
95 g/L
WBC counts
3 x 109/L 
20 x 109/L
Eosinophils
10%
ANC
1 x 109/L
Platelet counts
75 x 109/L 
700 x 109/L
Urinalysis
HGB
2 unit increase from baseline
Glucose
2 unit increase from baseline
Ketones
2 unit increase from baseline
Total protein
2 unit increase from baseline
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 visits 1 and 5. Urine β-HCG tests will be performed for women of 
childbearing potential at visits 2 through 4. Pregnancy test results will be listed.
Current menstruating status (yes or no) will be collected at all visits and 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 1, 2, and 5. Any physical examination finding 
that is judged by the investigator as a clinically significant change (worsening) compared with a 
baseline value will be considered an adverse event, recorded on the CRF, and monitored as 
described in Section 7.1.2 of the study protocol.
Abnormal physical examination findings will be listed.
Weight and height will be summarized and listed with vital signs data.
8.10.
Vital Signs
Vital signs (pulse, systolic and diastolic blood pressure, and body temperature) will be measured 
at each (visit 1 through 5). Weight will be measured at visits 1, 2, and 5. 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 (also see Section 4.2).
Table 3 specifies the criteria for identifying vital signs as potentially clinically significant 
abnormal values. Note that in order to qualify as potentially clinically significant abnormal, a 
value needs to meet both criteria below: ie, have a value beyond the criterion value and a change 
of at least the magnitude specified in the change relative to baseline column. The potentially 
clinically significant abnormal vital signs values will include all postbaseline values (including 
scheduled, unscheduled, and early withdrawal visits) for the summaries.
Table 3:
Criteria for Potentially Clinically Significant Vital Signs
Vital Sign
Criterion value
Change relative to baseline
Pulse
120 bpm
Increase of 15 bpm
50 bpm
Decrease of 15 bpm
Systolic blood pressure
180 mm Hg
Increase of 20 mm Hg
90 mm Hg
Decrease of 20 mm Hg
Diastolic blood pressure
105 mm Hg
Increase of 15 mm Hg
50 mm Hg
Decrease of 15 mm Hg
Temperature
≥38.3C
Change of 1.1C
bpm=beats per minute
Height will be measured at screening visit, and data will be listed in the vital sign listing.


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8.11.
Electrocardiography
Triplicate 12-lead ECGs will be collected at visits 1, 2, and 5. 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 EOT 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 (also see Section 4.2 ).
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.


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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. 
Fremanezumab plasma concentration will be summarized using descriptive statistics at each 
planned sampling time point for each of the active treatment groups (samples from patients who 
received placebo will not be analyzed). The summary will be based on the safety analysis set.
The plasma concentration will be listed by 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. Results 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 pharmacokinetics 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.
ANCILLARY STUDY ANALYSIS – WEARABLE SENSOR 
SUBSTUDY
A subset of patients (n=45, approximately 15 patients from each treatment group) from each 
pivotal study (TV48125-30056 and TV48125-30057), approximately 90 patients in total, will be 
asked to wear a sensor monitoring system (digital wearable device) on the wrist to track sleep 
patterns and activity patterns. These patients will be allowed to continue in the substudy during 
the long-term safety study (TV48124-30058).
Analyses for endpoints from the wearable sensor substudy will include summary statistics and 
 
 Results will be reported separately.


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15.
STATISTICAL SOFTWARE
All data listings, summaries, and statistical analyses will be generated using SAS®.


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16.
CHANGES TO ANALYSES SPECIFIED IN THE STUDY 
PROTOCOL
None.


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17.
REFERENCES
Scoring Software (v5.0) Copyright© 2004, 2007, 2009, 2010, 2016 QualityMetric Incorporated 
24 Albion Road, Bldg 400. Lincoln, R.I. 02865, U.S.A.


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APPENDIX A.
 
 
 
 
   
 
 
 
 
 
 


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APPENDIX B.
 
 
 
 
 


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APPENDIX C.
 
 
 
 
 
 
 
 
 
       
 
 
 
 
 
                     
 
 
 
 
 
 
 
 


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APPENDIX D.
 
 
 


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APPENDIX E.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX F.
 
 
 
 
 
 
 


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APPENDIX G.
 
 
 
 
 
 
 
 
 


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APPENDIX H.
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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