Conditions: Chronic Cluster Headache
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 259
Healthy volunteers: no

Brief summary:
The purpose of the current study is to evaluate the efficacy and safety of Fremanezumab (TEV-48125), in the prevention of CCH in adult participants.

Detailed description:

Arms:
arm 1: Participants received placebo via an approximately 1-hour intravenous infusion and as 3 subcutaneous injections at Week 0 followed by placebo administered as single subcutaneous injections at Weeks 4 and 8. arm 2: Participants received placebo via an approximately 1-hour intravenous infusion and fremanezumab at 675 milligrams (mg) as 3 subcutaneous injections (225 mg/1.5 milliliters \[mL\]) at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8. arm 3: Participants received fremanezumab at 900 mg via an approximately 1-hour intravenous infusion and placebo administered as 3 subcutaneous injections at Week 0 followed by fremanezumab at 225 mg administered as single subcutaneous injections (225 mg/1.5 mL) at Weeks 4 and 8.

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

Protocol document:
Prot_000.pdf: 
Clinical Study Protocol with Amendment 02 
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 Chronic Cluster Headache 
Study Number TV48125-CNS-30057 
NCT02964338 
Protocol with Amendment 02 Approval Date: 01 May 2017 


Placebo-Controlled Study–Chronic Cluster Headache 
Clinical Study Protocol with Amendment 02 
Study TV48125-CNS-30057 
1 
 
 
Clinical Study Protocol with Amendment 02 
Study Number TV48125-CNS-30057 
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 Chronic Cluster Headache 
Efficacy and Safety Study (Phase 3) 
IND number: 129606 
EudraCT number: 2016-003171-21 
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. 


 
Placebo-Controlled Study–Chronic Cluster Headache 
Clinical Study Protocol with Amendment 02 
Study TV48125-CNS-30057 
2 
AMENDMENT HISTORY 
The protocol for Study TV48125-CNS-30057 (original protocol dated 08 August 2016) has been 
amended and reissued as follows: 
Amendment 02 
01 May 2017 
20 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. 


 
Placebo-Controlled Study–Chronic Cluster Headache 
Clinical Study Protocol with Amendment 02 
Study TV48125-CNS-30057 
3 
INVESTIGATOR AGREEMENT 
 


 
Placebo-Controlled Study–Chronic Cluster Headache 
Clinical Study Protocol with Amendment 02 
Study TV48125-CNS-30057 
4 
COORDINATING INVESTIGATOR AGREEMENT 
Clinical Study Protocol with Amendment 02  
Original Protocol Dated 08 August 2016 
IND Number: 129606; EudraCT Number: 2016-003171-21 
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 Chronic Cluster Headache 
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: 
 
Title: ________________________________________________ 
Address of Investigational Center: __________________________________ 
 
__________________________________ 
 
__________________________________ 
Tel: ______________ 
 
Coordinating Investigator 
 
Signature 
Date 


 
Placebo-Controlled Study–Chronic Cluster Headache 
Clinical Study Protocol with Amendment 02 
Study TV48125-CNS-30057 
5 
CLINICAL STUDY PROTOCOL SYNOPSIS 
with Amendment 02 
Study TV48125-CNS-30057 
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 Chronic Cluster Headache 
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc.  
Investigational New Drug (IND) Number: 129606 
EudraCT Number: 2016-003171-21 
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: Chronic cluster headache (CCH) 
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 Q3/2018 (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 CCH (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. 


 
Placebo-Controlled Study–Chronic Cluster Headache 
Clinical Study Protocol with Amendment 02 
Study TV48125-CNS-30057 
6 
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 CCH in adult 
patients. 
The primary efficacy endpoint of this study is the mean change 
from baseline (run-in period) in the monthly average number 
of cluster headache (CH) attacks during the 12-week period 
after administration of the first dose of the IMP, ie, based on 
week 0 to 12 data. 
A secondary objective of this 
study is to further demonstrate 
the efficacy of fremanezumab 
in the prevention of CCH 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 monthly 
average number of CH attacks over the 12-week 
period after the administration of the first dose of 
the IMP, ie, based on week 0 to 12 data 
• 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 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 CCH 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) 


 
Placebo-Controlled Study–Chronic Cluster Headache 
Clinical Study Protocol with Amendment 02 
Study TV48125-CNS-30057 
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Objectives 
Endpoints 
A secondary objective of this 
study is to evaluate the safety 
of fremanezumab in adult patients 
with CCH.  
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: 
• to further evaluate the efficacy of fremanezumab in the prevention of CH in adult 
patients 
• to explore the correlation between pharmacokinetic parameters and IMP efficacy 


 
Placebo-Controlled Study–Chronic Cluster Headache 
Clinical Study Protocol with Amendment 02 
Study TV48125-CNS-30057 
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• to explore the relationship between biofluid biomarkers and fremanezumab 
concentrations 
• to explore the relationship between pharmacogenetics versus headache response, CH 
attack characteristics, and/or safety 
• to explore the relationship between soluble exploratory biomarkers versus CH 
response  
The exploratory endpoints are as follows: 
• proportion of patients with ≥50% reduction from baseline (run-in period) in the 
weekly average 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  
• proportion of patients with ≥75% reduction from baseline (run-in period) in the 
weekly average 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 
• proportion of patients reaching 100% reduction 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 
• mean change from baseline (run-in period) in the number of CH attacks during 
weeks 1, 2, 3, 4, 8, and 12, after administration of the first dose of the IMP 
• mean change from baseline (run-in period) in the number of CH attacks during the 
8-week period after administration of the first dose of the IMP, ie, based on week 0 to 
8 data 
• mean change from baseline (run-in period) in the number of CH attacks during the 
4-week period after administration of the second dose of the IMP, ie, based on week 4 
to 8 data 
• change from baseline (run-in period) in the severity of CH attacks (mild, moderate, 
severe, or very severe) during weeks 1, 2, 3, 4, 8, and 12 after administration of the 
first dose of the IMP  
• mean change from baseline (run-in period) 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, ie, based week 0 to 12 data  
• total cumulative distribution of percent reduction (≥0%, ≥10%, ≥20%, ≥30%, ≥40%, 
≥50%, ≥60%, ≥70%, or ≥80%) from baseline (run-in period) in the monthly average 
number of CH attacks during the 12-week period after the first dose of the IMP, 
ie, based on week 0 to 12 data 
• cumulative distribution function plot of percent reduction (≥0%, ≥10%, ≥20%, ≥30%, 
≥40%, ≥50%, ≥60%, ≥70%, or ≥80%) from baseline (run-in period) in the monthly 
average number of CH attacks during the 12-week period after the first dose of the 
IMP, ie, based on week 0 to 12 data 


 
Placebo-Controlled Study–Chronic Cluster Headache 
Clinical Study Protocol with Amendment 02 
Study TV48125-CNS-30057 
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• mean change from baseline (run-in period) in the monthly average number of CH 
attacks of at least severe severity during the 12-week period after administration of 
the first dose of the IMP, ie, based on week 0 to 12 data 
• changes from baseline (day 0) in responses to questionnaires that measure quality of 
life, satisfaction with treatment, and health status  
• the relationship between biofluid biomarkers and fremanezumab concentrations 
• the relationship between specific genetic polymorphisms within the calcitonin gene 
related peptide (CGRP) receptor-ligand complex and headache-associated genes 
versus headache response, specific CH attack clinical features (eg, severity, IMP 
effects, IMP efficacy), and/or safety (eg, adverse events to IMP) 
• the relationship between baseline levels and/or mean changes in levels from baseline 
(day 0) in biofluid biomarkers versus treatment, CH response status (onset/duration), 
and response status (ie, responders versus nonresponders) 
Wearable sensor substudy exploratory objectives are the following: 
• to evaluate changes in sleep-wake parameters during days patients experience CH 
attacks relative to days free of attacks 
• to evaluate changes in sleep-wake parameters in predicting seasonal onset of new CH 
epoch 
• to evaluate changes in activity during days patients experience CH attacks relative to 
days free of attacks 
• to determine the relationship between activity and sleep pattern and the frequency of 
CH attacks 
• to determine the relationship between activity and sleep pattern and the intensity of 
CH attacks 
• to determine the relationship between activity and sleep pattern and the duration of 
CH attacks 
• to explore the differences in activity and sleep pattern in patients with CCH 
• to examine the relationship between activity and sleep pattern and that of genetic and 
biomarker measures 
• to evaluate changes in activity in predicting seasonal onset of new CH episode 
• to explore the capability of predicting the onset of a new CH epoch ahead of time 
Wearable sensor substudy exploratory endpoints are the following: 
• change in total sleep time, sleep onset latency, wake after sleep onset, and sleep 
efficiency on days with and without CH attacks 
• the change in the total time of sedentary, light, moderate, and vigorous activity before 
(6-hour period), during, and after (6-hour period) CH attack relative to days free of 
attacks 


 
Placebo-Controlled Study–Chronic Cluster Headache 
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Study TV48125-CNS-30057 
10 
• the correlation between total time in sedentary, light, moderate, and vigorous activity; 
total sleep time; sleep onset latency; wake after sleep onset; and sleep efficiency and 
the frequency of CH attacks 
• the correlation between total time in sedentary, light, moderate, and vigorous activity; 
total sleep time; sleep onset latency; wake after sleep onset; and sleep efficiency and 
headache intensity during CH attacks 
• the correlation between total time in sedentary, light, moderate, and vigorous activity; 
total sleep time; sleep onset latency; wake after sleep onset; and sleep efficiency and 
headache duration during CH attacks 
• the average total time in sedentary, light, moderate, and vigorous activity; total sleep 
time; sleep onset latency; wake after sleep onset; and sleep efficiency in patients with 
CCH 
• the correlation between the total time in sedentary, light, moderate, and vigorous 
activity; total sleep time; sleep onset latency; wake after sleep onset; and sleep 
efficiency and the genetic and biomarker profiles 
• detection of time-dependent patterns composed of lower- and higher-level activity 
metrics (eg, activity score and sleep/wake patterns) 
• cross-correlation between the time-dependent activity patterns and CH attacks 
• prediction model for the coming CH attack, intensity, and duration. The input to the 
prediction model (ie, features) will be selected from the measurements collected by 
the digital wearable devices, information collected by the self-reporting devices, and 
aggregated information provided by the calculated endpoints (ie, various statistics). 
General Design:  
This is a 16-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 CCH. The study will consist of a screening 
visit, a run-in period lasting approximately 4 weeks (+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 4 weeks (+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 10 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) 


 
Placebo-Controlled Study–Chronic Cluster Headache 
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Study TV48125-CNS-30057 
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• fremanezumab 675-mg sc loading dose group: fremanezumab at 675 mg administered 
as 3 sc injections (225 mg/1.5 mL) 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) 
• 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 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).  
Brief Summary of Study Design for the Trial Registry(s): This is a 16-week study to evaluate 
the efficacy and safety of 2 dose regimens of fremanezumab versus placebo in adult patients for 
the prevention of CCH. Patients who provide written informed consent and complete a screening 
visit (visit 1) will enter a run-in period lasting at least 4 weeks (+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 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, 
health status, and satisfaction with treatment. 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 


 
Placebo-Controlled Study–Chronic Cluster Headache 
Clinical Study Protocol with Amendment 02 
Study TV48125-CNS-30057 
12 
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. 
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 loading dose 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 followed by 225 mg sc 
monthly 
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 
investigational center. 


 
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Study TV48125-CNS-30057 
13 
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. 
145 Brandywine Parkway 
West Chester, PA 19380 
Teva Branded Pharmaceutical 
Products R&D, Inc. 
145 Brandywine Parkway 
West Chester, PA 19380 
IMP=investigational medicinal product; 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 occurs 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 both the initial 
dose of 900 mg iv and 675 mg sc for maintenance of efficacy. Based on modelling, the inclusion 
of a loading dose should allow patients to reach steady state faster. The monthly doses of 225 mg 
sc in this CCH population will account for the continuous attacks, with less than 1 month free of 
headaches between attacks, 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 16 weeks (including a run-in period lasting approximately 4 weeks 
[+3 days] and a 12-week double-blind treatment period). 
Study Duration: 24 months from Q4/2016 to Q3/2018 


 
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Study TV48125-CNS-30057 
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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 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 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 history of CCH 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 for more than 1 year without remission, or with remission 
periods lasting less than 1 month. 
d. The patient has a total body weight of ≥45 kg. 
e. 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.  
f. 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. 


 
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g. The patient 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.  
h. The patient has at least 10 CH attacks during the run-in period. 
i. 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.  
j. 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. 
k. 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. 
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 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. 
m. 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 10 days during the 4 weeks prior to 
screening or using butalbital on more than 10 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 15 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. 


 
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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 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. 
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 
− has any other condition, which, in the opinion of the investigator, makes the 
patient inappropriate for inclusion in the study 


 
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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:  
Sample Size Rationale: 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 
4 CH attacks in the monthly average (assuming a common standard deviation [SD] of 8 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. 
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. 
Primary Efficacy Analysis: The primary efficacy endpoint, the mean change from baseline 
(run-in period) in the monthly average number of CH attacks during the 12-week period after 


 
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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 monthly 
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. 
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 


 
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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 12-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 ..................................30 
1.1. 
Cluster Headache ........................................................................................................30 
1.1.1. 
Rationale for Fremanezumab Development as a Preventive Treatment for 
Cluster Headache ........................................................................................................31 
1.1.2. 
Study Purpose .............................................................................................................31 
1.2. 
Findings from Nonclinical and Clinical Studies .........................................................32 
1.2.1. 
Nonclinical Studies .....................................................................................................32 
1.2.2. 
Clinical Studies ...........................................................................................................33 
1.2.2.1. 
Clinical Pharmacology Studies ...................................................................................33 
1.2.2.2. 
Clinical Safety and Efficacy Studies ..........................................................................34 
1.3. 
Known and Potential Benefits and Risks to Patients ..................................................35 
1.3.1. 
Known and Potential Benefits and Risks of the Test Investigational 
Medicinal Product(s) ..................................................................................................35 
1.3.2. 
Overall Benefit and Risk Assessment for This Study ................................................36 
2. 
STUDY OBJECTIVES AND ENDPOPINTS ...........................................................37 
2.1. 
Primary and Secondary Study Objectives and Endpoints ..........................................37 
2.1.1. 
Justification of Primary Endpoint ...............................................................................38 
2.2. 
Exploratory Objectives and Endpoints .......................................................................39 
2.2.1. 
Exploratory Objectives and Endpoints .......................................................................39 
2.2.2. 
Wearable Sensor Substudy Exploratory Objectives and Endpoints ...........................40 
3. 
STUDY DESIGN .......................................................................................................42 
3.1. 
General Design and Study Schematic Diagram ..........................................................42 
3.2. 
Planned Number of Patients and Countries ................................................................44 
3.3. 
Justification for Study Design and Selection of Population .......................................45 
3.4. 
Stopping Rules for the Study ......................................................................................45 
3.5. 
Schedule of Study Procedures and Assessments ........................................................46 


 
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4. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................52 
4.1. 
Patient Inclusion Criteria ............................................................................................52 
4.2. 
Patient Exclusion Criteria ...........................................................................................53 
4.3. 
Withdrawal Criteria and Procedures ...........................................................................55 
4.4. 
Replacement of Patients .............................................................................................56 
4.5. 
Rescreening .................................................................................................................56 
4.6. 
Screening Failure ........................................................................................................56 
5. 
TREATMENTS ..........................................................................................................57 
5.1. 
Investigational Medicinal Products Used in the Study ...............................................57 
5.1.1. 
Test Investigational Medicinal Product ......................................................................58 
5.1.1.1. 
Starting Dose and Dose Levels ...................................................................................58 
5.1.2. 
Placebo Investigational Medicinal Product ................................................................58 
5.2. 
Preparation, Handling, Labeling, Storage, and Accountability for 
Investigational Medicinal Products ............................................................................58 
5.3. 
Justification for Investigational Medicinal Products ..................................................58 
5.3.1. 
Justification for Dose of Test Investigational Medicinal Product ..............................58 
5.3.2. 
Justification for Use of Placebo Investigational Medicinal Product ..........................59 
5.4. 
Treatment after the End of the Study ..........................................................................59 
5.5. 
Restrictions .................................................................................................................59 
5.5.1. 
Activity .......................................................................................................................59 
5.5.2. 
Blood Donation ...........................................................................................................59 
5.5.3. 
Pregnancy ...................................................................................................................59 
5.6. 
Prior and Concomitant Medication or Treatment .......................................................60 
5.7. 
Procedures for Monitoring Patient Compliance .........................................................60 
5.8. 
Randomization and Blinding ......................................................................................60 
5.9. 
Maintenance of Randomization and Blinding ............................................................61 
5.9.1. 
Maintenance of Randomization ..................................................................................61 
5.9.2. 
Blinding and Unblinding ............................................................................................61 
5.9.3. 
Data Monitoring Committee .......................................................................................62 
5.10. 
Total Blood Volume ...................................................................................................62 
6. 
ASSESSMENT OF EFFICACY ................................................................................63 
6.1. 
Electronic Diary Device .............................................................................................63 
6.2. 
Hospital Anxiety and Depression Scale .....................................................................63 


 
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6.3. 
EuroQol-5 Dimension Questionnaire .........................................................................64 
6.4. 
Twelve-Item Short-Form Health Survey ....................................................................64 
6.5. 
Work Productivity and Activity Impairment Questionnaire ......................................64 
6.6. 
Impact on Partner and Family Questionnaire .............................................................64 
6.7. 
Patient-Perceived Satisfactory Improvement .............................................................65 
6.8. 
Patient Global Impression of Change Scale ...............................................................65 
7. 
ASSESSMENT OF SAFETY .....................................................................................66 
7.1. 
Adverse Events ...........................................................................................................66 
7.1.1. 
Definition of an Adverse Event ..................................................................................66 
7.1.2. 
Recording and Reporting of Adverse Events .............................................................67 
7.1.3. 
Severity of an Adverse Event .....................................................................................67 
7.1.4. 
Relationship of an Adverse Event to the Test Investigational Medicinal 
Product ........................................................................................................................68 
7.1.5. 
Serious Adverse Events ..............................................................................................68 
7.1.5.1. 
Definition of a Serious Adverse Event .......................................................................68 
7.1.5.2. 
Expectedness ...............................................................................................................69 
7.1.5.3. 
Reporting a Serious Adverse Event ............................................................................70 
7.1.6. 
Protocol-Defined Adverse Events not for Expedited Reporting ................................71 
7.1.7. 
Protocol-Defined Adverse Events of Special Interest ................................................72 
7.1.8. 
Protocol Deviations Because of an Adverse Event ....................................................72 
7.2. 
Pregnancy ...................................................................................................................72 
7.3. 
Medication Error and Special Situations Related to the Investigational 
Medicinal Products .....................................................................................................73 
7.4. 
Clinical Laboratory Tests ...........................................................................................74 
7.4.1. 
Serum Chemistry, Hematology, and Urinalysis .........................................................74 
7.4.1.1. 
Human Chorionic Gonadotropin Tests .......................................................................74 
7.4.1.2. 
Follicle-Stimulating Hormone Tests ...........................................................................74 
7.5. 
Physical Examinations ................................................................................................74 
7.6. 
Vital Signs ..................................................................................................................75 
7.7. 
Electrocardiography ....................................................................................................75 
7.8. 
Immunogenicity ..........................................................................................................76 
7.9. 
Assessment of Suicidality ...........................................................................................76 
7.10. 
Concomitant Therapy or Medication ..........................................................................77 


 
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7.11. 
Injection Site Assessments .........................................................................................77 
8. 
ASSESSMENT OF 
PHARMACOKINETICS/BIOMARKERS/PHARMACOGENOMIC/IMMU
NOGENICITY/ANCILLARY STUDIES ..................................................................78 
8.1. 
Pharmacokinetics Assessment ....................................................................................78 
8.2. 
Pharmacodynamics Assessment .................................................................................78 
8.3. 
Immunogenicity Testing .............................................................................................78 
8.4. 
Assessment of Exploratory Biomarkers .....................................................................78 
8.5. 
Pharmacogenomics .....................................................................................................79 
8.6. 
Ancillary Studies – Wearable Sensor Substudy .........................................................79 
9. 
STATISTICS ..............................................................................................................81 
9.1. 
Sample Size and Power Considerations .....................................................................81 
9.2. 
Analysis Sets ...............................................................................................................81 
9.2.1. 
Intent-to-Treat Analysis Set ........................................................................................81 
9.2.2. 
Safety Analysis Set .....................................................................................................81 
9.2.3. 
Full Analysis Set .........................................................................................................81 
9.2.4. 
Per-Protocol Analysis Set ...........................................................................................81 
9.3. 
Data Handling Conventions ........................................................................................81 
9.3.1. 
Handling Withdrawals and Missing Data ...................................................................82 
9.4. 
Study Population .........................................................................................................82 
9.4.1. 
Patient Disposition ......................................................................................................82 
9.4.2. 
Demographic and Baseline Characteristics ................................................................82 
9.5. 
Efficacy Analysis ........................................................................................................82 
9.5.1. 
Primary Endpoint ........................................................................................................83 
9.5.2. 
Secondary Endpoints ..................................................................................................83 
9.5.3. 
Exploratory Endpoints ................................................................................................83 
9.5.4. 
Planned Method of Analysis .......................................................................................85 
9.5.4.1. 
Primary Efficacy Analysis ..........................................................................................85 
9.5.4.2. 
Sensitivity Analysis ....................................................................................................86 
9.5.4.3. 
Secondary and Exploratory Efficacy Analysis ...........................................................86 
9.6. 
Multiple Comparisons and Multiplicity......................................................................86 
9.7. 
Safety Analysis ...........................................................................................................86 
9.8. 
Tolerability Analysis ..................................................................................................87 


 
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9.9. 
Pharmacokinetics Analysis .........................................................................................87 
9.10. 
Pharmacokinetic/Pharmacodynamics Analysis ..........................................................87 
9.11. 
Pharmacogenomic Analysis........................................................................................88 
9.12. 
Biomarker Analysis ....................................................................................................88 
9.13. 
Immunogenicity Analysis ...........................................................................................88 
9.14. 
Ancillary Study Analysis ............................................................................................88 
9.15. 
Planned Interim Analysis ............................................................................................88 
9.16. 
Reporting Deviations from the Statistical Plan ..........................................................88 
10. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................89 
11. 
COMPLIANCE STATEMENT ..................................................................................90 
12. 
DATA MANAGEMENT AND RECORD KEEPING ..............................................91 
13. 
FINANCING AND INSURANCE .............................................................................92 
14. 
PUBLICATION POLICY ..........................................................................................93 
15. 
REFERENCES ...........................................................................................................94 
16. 
SUMMARY OF CHANGES TO THE PROTOCOL ................................................96 
16.1. 
Amendment 02 Dated 01 May 2017 ...........................................................................96 
16.2. 
Amendment 01 Dated 30 November 2016 ...............................................................116 
16.3. 
Letter of Clarification 04 Dated 13 December 2016 ................................................136 
APPENDIX A. CLINICAL LABORATORIES AND OTHER DEPARTMENTS AND 
INSTITUTIONS .......................................................................................................139 
APPENDIX B. STUDY PROCEDURES AND ASSESSMENTS BY VISIT .........................142 
APPENDIX C. QUALITY CONTROL AND QUALITY ASSURANCE ..............................148 
APPENDIX D. ETHICS ...........................................................................................................150 
APPENDIX E. WOMEN OF CHILDBEARING POTENTIAL AND BIRTH 
CONTROL METHODS ...........................................................................................151 
APPENDIX F. LOST TO FOLLOW-UP .................................................................................153 
APPENDIX G. HANDLING, LABELING, STORAGE, AND ACCOUNTABILITY 
FOR INVESTIGATIONAL MEDICINAL PRODUCT(S) .....................................154 
APPENDIX H. PREVENTIVE CLUSTER HEADACHE MEDICATIONS AND 
DISALLOWED MEDICATIONS............................................................................156 
APPENDIX I. ICHD 3-BETA DIAGNOSTIC CRITERIA .....................................................157 
APPENDIX J. GUIDANCE ON SAFETY MONITORING ....................................................158 
APPENDIX K. CLINICAL CRITERIA FOR DIAGNOSING ANAPHYLAXIS ...................161 
APPENDIX L. TOTAL BLOOD VOLUME ............................................................................162 


 
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APPENDIX M. CLINICAL LABORATORY TESTS .............................................................163 
APPENDIX N. PHARMACOKINETICS SAMPLES .............................................................164 
APPENDIX O. IMMUNOGENICITY SAMPLES ..................................................................165 
APPENDIX P. EXPLORATORY BIOMARKERS SAMPLES ..............................................166 
APPENDIX Q. PHARMACOGENOMIC ASSESSMENTS ...................................................167 
APPENDIX R. PRODUCT COMPLAINTS ............................................................................168 
APPENDIX S. DATA MANAGEMENT AND RECORD KEEPING ....................................170 
APPENDIX T. PUBLICATION POLICY................................................................................173 
APPENDIX U. NATIONAL INSTITUTES OF HEALTH PATIENT EDUCATION 
GUIDELINES OF SEPTEMBER 2015 ...................................................................174 


 
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LIST OF TABLES 
Table 1: 
Investigational Medicinal Products Used in the Study ...............................................12 
Table 2: 
Study Procedures and Assessments ............................................................................47 
Table 3: 
Investigational Medicinal Products Used in the Study ...............................................57 
Table 4: 
The Relationship of an Adverse Event to the Test Investigational Medicinal 
Product ........................................................................................................................68 
Table 5: 
Severity of Pain Scale for Injection Site Assessments ...............................................77 
 
LIST OF FIGURES 
Figure 1: 
Overall Study Schematic Diagram .............................................................................44 
 


 
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LIST OF ABBREVIATIONS 
List of Abbreviations 
Abbreviation 
Term 
β-HCG 
beta-human chorionic gonadotropin 
ADA 
antidrug antibody 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
ANOVA 
analysis of variance 
AST 
aspartate aminotransferase (SGOT) 
AUC 
area under the plasma concentration-time curve 
AUC0-∞ 
area under the plasma concentration-time curve from time 0 to infinity 
CBC 
complete blood count 
CCH 
chronic cluster headache  
CDMS 
clinical data management system  
CFR 
Code of Federal Regulations (US) 
CGRP 
calcitonin gene-related peptide 
CH 
cluster headache 
CL/F 
apparent total plasma clearance 
CM 
chronic migraine 
Cmax 
maximum observed concentration 
CNS 
central nervous system 
CRF 
case report form (refers to any media used to collect study data [ie, paper or electronic]) 
CRO 
contract research organization 
ECG 
electrocardiography/electrocardiogram 
ECH 
episodic cluster headache 
eC-SSRS 
electronic Columbia Suicide Severity Rating Scale  
EDTA 
ethylenediaminetetraacetic acid  
EFD 
embryo/fetal developmental toxicity 
EM 
episodic migraine 
EOT 
end of treatment (visit) 
EQ-5D 
EuroQol-5 Dimension 
EQ-5D-5L 
EuroQol-5 Dimension, 5 response level version 
FDA 
Food and Drug Administration 


 
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Abbreviation 
Term 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transpeptidase 
GLP 
Good Laboratory Practice 
HADS 
Hospital Anxiety and Depression Scale 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
ICHD-3 
International Classification of Headache Disorders, third revision 
IEC 
Independent Ethics Committee 
IgG 
immunoglobulin G 
IHS 
International Headache Society 
IMP 
investigational medicinal product 
INR 
international normalized ratio  
IRB 
Institutional Review Board 
IRT 
interactive response technology 
ITT 
intent-to-treat  
iv 
intravenous(ly) 
LSO 
local safety officer  
mAb 
monoclonal antibody 
PEF 
peak expiratory flow 
PGIC 
Patients’ Global Impression of Change 
PPSI 
Patient-Perceived Satisfactory Improvement 
PRN 
as needed 
RNA 
ribonucleic acid 
RSI 
reference safety information 
sc 
subcutaneous(ly) 
SD 
standard deviation 
SF-12 
12-Item Short-Form Health Survey 
SOP 
standard operating procedure 
SUSAR 
suspected unexpected serious adverse reaction 
t½ 
terminal elimination half-life  
tmax 
time to maximum observed concentration 
ULN 
upper limit of the normal range 
Vz/F 
apparent total volume of distribution during the terminal phase 


 
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Abbreviation 
Term 
WOCBP 
women of childbearing potential 
WPAI 
Work Productivity and Activity Impairment 


 
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1. 
INTRODUCTION AND BACKGROUND INFORMATION 
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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1.1.1. 
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 (>2 µM 
equilibrium dissociation constant). 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.  
1.1.2. 
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 CCH 
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.  
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- 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. 
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 (CL), 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). 
These Phase 1 studies were analyzed using the original bioanalytical method that has since been 
determined to underestimate measured plasma concentrations. In those analyses, fremanezumab 
pharmacokinetics appeared linear over the dose range from 100 to 2000 mg with Cmax and AUC 
generally increasing in proportion to the dose. 
A recently completed pharmacokinetic, safety, and tolerability study in healthy Japanese and 
Caucasian subjects (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 generally occurred 5 
to 7 days post sc doses. Mean values for apparent total volume of distribution during the terminal 
phase (Vz/F) after a single sc dose ranged from 5.7 to 6.4 L at 225- to 900-mg sc doses. The 
mean apparent total plasma clearance (CL/F) ranged from 0.0777 to 0.0895 mL/min at this dose 
range. The mean t½ ranged from 32.2 to 36.2 days. Fremanezumab exposure parameters and 
overall pharmacokinetic profile were similar for healthy Japanese and Caucasian subjects. 
Comparison of exposure parameters (Cmax and AUC0-∞) from Studies LBR-101-011 and 
TV48125-PK-10078 at the 225-mg and 900-mg sc dose levels indicates a 2.9- to 3.5-fold higher 
exposure in Study TV48125-PK-10078 relative to Study LBR-101-011. The main reason for the 
difference in exposure appears to be the underestimated concentration values from the original 
method. 
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 TEV-48125 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 ENDPOPINTS 
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 chronic 
cluster headache (CCH) in 
adult patients. 
The primary efficacy endpoint of this study is the mean change 
from baseline (run-in period) in the monthly average number 
of cluster headache (CH) attacks during the 12-week period 
after administration of the first dose of the investigational 
medicinal product (IMP), ie, based on week 0 to 12 data. 
A secondary objective of this 
study is to further demonstrate 
the efficacy of fremanezumab 
in the prevention of CCH 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 monthly 
average number of CH attacks over the 12-week 
period after the 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 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 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 CCH 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 


 
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Objectives 
Endpoints 
administration of the first dose of the IMP relative 
to baseline (day 0) 
A secondary objective of this 
study is to evaluate the safety 
of fremanezumab in adult 
patients with CCH.  
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 CCH, headache attacks occur for more than 1 year without remission, or with 
remission periods lasting less than 1 month (May 2005). The duration of pain in these patients 
supports the need to evaluate time point of the primary endpoint of 12 weeks. This longer 


 
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duration of assessment at 12 weeks in CCH patients should capture the effect on fluctuations in 
frequency of headaches within the clusters. 
2.2. 
Exploratory Objectives and Endpoints 
2.2.1. 
Exploratory Objectives and Endpoints  
The exploratory objectives are as follows: 
• to further evaluate the efficacy of fremanezumab in the prevention of CH in adult 
patients 
• to explore the correlation between pharmacokinetic parameters and IMP efficacy 
• to explore the relationship between biofluid biomarkers and fremanezumab 
concentrations 
• to explore the relationship between pharmacogenetics versus headache response, CH 
attack characteristics, and/or safety 
• to explore the relationship between soluble exploratory biomarkers versus CH 
response  
The exploratory endpoints are as follows: 
• proportion of patients with ≥50% reduction from baseline (run-in period) in the 
weekly average 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  
• proportion of patients with ≥75% reduction from baseline (run-in period) in the 
weekly average 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  
• proportion of patients reaching 100% reduction 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 
• mean change from baseline (run-in period) in the number of CH attacks during 
weeks 1, 2, 3, 4, 8, and 12, after administration of the first dose of the IMP 
• mean change from baseline (run-in period) in the number of CH attacks during the 
8-week period after administration of the first dose of the IMP, ie, based on week 0 to 
8 data 
• mean change from baseline (run-in period) in the number of CH attacks during the 
4-week period after administration of the second dose of the IMP, ie, based on week 4 
to 8 data 
• change from baseline (run-in period) 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  


 
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• mean change from baseline (run-in period) 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, ie, based on week 0 to 12 data  
• total cumulative distribution of percent reduction (≥0%, ≥10%, ≥20%, ≥30%, ≥40%, 
≥50%, ≥60%, ≥70%, or ≥80%) from baseline (run-in period) in the monthly average 
number of CH attacks during the 12-week period after the first dose of the IMP, ie, 
based on week 0 to 12 data 
• cumulative distribution function plot of percent reduction (≥0%, ≥10%, ≥20%, ≥30%, 
≥40%, ≥50%, ≥60%, ≥70%, or ≥80%) from baseline (run-in period) in the monthly 
average number of CH attacks during the 12-week period after the first dose of the 
IMP, ie, based on week 0 to 12 data 
• mean change from baseline (run-in period) in the monthly average number of CH 
attacks of at least severe severity during the 12-week period after administration of 
the first dose of the IMP, ie, based on week 0 to 12 data 
• changes from baseline (day 0) in responses to questionnaires that measure quality of 
life, satisfaction with treatment, and health status  
• the relationship between biofluid biomarkers and fremanezumab concentrations 
• the relationship between specific genetic polymorphisms within the calcitonin 
gene-related peptide (CGRP) receptor-ligand complex and headache-associated genes 
versus headache response, specific CH attack clinical features (eg. severity, IMP 
effects, IMP efficacy), and/or safety (eg, adverse events to IMP) 
• the relationship between baseline levels and/or mean changes in levels from baseline 
(day 0) in biofluid biomarkers versus treatment, CH response status (onset/duration), 
and response status (ie, responders versus nonresponders) 
2.2.2. 
Wearable Sensor Substudy Exploratory Objectives and Endpoints 
Wearable sensor substudy exploratory objectives are the following: 
• to evaluate changes in sleep-wake parameters during days patients experience CH 
attacks relative to days free of attacks 
• to evaluate changes in sleep-wake parameters in predicting seasonal onset of new CH 
epoch 
• to evaluate changes in attacks during days patients experience CH attacks relative to 
days free of attacks 
• to determine the relationship between attacks and sleep pattern and the frequency of 
CH attacks 
• to determine the relationship between attacks and sleep pattern and the intensity of 
CH attacks 
• to determine the relationship between attacks and sleep pattern and the duration of 
CH attacks 


 
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• to explore the differences in attacks and sleep pattern in patients with CCH 
• to examine the relationship between attacks and sleep pattern and that of genetic and 
biomarker measures 
• to evaluate changes in attacks in predicting seasonal onset of new CH episode 
• to explore the capability of predicting the onset of a new CH epoch ahead of time 
Wearable sensor substudy exploratory endpoints are the following: 
• change in total sleep time, sleep onset latency, wake after sleep onset, and sleep 
efficiency on days with and without CH attacks 
• the change in the total time of sedentary, light, moderate, and vigorous activity before 
(6-hour period), during, and after (6-hour period) CH attack relative to days free of 
attacks 
• the correlation between total time in sedentary, light, moderate, and vigorous activity; 
total sleep time; sleep onset latency; wake after sleep onset; and sleep efficiency and 
the frequency of CH attacks 
• the correlation between total time in sedentary, light, moderate, and vigorous activity; 
total sleep time; sleep onset latency; wake after sleep onset; and sleep efficiency and 
headache intensity during CH attacks 
• the correlation between total time in sedentary, light, moderate, and vigorous activity; 
total sleep time; sleep onset latency; wake after sleep onset; and sleep efficiency and 
headache duration during CH attacks 
• the average total time in sedentary, light, moderate, and vigorous activity; total sleep 
time; sleep onset latency; wake after sleep onset; and sleep efficiency in patients with 
CCH 
• the correlation between the total time in sedentary, light, moderate and vigorous 
activity; total sleep time; sleep onset latency; wake after sleep onset; and sleep 
efficiency and the genetic and biomarker profiles 
• detection of time-dependent patterns composed of lower- and higher-level activity 
metrics (eg, activity score and sleep/wake patterns) 
• cross-correlation between the time-dependent activity patterns and CH attacks 
• prediction model for the coming CH attack, intensity, and duration. The input to the 
prediction model (ie, features) will be selected from the measurements collected by 
the digital wearable devices, information collected by the self-reporting devices, and 
aggregated information provided by the calculated endpoints (ie, various statistics) 


 
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3. 
STUDY DESIGN 
3.1. 
General Design and Study Schematic Diagram 
This is a 16-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 CCH. The study will consist of a screening 
visit, a run-in period lasting approximately 4 weeks (+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 4 weeks (+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 have 
at least 10 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 loading dose group: fremanezumab at 675 mg administered 
as 3 sc injections (225 mg/1.5 mL) 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) 
• 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 the test IMP or placebo IMP 
followed by 3 sc injections of the test IMP or placebo IMP at visit 2 (week 0), and all patients 
will receive single sc injections of the 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 loading dose 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 


 
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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 Patient 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 last visit of the last patient. 
The study duration will be approximately 24 months from Q4/2016 to Q3/2018. 
The study schematic diagram is presented in Figure 1. 


 
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Figure 1: 
Overall Study Schematic Diagram 
 
CCH=chronic 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 3 placebo sc injections at visit 2 (week 0) and fremanezumab at 
225 mg administered as single sc injections at visits 3 and 4 (weeks 4 and 8, respectively). Patients randomized to 
the 675-mg sc loading dose group will receive placebo administered via an approximately 1-hour iv infusion and 
fremanezumab at 675 mg administered as 3 sc injections (225 mg/1.5 mL) at visit 2 (week 0) and fremanezumab at 
225 mg administered as single sc injections at visits 3 and 4 (weeks 4 and 8, respectively). Patients randomized to 
the placebo group will receive placebo as an approximately 1-hour iv infusion followed by placebo administered as 
3 placebo sc injections at visit 2 (week 0) and placebo 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 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). Refer to Section 8.6 for 
additional details. 
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 the definition of evaluable patients and sample 
size are given in Section 9. 


 
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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 
Q3/2018. 
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 CCH (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 12-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, and indirect], or international normalized ratio [INR]) may meet 
criteria for discontinuation from the IMP as summarized in Appendix J. 
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). 


 
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3.5. 
Schedule of Study Procedures and Assessments 
Study procedures and assessments with their time points are summarized 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 -4 - 0 
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 -4 - 0 
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 
Provide wearable substudy sensor device and 
accessories 
 
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 -4 - 0 
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) 
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 4 weeks (+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. 
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. 


 
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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. 
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 will 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 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: 8.5 mL for serum, 
6 mL for plasma, and 2.5 mL for PAXgene® RNA. 
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 3 placebo sc injections at visit 2 (week 0) and fremanezumab at 225 mg administered as single sc injections at visits 3 and 4 (weeks 4 and 8, respectively). 
Patients randomized to the 675 mg sc loading dose 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 fremanezumab at 225 mg administered as single sc injections at visits 3 and 4 
(weeks 4 and 8, respectively). Patients randomized to the placebo group will receive placebo as an approximately 1-hour iv infusion followed by placebo 
administered as 3 placebo sc injections at visit 2 (week 0) and placebo 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). 


 
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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 enrolled are not granted by Teva (see 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 history of CCH 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 for more than 1 year without remission, or with remission 
periods lasting less than 1 month. 
d. The patient has a total body weight of ≥45 kg. 
e. 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.  
f. 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. The patient 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.  
h. The patient has at least 10 CH attacks during the run-in period. 


 
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i. 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.  
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. Definitions of sterile and postmenopausal are given in Appendix E. 
k. 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. 
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 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. 
m. 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 10 days during the 4 weeks prior to 
screening or using butalbital on more than 10 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 15 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. 


 
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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 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. 
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 


 
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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. 
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. 


 
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If a patient is withdrawn from the study for multiple reasons that include also adverse events, the 
termination page of the CRF should indicate that the withdrawal was related to an adverse event. 
An exception to this requirement will be the occurrence of an adverse event that in the opinion of 
the investigator is not severe enough to warrant discontinuation but that requires the use of a 
prohibited medication, thereby requiring discontinuation of the patient. In such a case, the reason 
for discontinuation would be “need to take a prohibited medication” and not the adverse event. 
Should a patient decide to withdraw after administration of the IMP or should the investigator 
decide to withdraw the patient, all efforts will be made to complete and report all observations up 
to the time of withdrawal. A complete final evaluation at the time of the patient’s withdrawal 
should be made and an explanation given as to why the patient is withdrawing or being 
withdrawn from the study. 
The reason for and date of withdrawal from the study must be recorded on the source 
documentation and transcribed to the CRF. If a patient withdraws consent, every attempt will be 
made to determine the reason.  
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 
withdraw early will be offered the opportunity to enter 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. 
4.6. 
Screening Failure 
Screening failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomized/enrolled in the study. Minimal information includes but is not 
limited to demography, screening failure details, eligibility criteria, and any adverse events or 
serious adverse events. 


 
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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/1.5 mL 
900 mg iv loading dose followed by 
225 mg sc monthly 
or 
675 mg sc dose followed by 225 mg 
sc monthly 
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. 
145 Brandywine Parkway 
West Chester, PA 19380 
Teva Branded Pharmaceutical 
Products R&D, Inc. 
145 Brandywine Parkway 
West Chester, PA 19380 
IMP=investigational medicinal product; 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 
previous injection sites to ensure that they are free of bruising and tenderness and that proper 


 
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rotation of sites is performed. The total number of 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 as an approximately 1-hour iv infusion followed by 3 placebo 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 in the 675-mg sc dose 
group will receive placebo as 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 fremanezumab at 
225 mg 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 
neuron would be necessary. Third, the favorable safety profile of the drug, as well as clinical and 


 
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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 occurs 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 both the initial 
dose of 900 mg iv and 675 mg sc for maintenance of efficacy. Based on modelling, the inclusion 
of a loading dose should allow patients to reach steady state faster. The monthly doses of 225 mg 
sc in this CCH population will account for the continuous attacks, with less than 1 month free of 
headaches between attacks, 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 the long-term safety extension study (Study TV48125-CNS-30058), which includes a 
treatment period lasting approximately 40 weeks.  
Patients who were 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 investigational 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. 
5.5.3. 
Pregnancy 
Restrictions related 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 4.1, 
respectively). Restrictions in regard to contraception methods are reviewed in Appendix E. 


 
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5.6. 
Prior and Concomitant Medication or Treatment 
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 CCH 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 contain 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 900-mg iv loading dose 
group, the fremanezumab 675-mg sc loading dose 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. 


 
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5.9. 
Maintenance of Randomization and Blinding 
5.9.1. 
Maintenance of Randomization 
The randomization code will be generated by the IRT third-party vendor, 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 treatment 
assignment is needed to make treatment decisions, the investigator may unblind the patient’s 
IMP assignment as deemed necessary, mainly in emergency situations, through specialized 
access in the 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 onto the CRF. The circumstances leading to the breaking of the code should be fully 
documented in the investigator’s study files and in the patient’s source documentation. 
Treatment assignment should not be recorded in any study documents or source document. 
In blinded studies, for an adverse event defined as a suspected unexpected serious adverse 
reaction (SUSAR) (ie, reasonable possibility; see Section 7.1.4), Global Patient Safety and 


 
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Pharmacovigilance may independently request that the treatment code be broken (on a 
case-by-case basis) to comply with regulatory requirements. The report will be provided in an 
unblinded manner for regulatory submission. If this occurs, blinding will be maintained for the 
investigator and for other personnel involved in the conduct of the study, and analysis and 
reporting of the data. 
5.9.3. 
Data Monitoring Committee 
There will be no Data Monitoring Committee 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 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 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 wellbeing 
compared with how they felt at the start of the study (the time after the patient received the first 
IMP dose) as “much worse,” “moderately worse,” “slightly worse,” “stayed the same,” “a little 
better,” “moderately better,” or “much better.” 
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 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), please 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. 
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 


 
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• is life-threatening adverse event (ie, the patient was at risk of death at the time of the 
event); it does not refer to an event which hypothetically might have caused death if it 
were more severe 
• requires inpatient hospitalization or prolongation of existing hospitalization, which 
means that hospital inpatient admission or prolongation of hospital stay were required 
for treatment of an adverse event, or that they occurred as a consequence of the event 
Hospitalizations scheduled before the patient signed the ICF will not be considered 
serious adverse events, unless there was worsening of the 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. 
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. 


 
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7.1.5.3. 
Reporting a Serious Adverse Event 
7.1.5.3.1. Investigator Responsibility 
To satisfy regulatory requirements, all serious adverse events that occur during the study, 
regardless of judged relationship to administration of the test IMP, must be reported to the 
sponsor by the investigator. The event must be reported within 24 hours of when the investigator 
learns about it. Completing the serious adverse event form and reporting the event must not be 
delayed, even if not all the information is available. The investigator does not need to actively 
monitor patients for adverse events once this study has ended. 
Serious adverse events occurring to a patient after the last administration of IMP of that patient 
has ended 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 
• 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 


 
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− 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 Board (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 
• modifying the existing consent form and informing all study participants of new 
findings 
• modifying listings of expected toxicities to include adverse events newly identified as 
related to fremanezumab 
7.1.6. 
Protocol-Defined Adverse Events not for Expedited Reporting 
Not applicable. 


 
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7.1.7. 
Protocol-Defined Adverse Events of Special Interest 
For purposes of this protocol, the following are considered protocol-defined adverse events of 
special interest to be sent to the sponsor’s 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 
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 


 
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voluntary abortion). Female partners of men participating in the study who become pregnant will 
be asked to sign an ICF. If the pregnancy continues to term, the outcome (health of the infant up 
to 8 weeks of age), including details of birth and presence or absence of any birth defect, 
congenital abnormalities, or maternal and newborn complications, will be reported to the 
sponsor. Any complication of pregnancy during the study and any complication of pregnancy 
that the investigator becomes aware of after withdrawal from the study will be reported as an 
adverse event or serious adverse event, as appropriate. 
If the pregnancy in the woman participating in the study and/or the female partners of men 
participating in the study does not continue to term, 1 of the following actions will be taken: 
• For a spontaneous abortion, report as a serious adverse event. 
• For an elective abortion due to developmental anomalies, report as a serious adverse 
event. 
• For an elective abortion not due to developmental anomalies, report on the pregnancy 
form; do not report as an adverse event.  
7.3. 
Medication Error and Special Situations Related to the 
Investigational Medicinal Products 
Any administration of IMP that is not in accordance with the study protocol should be reported 
as an important deviation, if it meets the important deviation criteria specified in the protocol 
(Appendix C), or as a deviation, in the patient’s source documents, regardless of whether or not 
an adverse event occurs as a result. When meeting important protocol deviation criteria, all 
instances of incorrect IMP administration should be reported in the clinical trial management 
system. A 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 
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 
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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. 
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 


 
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examination finding that is judged by the investigator as a potentially clinically significant 
change (worsening) compared with a baseline value will be considered an adverse event, 
recorded on the CRF, and monitored as described in in Section 7.1.2. 
7.6. 
Vital Signs 
Vital signs (blood pressure [systolic/diastolic], body temperature, and pulse) will be measured 
before other assessments (eg, blood draws and administration of questionnaires) at the time 
points detailed in Table 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. 
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). 


 
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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 will not enroll in the double-blind, long-term safety study 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 
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 


 
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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, or pain at 1 hour after 
completion of IMP administration, the patient will be reassessed at 3 hours (±15 minutes) after 
completion of IMP administration and hourly (±15 minutes) thereafter until the reaction is of 
moderate or less severity. 
Appropriate treatment may be provided if necessary, in which case it must be recorded as 
concomitant medication. 
Injection-site reactions (injection site erythema, induration, ecchymosis, and pain) should be 
recorded as adverse events. 


 
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8. 
ASSESSMENT OF 
PHARMACOKINETICS/BIOMARKERS/PHARMACOGENOMIC
/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 (4 mL) 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 (5 mL) 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 pre-dose (baseline) sample from the rolled-over placebo patient will 
be analyzed along with post-treatment 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. In the current study, exploratory analysis may be conducted on 


 
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blood (serum, plasma, and ribonucleic acid [RNA]) and urine biomarkers for extracellular matrix 
turnover, bone formation, and bone resorption. 
In preclinical models, CGRP can promote angiogenesis in ischemia, capsaicin-induced synovitis, 
and neovascularization of tumors. Exploratory analysis will be conducted on 
endothelial/angiogenic markers to determine if fremanezumab alters angiogenic markers. 
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 on inflammatory endpoints in blood to examine effects of fremanezumab in patients 
with CH. 
Based on the known biology of CGRP’s mechanism of action, biomarker assessment will 
potentially include markers of bone remodeling, inflammation, and angiogenesis. The validated 
multiplex immunoassay panels will be applied to measure changes in urine, serum, plasma, and 
RNA biomarkers. 
The planned biomarker analysis will be detailed in a separate document, which may be updated 
at a later stage before the analysis to allow updating with new scientific information. 
8.5. 
Pharmacogenomics 
For information regarding pharmacogenomics assessments, see Appendix Q. Multiple genetic 
loci have been identified that could affect the binding affinity of the CGRP-receptor-ligand 
complex, while other genetic loci have been identified as having roles in migraine and/or 
headache onset (Anttila et al 2013). To explore the potential impact of normal variations in these 
loci on parameters in this study, a blood sample (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. The objective of this substudy is to evaluate changes in 
sleep-wake parameters and changes in activity as they relate to the occurrence of CH attacks. 
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. The relationship between sleep-wake parameters, activity levels, and the frequency, 
intensity, and duration of CH attacks will also be determined.  
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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The data will be used to assess whether changes in patterns of sleep and/or activity as captured 
by the digital wearable device can be used for early prediction and possible intervention of CH 
attacks. 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 4 CH attacks in the monthly 
average (assuming a common standard deviation [SD] of 8 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 be considered as nonresponders. 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 the statistical analysis plan. 
9.4. 
Study Population 
The ITT analysis set (see Section 9.2.1) will be used for all study population summaries unless 
otherwise specified. Summaries will be presented 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 monthly average 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. 
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 
monthly average number of CH attacks over the 12-week period after the 
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 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 
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 CCH 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: 
• proportion of patients with ≥50% reduction from baseline (run-in period) in the 
weekly average 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  
• proportion of patients with ≥75% reduction from baseline (run-in period) in the 
weekly average 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 


 
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• proportion of patients reaching 100% reduction 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 
• mean change from baseline (run-in period) in the number of CH attacks during 
weeks 1, 2, 3, 4, 8, and 12, after administration of the first dose of the IMP 
• mean change from baseline (run-in period) in the number of CH attacks during the 
8-week period after administration of the first dose of the IMP, ie, based on week 0 to 
8 data 
• mean change from baseline (run-in period) in the number of CH attacks during the 
4-week period after administration of the second dose of the IMP, ie, based on week 4 
to 8 data 
• change from baseline (run-in period) in the severity of CH attacks (mild, moderate, 
severe, or very severe) during weeks 1, 2, 3, 4, 8, and 12 after administration of the 
first dose of the IMP  
• mean change from baseline (run-in period) 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, ie, based week 0 to 12 data  
• total cumulative distribution of percent reduction (≥0%, ≥10%, ≥20%, ≥30%, ≥40%, 
≥50%, ≥60%, ≥70%, or ≥80%) from baseline (run-in period) in the monthly average 
number of CH attacks during the 12-week period after the first dose of the IMP, ie, 
based on week 0 to 12 data 
• cumulative distribution function plot of percent reduction (≥0%, ≥10%, ≥20%, ≥30%, 
≥40%, ≥50%, ≥60%, ≥70%, or ≥80%) from baseline (run-in period) in the monthly 
average number of CH attacks during the 12-week period after the first dose of the 
IMP, ie, based on week 0 to 12 data 
• mean change from baseline (run-in period) in the monthly average number of CH 
attacks of at least severe severity during the 12-week period after administration of 
the first dose of the IMP, ie, based on week 0 to 12 data 
• changes from baseline (day 0) in responses to questionnaires that measure quality of 
life, satisfaction with treatment, and health status  
• the relationship between biofluid biomarkers and fremanezumab concentrations 
• the relationship between specific genetic polymorphisms within the CGRP 
receptor-ligand complex and headache-associated genes versus headache response, 
specific CH attack clinical features (eg. severity, IMP effects, IMP efficacy), and/or 
safety (eg, adverse events to IMP) 
• the relationship between baseline levels and/or mean changes in levels from baseline 
(day 0) in biofluid biomarkers versus treatment, CH response status (onset/duration), 
and response status (ie, responders versus nonresponders) 


 
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Wearable sensor substudy exploratory endpoints are the following: 
• change in total sleep time, sleep onset latency, wake after sleep onset, and sleep 
efficiency on days with and without CH attacks 
• the change in the total time of sedentary, light, moderate, and vigorous activity before 
(6-hour period), during, and after (6-hour period) CH attack relative to days free of 
attacks 
• the correlation between total time in sedentary, light, moderate, and vigorous activity; 
total sleep time; sleep onset latency; wake after sleep onset; and sleep efficiency and 
the frequency of CH attacks 
• the correlation between total time in sedentary, light, moderate, and vigorous activity; 
total sleep time; sleep onset latency; wake after sleep onset; and sleep efficiency and 
headache intensity during CH attacks 
• the correlation between total time in sedentary, light, moderate, and vigorous activity; 
total sleep time; sleep onset latency; wake after sleep onset; and sleep efficiency and 
headache duration during CH attacks 
• the average total time in sedentary, light, moderate, and vigorous activity; total sleep 
time; sleep onset latency; wake after sleep onset; and sleep efficiency in patients with 
CCH 
• the correlation between the total time in sedentary, light, moderate, and vigorous 
activity; total sleep time; sleep onset latency; wake after sleep onset; and sleep 
efficiency and the genetic and biomarker profiles 
• detection of time-dependent patterns composed of lower- and higher-level activity 
metrics (eg, activity score and sleep/wake patterns) 
• cross-correlation between the time-dependent activity patterns and CH attacks 
• prediction model for the coming CH attack, intensity, and duration. The input to the 
prediction model (ie, features) will be selected from the measurements collected by 
the digital wearable devices, information collected by the self-reporting devices, and 
aggregated information provided by the calculated endpoints (ie, various statistics). 
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 monthly 
average number of CH attacks during the 12-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 may 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 monthly 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 
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 loading dose 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: 
1. 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. 
2. 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 (α/2=0.025; reject the null 
hypothesis), 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. 
3. If the resulting 2-sided p-value from both comparisons are >0.05 (fail to reject both null 
hypotheses), no statistical significant 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 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. 
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. 
Pharmacokinetic/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 to monitor physiological 
activity, sleep/wake activity, and treatment responses. 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 12-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 clinical study report, or any 
combination of these, as appropriate, and in accordance with applicable national, local, and 
regional requirements and regulations. 


 
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10. 
QUALITY CONTROL AND QUALITY ASSURANCE 
Refer to Appendix C for information regarding quality control and quality assurance. This 
includes information about protocol amendments, deviations, and 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. 
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ten Klooster PM, Drossaers-Bakker KW, Taal E, van de Laar MAFJ. Patient-perceived 
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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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96 
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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Reason/justification 
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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 factorvalue 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 least 20-fold higher relative to Cmax. 
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 
Added updated 
information for 
nonclinical studies. 


 
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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. 
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 fremanezumab in healthy subjects (Study LBR-101-011).  
A total of 118 healthy subjects received fremanezumab 
across 6 completed Phase 1 studies in doses ranging from 
0.2 through 2000 mg. Studies included 2 single-ascending-
dose pharmacokinetic and pharmacodynamic studies in 
healthy men (Studies B0141001 and B0141002); a 2-
cohort, placebo-controlled crossover study to examine the 
acute effects of administration of fremanezumab on 
capsaicin flare response in healthy men (Study 
B0141006); a parallel-group, repeat-dose study of 
fremanezumab in healthy subjects (Study B0141007); a 
single-dose study evaluating the safety, tolerability, and 
pharmacokinetics of doses up to 2000 mg administered iv 
in healthy women (Study LBR-101-008 [formerly referred 
to as Study B0141008]); and a study assessing the safety, 
tolerability, absolute bioavailability, and pharmacokinetics 
of single iv or sc doses of fremanezumab in healthy 
Added updated 
information for 
pharmacology 
studies. 


 
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These Phase 1 studies were analyzed using the original 
bioanalytical method that has since been determined to 
underestimate measured plasma concentrations compared with 
the current validated assay. In those analyses, fremanezumab 
pharmacokinetics The pharmacokinetics (noncompartmental 
analysis) of fremanezumab appeared linear over the dose 
range from 100 to 2000 mg, with Cmax and AUC parameters 
generally increasing in proportion to the dose. 
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 At lower doses 
(1 to 30 mg), exposure was lower than expected based upon 
the proportional pharmacokinetics observed at higher doses. 
Cmax generally occurred at or shortly after the end of infusion, 
with median time of maximum observed concentration (tmax) 
values was generally of 1.0 to 5 to 7 days post sc doses.0 hours 
postdose after a 1 hour infusion. However, absorption was 
prolonged following sc administration, as indicated by the 
delayed Cmax (median tmax of 96 to 108 hours postdose). 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 parameters and overall pharmacokinetic profile were 
subjects (Study LBR-101-011). 
These Phase 1 studies were analyzed using the original 
bioanalytical method that has since been determined to 
underestimate measured plasma concentrations. In those 
analyses, fremanezumab pharmacokinetics appeared linear 
over the dose range from 100 to 2000 mg with Cmax and 
AUC generally increasing in proportion to the dose. 
A recently completed pharmacokinetic, safety, and 
tolerability study in healthy Japanese and Caucasian 
subjects (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. Comparison of exposure 
parameters (Cmax and AUC0-∞) from Studies LBR-101-011 
and TV48125-PK-10078 at the 225- and 900-mg sc dose 
levels indicates a 2.9- to 3.5-fold higher exposure in 
Study TV48125-PK-10078 relative to Study LBR-101-
011. The main reason for the difference in exposure 
appears to be the bioanalytical method used in the plasma 


 
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2000 mg. Absolute bioavailability of the sc dose was similar 
for healthy Japanese and Caucasian subjects. Comparison of 
exposure parameters (Cmax and AUC0-∞)the 2 different doses 
(225 and 900 mg) and ranged from Studies LBR-101-011 and 
TV48125-PK-10078 at the 225- and 900-mg sc dose levels 
indicate a 2.9- approximately 54% to 56% for the 225 and 990 
mgto 3.5-fold higher exposure in Study TV48125-PK-10078 
relative to Study LBR-101-011. The main reason for the 
difference in exposure appears to be the underestimated 
concentration values from the original methoddoses, 
respectively. 
sample analysis. 
Section 1.2.2.2, Clinical Safety and Efficacy Studies 
Fremanezumab was well tolerated with favorable safety 
profile across the 6 completed Phase 1 and 2 completed Phase 
2b studies. In addition, no new safety findings were observed 
in the first cohort of 12 Japanese subjects from the ongoing 
Phase 1 study (Study TV48125 PK 10078), and no serious 
adverse events considered related to the investigational 
medicinal product (IMP) have been reported for the ongoing 
pivotal efficacy studies (Studies 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) 
• 
changes from baseline (day 0) in responses to 
questionnaires that measure quality of life, satisfaction 
with treatment, and, health status, and CH associated 
disability  
• 
changes from baseline (day 0) in responses to 
questionnaires that measure quality of life, 
satisfaction with treatment, and health status 
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 
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 
Added clarification 
that all patients will 
be offered 


 
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study (visit 5), approximately 12 weeks after administration of 
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 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 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 
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-
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. 
opportunity to 
participate in the 
long-term safety 
study either for 
treatment and 
long-term safety 
assessment or for 
long-term safety 
assessment alone. 


 
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[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. 
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/ana
phylaxis 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) 
e. The patient is not using or using ≤a maximum of 2 
concomitant medications that are commonly prescribed as 
e. The patient is not using or using ≤2 concomitant 
medications that are commonly prescribed as 
Updated for 
clarification. 


 
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Reason/justification 
for change 
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.  
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. 
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. 
f. 
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. 
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.Definitions of sterile and postmenopausal are 
given in Appendix E. 
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. Definitions of sterile and 
postmenopausal are given in Appendix E. 
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. 
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 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 
a. The patient has used systemic steroids for any medical 
reason (including treatment of short corticosteroid 
Updated for 
clarification. 


 
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treat the current CH cycle) within ≤7 days prior to 
screening. 
cycle to treat the current CH cycle) within ≤7 days 
prior to screening. 
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 section affected by this change: Appendix C, Quality Control and Quality 
Assurance) 


 
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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. 
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. 
Added text for 
clarification for 
reasons 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 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 


 
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Third, the favorable safety profile of the drug and calculated 
safety margins based modelling and simulations, 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 
concentrations (Cmax) generally occur at or shortly after the 
end of infusion (median tmax values of 1.0 to 5.0 hours after 
starting the iv infusion) compared with 96 to 108 hours 5 to 7 
days postdose for sc injections. 
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. 
Revised for 
clarification. 
Section 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 the 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 the 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 
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 
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 
Revised for 
clarification. 


 
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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. 
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 allowed on a 
case by case basis warranted to ensure patient safety. To 
ensure patient safety, aAfter the event has stabilized or 
treatment has been administered (or both), the investigator or 
other physician in attendance must contact the physician 
identified in the Clinical Study Personnel Contact Information 
section of this protocol as soon as possible to discuss the 
situation. The investigator, in consultation with the sponsor, 
will decide whether the patient should continue to participate 
in the study. The same reporting process as for all other 
protocol deviations will apply. A noncompliant patient may 
continue taking the study treatment only if this does not 
jeopardize the patient’s safety. The sponsor will assess each 
protocol deviation and decide whether any of these 
noncompliances should be reported to the Regulatory 
Authority as a serious breach of Good Clinical Practice (GCP) 
and the protocol. 
If a patient experiences an adverse event or medical 
emergency, deviations from the protocol may be 
warranted to ensure patient safety. After the event has 
stabilized or treatment has been administered (or both), the 
investigator or other physician in attendance must contact 
the physician identified in the Clinical Study Personnel 
Contact Information section of this protocol as soon as 
possible to discuss the situation. The investigator, in 
consultation with the sponsor, will decide whether the 
patient should continue to participate in the study. The 
same reporting process as for all other protocol deviations 
will apply. A noncompliant patient may continue taking 
the study treatment only if this does not jeopardize the 
patient’s safety. The sponsor will assess each protocol 
deviation and decide whether any of these noncompliances 
should be reported to the Regulatory Authority as a 
serious breach of Good Clinical Practice (GCP) and the 
protocol. 
Revised for 
clarification. 
Section 7.3, Medication Error and Special Situations Related to the Investigational Medicinal Products 


 
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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 
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 
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 
Added clarification 
for injection site 
assessment windows. 


 
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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. 
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. 
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. 
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 
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 
Details about 
multiple 
comparisons and 
multiplicity added 


 
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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. 
4. 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. 
5. 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 (α/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. 
6. 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 
interpreted inferentially or until the point at which the 
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: 
7. 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. 
8. 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 (α/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. 
9. 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 
for clarification. 


 
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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. 
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 12-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 has to take place and a strong clinical justification 
must be provided in case the patient is not withdrawn from the 
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 has 
to take place and a strong clinical justification must be 
Revised for 
clarification. 


 
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study drug. 
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 an increased concentration of follicle-
stimulating hormone (FSH) serum level in the 
postmenopausal range of more than 35 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 an increased concentration of 
follicle-stimulating hormone (FSH) serum 
level in the postmenopausal range) in women 
not using hormonal contraception or hormonal 
replacement therapy 
• 
Women in stable post-menopause, but are 
taking hormone replacement therapy for 
treatment of menopausal symptoms may be 
considered eligible for the study even with the 
lower serum FSH. They do not need to use 
other contraception. 
Revised for 
clarification. 
• 
Bilateral tubal occlusion and vVasectomized 
partner provided that he is the sole sexual partner 
and has received medical assessment of the 
surgical process. 
• 
Bilateral tubal occlusion  
• 
Vasectomized partner provided that he is the 
sole sexual partner and has received medical 
assessment of the surgical process. 
Revised for 
clarification. 
Appendix F, LOST TO FOLLOW-UP 
A patient will be considered lost to follow-up if he/she 
repeatedly fails to return for scheduled visits and if the site is 
unable to establish contact with the patient after 3 documented 
attempts via 2 different methods (phone, text, e-mail, certified 
letter, etc) be contacted by the investigational center. 
A patient will be considered lost to follow-up if he/she 
repeatedly fails to return for scheduled visits and if the site 
is unable to establish contact with the patient after 
3 documented attempts via 2 different methods (phone, 
text, e-mail, certified letter, etc). 
Revised for 
clarification. 
Appendix G, 
HANDLING, LABELING, STORAGE, AND ACCOUNTABILITY FOR INVESTIGATIONAL MEDICINAL 
PRODUCT(S) 
Preparation instructions for iv infusions: Investigational 
Preparation instructions for iv infusions: Investigational 
Revised for 


 
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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 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. 
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 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. 
correctness. 
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). 
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 
Revised for 
clarification 


 
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Original text with changes shown 
New wording 
Reason/justification 
for change 
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. 
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. 
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 
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 2-mL polypropylene tubes (Sets A and 
B). 
Separated plasma will be transferred in approximately 
equal portions in 2 labeled 2-mL polypropylene tubes 
(Sets A and B). 
Revised for 
clarification. 
Set A samples will be transported frozen, with a temperature 
data logger and frozen with dry ice 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 dry ice 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 
Set A samples will be transported frozen, with a 
temperature data logger and with dry ice sufficient for 4 
days, on a monthly basis to the central laboratory. Central 
laboratory will ship the Set A samples on a monthly basis 
to the or bioanalytical laboratory with dry ice sufficient for 
4 days and with a temperature data logger. 
Set B samples will be sent to the same laboratory as that 
for Set A. Instructions as to the disposition of the Set B 
samples will be provided by the sponsor. 
Revised for 
clarification. 


 
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Reason/justification 
for change 
the disposition of the Set B samples will be provided by the 
sponsor. 
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= 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 needed; 
sc=subcutaneous; RNA=ribonucleic acid; tmax=time to maximum observed 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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New wording 
Reason/Justification for change 
Global change (except for protocol title) 
fremanezumabTEV 48125 
fremanezumab 
Generic name will now be used rather 
than the Teva-assigned number. 
Section 2.1, Primary and Secondary Study Objectives and Endpoints (other sections affected by this change: Section 9.5.1, Primary 
Endpoint and Section 9.5.2, Secondary Endpoints  
The primary efficacy endpoint of this study is the 
mean change from baseline (run-in period) in the 
monthly average number of cluster headache (CH) 
attacks during the 12-week period after 
administration of the first dose of the investigational 
medicinal product (IMP), ie, based on week 0 to 12 
dataproportion of patients with a ≥50% reduction 
from baseline (run in period) in the monthly average 
number of cluster headache (CH) attacks over the 
12 week period after the administration of the first 
dose of the IMP, ie, based on week 0 to 12 data. 
The primary efficacy endpoint of this study is 
the mean change from baseline (run-in period) 
in the monthly average number of cluster 
headache (CH) attacks during the 12-week 
period after administration of the first dose of 
the investigational medicinal product (IMP), 
ie, based on week 0 to 12 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 
monthly average number of cluster headache 
(CH) attacks over the 12-week period after 
the 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 12 week period after 
administration of the first dose of the 
IMP, ie, based on week 0 to 12 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 monthly average 
number of CH attacks over the 
12-week period after the 
administration of the first dose of the 
IMP, ie, based on week 0 to 12 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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Original text with changes shown 
New wording 
Reason/Justification for change 
Section 2.2.1 Exploratory Objectives and Endpoints (other section affected by this change: Section 9.5.3, Exploratory Endpoints): 
• 
mean change from baseline (run-in period) in 
the number of CH attacks during weeks 1, 2, 
3, 4, 8, and 12, after administration of the 
first dose of the IMP 
• 
mean change from baseline (run-in 
period) in the number of CH attacks 
during weeks 1, 2, 3, 4, 8, and 12, after 
administration of the first dose of the 
IMP 
Analyses were added for additional time 
points at weeks 2 and 3 to further 
explore the time to the onset of 
treatment effect.  
• 
mean change from baseline (run-in period) in 
the number of CH attacks during the 4-week 
period after administration of the second dose 
of the IMP, ie, based on week 4 to 8 data 
• 
mean change from baseline (run-in 
period) in the number of CH attacks 
during the 4-week period after 
administration of the second dose of 
the IMP, ie, based on week 4 to 8 data 
An endpoint to assess the efficacy 
during the second month of treatment to 
further explore the time course and to 
explore maintenance of efficacy during 
the second month of treatment.  
• 
mean change from baseline (run-in period) in 
the severity of CH attacks (mild, moderate, 
severe, or very severe) during weeks 1, 2, 3, 
4, 8, and 12 as measured by the NRS 11, 
after administration of the first dose of the 
IMP 
• 
change from baseline (run-in period) 
in the severity of CH attacks (mild, 
moderate, severe, or very severe) 
during weeks 1, 2, 3, 4, 8, and 12 after 
administration of the first dose of the 
IMP 
Severity will no longer be recorded 
numerically using the NRS scale. The 
scale to be used is categorical, and 
consequently “mean” is no longer 
applicable. Finally, analyses were added 
at weeks 2 and 3 to further explore the 
onset of treatment effect. 
• 
total cumulative distribution of percent 
reduction (≥0%, ≥10%, ≥20%, ≥30%, ≥40%, 
≥50%, ≥60%, ≥70%, or ≥80%) from baseline 
(run-in period) in the monthly average 
number of CH attacks during the 12-week 
period after the first dose of the IMP, ie, 
based on week 0 to 12 data 
• 
cumulative distribution function plot of 
percent reduction (≥0%, ≥10%, ≥20%, ≥30%, 
≥40%, ≥50%, ≥60%, ≥70%, or ≥80%) from 
baseline (run-in period) in the monthly 
average number of CH attacks during the 12-
week period after the first dose of the IMP, 
ie, based on week 0 to 12 data 
• 
total cumulative distribution of percent 
reduction (≥0%, ≥10%, ≥20%, ≥30%, 
≥40%, ≥50%, ≥60%, ≥70%, or ≥80%) 
from baseline (run-in period) in the 
monthly average number of CH 
attacks during the 12-week period after 
the first dose of the IMP, ie, based on 
week 0 to 12 data 
• 
cumulative distribution function plot 
of percent reduction (≥0%, ≥10%, 
≥20%, ≥30%, ≥40%, ≥50%, ≥60%, 
≥70%, or ≥80%) from baseline (run-in 
period) in the monthly average number 
of CH attacks during the 12-week 
period after the first dose of the IMP, 
Added 3 more exploratory endpoints to 
further evaluate the efficacy of 
fremanizumab. 


 
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Original text with changes shown 
New wording 
Reason/Justification for change 
• 
mean change from baseline (run-in period) in 
the monthly average number of CH attacks of 
at least severe severity during the 12-week 
period after administration of the first dose of 
the IMP, ie, based on week 0 to 12 data 
ie, based on week 0 to 12 data 
• 
mean change from baseline (run-in 
period) in the monthly average number 
of CH attacks of at least severe 
severity during the 12-week period 
after administration of the first dose of 
the IMP, ie, based on week 0 to 12 
data 
Section 2.2.2, Wearable Sensor Substudy Exploratory Objectives and Endpoints (other section affected by the change: Section 9.5.3, 
Exploratory Endpoints) 
• 
to evaluate changes in physical 
movementsattacks during days patients 
experience CH attacks relative to days free of 
attacks 
• 
to determine the relationship between 
physical movementsattacks and sleep pattern 
and the frequency of CH attacks 
• 
to determine the relationship between 
physical movementsattacks and sleep pattern 
and the intensity of CH attacks 
• 
to determine the relationship between 
physical movementsattacks and sleep pattern 
and the duration of CH attacks 
• 
to explore the differences in physical 
movementsattacks and sleep pattern in 
patients with CCH 
• 
to examine the relationship between physical 
movementsattacks and sleep pattern and that 
of genetic and biomarker measures 
• 
to evaluate changes in physical 
movementsattacks in predicting seasonal 
• 
to evaluate changes in attacks during 
days patients experience CH attacks 
relative to days free of attacks 
• 
to determine the relationship between 
attacks and sleep pattern and the 
frequency of CH attacks 
• 
to determine the relationship between 
attacks and sleep pattern and the 
intensity of CH attacks 
• 
to determine the relationship between 
attacks and sleep pattern and the 
duration of CH attacks 
• 
to explore the differences in attacks 
and sleep pattern in patients with CCH 
• 
to examine the relationship between 
attacks and sleep pattern and that of 
genetic and biomarker measures 
• 
to evaluate changes in attacks in 
predicting seasonal onset of new CH 
episode 
Changed to align with how the Phillips 
device reports activity. 


 
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Original text with changes shown 
New wording 
Reason/Justification for change 
onset of new CH episode 
• 
the change in the total time of sedentary, 
light, moderate, intense, and very intenseand 
vigorous activity before (6-hour period), 
during, and after (6-hour period) CH attack 
relative to days free of attacks 
• 
the correlation between total time in 
sedentary, light, moderate, intense, and very 
intenseand vigorous activity; total sleep time; 
sleep onset latency; wake after sleep onset; 
and sleep efficiency and the frequency of CH 
attacks 
• 
the correlation between total time in 
sedentary, light, moderate, intense, and very 
intenseand vigorous activity; total sleep time; 
sleep onset latency; wake after sleep onset; 
and sleep efficiency and headache intensity 
during CH incidentsattacks 
• 
the correlation between total time in 
sedentary, light, moderate, intense, and very 
intenseand vigorous activity; total sleep time; 
sleep onset latency; wake after sleep onset; 
and sleep efficiency and headache duration 
during CH incidentsattacks 
• 
the average total time in sedentary, light, 
moderate, intense, and very intenseand 
vigorous activity; total sleep time; sleep onset 
latency; wake after sleep onset; and sleep 
efficiency in patients with CCH 
• 
the correlation between the total time in 
sedentary, light, moderate, intense, and very 
intenseand vigorous activity; total sleep time; 
sleep onset latency; wake after sleep onset; 
• 
the change in the total time of 
sedentary, light, moderate, and 
vigorous activity before (6-hour 
period), during, and after (6-hour 
period) CH attack relative to days free 
of attacks 
• 
the correlation between total time in 
sedentary, light, moderate, and 
vigorous activity; total sleep time; 
sleep onset latency; wake after sleep 
onset; and sleep efficiency and the 
frequency of CH attacks 
• 
the correlation between total time in 
sedentary, light, moderate, and 
vigorous activity; total sleep time; 
sleep onset latency; wake after sleep 
onset; and sleep efficiency and 
headache intensity during CH attacks 
• 
the correlation between total time in 
sedentary, light, moderate, and 
vigorous activity; total sleep time; 
sleep onset latency; wake after sleep 
onset; and sleep efficiency and 
headache duration during CH attacks 
• 
the average total time in sedentary, 
light, moderate, and vigorous activity; 
total sleep time; sleep onset latency; 
wake after sleep onset; and sleep 
efficiency in patients with CCH 
• 
the correlation between the total time 
in sedentary, light, moderate, and 
vigorous activity; total sleep time; 
Changed to align with how the Phillips 
device reports activity. Phillips device 
does no report steps. 


 
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Original text with changes shown 
New wording 
Reason/Justification for change 
and sleep efficiency and the genetic and 
biomarker profiles 
• 
the change in total time in sedentary, light, 
moderate, intense, and very intense activity 
and total number of steps during the 
remission period of patients with CCH and 
15 days preceding a new epoch of CH attacks 
• 
detection of time-dependent patterns 
composed of lower- and higher-level activity 
matricesmetrics (eg, activity score, and 
sleep/wake patterns, and physical 
movements) 
sleep onset latency; wake after sleep 
onset; and sleep efficiency and the 
genetic and biomarker profiles 
• 
detection of time-dependent patterns 
composed of lower- and higher-level 
activity metrics (eg, activity score and 
sleep/wake patterns) 
Section 3.1, General Design and Study Schematic Diagram 
The study will consist of a screening visit, a run-in 
period lasting approximately 4 weeks (+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 approximately 4 weeks 
(+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 willmay 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 
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 
Edited to allow flexibility regarding 
enrollment in the long-term safety 
study. 


 
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Original text with changes shown 
New wording 
Reason/Justification for change 
the long-term safety study for any reason willmay be 
offered the opportunity 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. 
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. 
Figure 1 was updated to show PBO SC and PBO IV 
at the first dosing visit (visit 2) for each of the active 
treatment groups. 
PBO SC 
PBO IV 
Update made to clarify how 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 ex-
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 
Q3/2018. 
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 Q3/2018. 
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 (other section affected by this change: Appendix C, Quality Control and Quality Assurance) 
The investigator and/or sponsor can withdraw a 
The investigator and/or sponsor can withdraw 
Change to terminology (violation 


 
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New wording 
Reason/Justification for change 
patient from the study at any time for any reason (eg, 
protocol violation or deviation as defined in 
Section 10, noncompliance, or adverse event). 
a patient from the study at any time for any 
reason (eg, protocol deviation as defined in 
Section 10, noncompliance, or adverse event). 
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 
concomitant medications). 
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 medications). 
Edited to allow flexibility regarding 
enrollment in the long-term safety 
study. 
Section 3.5, Schedule of Study Procedures and Assessments 
n. 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. 
n. The blood sample for pharmacokinetics 
analysis collected immediate 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 
b. The patient reports using butalbital on more than 
107 days during the 4 weeks prior to screening or 
using butalbital on more than 10 days during the 
screening/run-in period. 
b. The patient reports using butalbital on 
more than 10 days during the 4 weeks prior 
to screening or using butalbital on more 
than 10 days during the screening/run-in 
period. 
Update made to align the 4-week period 
before the run-in with the run-in period. 
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 
h. The patient has a history of clinically 
significant cardiovascular disease or 
vascular ischemia (such as myocardial, 
neurological [eg, cerebral ischemia], 
Time period expanded as it is important 
to include patients with CH who are 
otherwise healthy. 


 
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New wording 
Reason/Justification for change 
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.  
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. 
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 
of the active IMP) after administration of the last 
dose of IMP in this study. 
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 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 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 
willmay 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 willmay 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. 


 
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New wording 
Reason/Justification for change 
Section 5.6, Prior and Concomitant Medication or Treatment 
A maximum of 2 concomitant preventive medications 
for CCHECH are allowed. 
A maximum of 2 concomitant preventive 
medications for CCH are allowed. 
Corrected to align with the patient 
population in this 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) 
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 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. 


 
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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 
treatment [EOT]; visit 5). 
 
Removed the NRS scale to meet the 
definition of the IHS for CH attack. 
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,” 
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 
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. 


 
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“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.” 
“slightly improved.” 
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 
Patients will rate the change in their overall health 
and wellbeing how 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 7 point scale, where 
1 isas “much worse,” “moderately worse,” “slightly 
worse,” “stayed the same,” “a little better,” 
“moderately better,” or “much better.” no change (or 
condition has got worse),” 4 is “somewhat better, but 
the change has not made any real difference,” and 7 
is “a great deal better, and a considerable 
improvement that has made all the difference.” 
New section number due to removal of 
Section 6.2: Section 6.8, Patient Global 
Impression of Change Scale 
Patients will rate the change in their overall 
health and wellbeing compared with how they 
felt at the start of the study (the time after the 
patient received the first IMP dose) as “much 
worse,” “moderately worse,” “slightly worse,” 
“stayed the same,” “a little better,” 
“moderately better,” or “much better.” 
Updated the text to align with the 
e-diary. 
Section 7.1.3, Severity of an Adverse Event 
For severity grading of local tolerability (injection 
site erythema, induration, ecchymosis, and pain), 
refer to Section 7.11. 
For severity grading of local tolerability 
(injection site erythema, induration, 
ecchymosis, and pain), refer to Section 7.11. 
Added reference to Section 7.11 to 
clarify how local tolerability findings 
will be graded. 
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 
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 
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 


 
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Reason/Justification for change 
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.” 
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. 
deviation information.  
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 
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 
Adapted text to the eC-SSRS electronic 
questionnaire format. 


 
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Reason/Justification for change 
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 
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. 
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. 
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.  
• 
… 
Symptom 
Severity 
Ggrade 
Assessment 
Pain 
0 
AbsentNo pain 
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 
Assessment 
Deleted grade 4 to align severity 
grading with severity scale for adverse 
events. 


 
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1 (mild) 
Painful on touchMild 
2 
(moderate) 
Pain on 
ambulationModerate 
3 (severe) 
Spontaneously 
painfulSevere 
4 
Worst possible 
If a patient has severe injection site induration, 
erythema, and/or ecchymosis, and/or grade 3 (severe) 
or grade 4 (worst possible) injection site pain at 1 
hour after completion of the IMP administration, the 
patient will be reassessed at 3 hours after completion 
ofreceiving the IMP administration and hourly 
thereafter until the reaction/pain is of moderate or 
less severity. 
Appropriate treatment may be provided if necessary, 
in which case it must be recorded as concomitant 
medication. 
Injection-site reactions (injection site erythema, 
induration, ecchymosis, and pain) will also be 
recorded as adverse events as described in Section 
7.1. 
Pain 
0 
Absent 
1 (mild) 
Painful on 
touch 
2 (moderate) 
Pain on 
ambulation 
3 (severe) 
Spontaneous
ly painful 
If a patient has severe injection site induration, 
erythema, ecchymosis, or pain at 1 hour after 
completion of IMP administration, the patient 
will be reassessed at 3 hours after completion 
of IMP administration and hourly thereafter 
until the reaction is of moderate or less 
severity. 
Appropriate treatment may be provided if 
necessary, in which case it must be recorded as 
concomitant medication. 
Injection-site reactions (injection site 
erythema, induration, ecchymosis, and pain) 
will also be recorded as adverse events. 
Section 8.6, Ancillary Studies – Wearable Sensor Substudy 
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. The 
objective of this substudy is to evaluate changes in 
sleep-wake parameters and changes in physical 
movementactivity as they relate to the occurrence of 
CH attacks. These changes will be evaluated during 
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. The objective of this substudy is to 
evaluate changes in sleep-wake parameters and 
changes in activity as they relate to the 
occurrence of CH attacks. These changes will 
Changed to align with how the Phillips 
device reports activity. 


 
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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. The 
relationship between sleep-wake parameters, physical 
movementactivity levels, and the frequency, 
intensity, and duration of CH attacks will also be 
determined. 
… 
The data will be used to assess whether changes in 
patterns of sleep and/or physical movementactivity as 
captured by the digital wearable device can be used 
for early prediction and possible intervention of CH 
attacks. It is anticipated that risks to patients beyond 
those listed in Section 1.3 are unlikely. 
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. 
The relationship between sleep-wake 
parameters, activity levels, and the frequency, 
intensity, and duration of CH attacks will also 
be determined. 
… 
The data will be used to assess whether 
changes in patterns of sleep and/or activity as 
captured by the digital wearable device can be 
used for early prediction and possible 
intervention of CH attacks. It is anticipated 
that risks to patients beyond those listed in 
Section 1.3 are unlikely. 
Section 9.1, Sample Size and Power Considerations 
A sample size of 258171 patients (8657 evaluable 
patients completing the study per treatment group) 
will provide at least 90% power to detect a treatment 
difference of 4 CH attacks in the monthly average 
(assuming a common standard deviation [SD] of 8 
CH attacks) at a 2-sided alpha level of 0.0530% in 
the proportion of patients (30% in placebo group and 
60% in each of active treatment groups) with ≥50% 
reduction at a 1 sided alpha level of 0.025. Assuming 
a 1420% discontinuation rate, 300216 patients will be 
randomized in the trial. 
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 4 CH attacks in 
the monthly average (assuming a common 
standard deviation [SD] of 8 CH attacks) at a 
2-sided alpha level of 0.05. Assuming a 14% 
discontinuation rate, 300 patients will be 
randomized in the trial. 
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. 
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 
majorimportant protocol violationsdeviations. 
The per-protocol (PP) analysis set is a subset 
of the ITT analysis set including only patients 
without any important protocol deviations. 
Change to terminology (violation to 
deviation) to align with guidance from 
the ICH. 


 
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MajorImportant protocol deviationsviolations will be 
determined before unblinding/database lock. 
Important protocol deviations will be 
determined before unblinding/database lock. 
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 
nonresponders. 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. 
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 nonresponders. 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. 
Added to clarify that imputation will be 
used. 
Section 9.5.4.1, Primary Efficacy Analysis 
The primary efficacy endpoint, the mean change from 
baseline (run-in period) in the monthly average 
number of CH attacks during the 12-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 monthly average 
number of CH attacks during the 12 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 
monthly average number of CH attacks during 
the 12-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 
The continuous endpoints will be analyzed 
using an ANCOVA or a mixed model for 
repeated measures. For the proportion of 
Update made due to new primary 
endpoint. 


 
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as 50% or more reduction from baseline in the 
monthly 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. 
responders, defined as 50% or more reduction 
from baseline in the monthly average number 
of CH attacks, data will be analyzed using a 
Cochran-Mantel-Haenszel test stratified by 
baseline preventive medication use (yes/no). 
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. 
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 
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. 
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. 
Visit 2, procedures before administration of the IMP 
• 
Obtain a 4-mL blood sample for 
With the exception of the blood sample 


 
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• 
Obtain a 4-mL blood sample for 
pharmacokinetics analysis from theeither arm 
that will not be used for dosing with IMP. 
pharmacokinetics analysis from either arm. 
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 blood sample 
for pharmacokinetics analysis will be collected 
immediately before the end of the IMP infusion from 
the arm that is not used for the IMP infusion. 
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 blood sample for 
pharmacokinetics analysis will be collected 
immediately before the end of the IMP 
infusion from the arm that is not used for the 
IMP infusion. 
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. 
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. 
• 
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 
• 
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 
To align with changes in Section 7.11. 


 
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severity of any observed injection site reaction 
and/or injection site pain. 
site reaction. 
Week 1 (Day 7) 
Patients will complete the PGIC scale and the PPSI 
(complete the VAS PI and respond to question about 
change in pain intensity) at 1 week after receiving 
IMP using the electronic diary device.  
Week 1 (Day 7) 
Patients will complete the PGIC scale and the 
PPSI at 1 week after receiving IMP using the 
electronic diary device. 
To align with changes in Section 6.7. 
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 -70°C to± 
-20°C (inclusive) in an upright position until they are 
shipped to the central laboratory. 
Samples will be stored at a temperature 
of -70°C to -20°C (inclusive) in an upright 
position until they are shipped to the central 
laboratory. 
Pharmacokinetic and ADA samples can 
be stored in a 70°C to -20°C freezer at 
the clinical sites before shipping. 
Appendix P, Exploratory Biomarkers Samples 
Blood samples (total of 148.5 mL; 6 mL each for 
plasma and serum and 26.5 mL for RNA [PAXgene]) 
will be collected via venipuncture or indwelling 
catheter at the time points detailed in Table 2 for 
serum, plasma, and RNA biomarker measures. 
Blood samples (total of 14.5 mL; 6 mL each 
for plasma and serum and 2.5 mL for RNA 
[PAXgene]) will be collected via venipuncture 
or indwelling catheter at the time points 
detailed in Table 2 for serum, plasma, and 
RNA biomarker measures. 
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. 
ADA=antidrug antibody; ANCOVA=analysis of covariance; CCH=chronic cluster headache; 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 on 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; RNA=ribonucleic acid 
SD=standard deviation; VAS=visual analog scale; VAS-PI-visual analog scale for pain intensity. 


 
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16.3. 
Letter of Clarification 04 Dated 13 December 2016 
 


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


 
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Study Principal Investigator 
 
 
 England 
 UK 
 
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. 
 
  
 
ratiopharm GmbH 
 
 
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. 
 
 
 
 
 
Teva Branded Pharmaceuticals R&D, Inc. 
 
Bioanalytical Immunogenicity Evaluation 
 
 
 
Teva Branded Pharmaceuticals R&D, Inc. 
 
 


 
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Pharmacogenomics/Biomarker Evaluation 
 
 
 
Teva Branded Pharmaceuticals R&D, Inc. 
 
  
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, 28 to 31 Days Before Visit 2) 
The screening visit (visit 1) will take place at during a run-in period lasting at least 4 weeks 
(+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. A subset of patients at selected sites in the US will also consent to 
participation in the wearable sensor biomarkers substudy. 
• 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 4 weeks (+3 days) during which they will enter CH 
attack information daily. 
2. Procedures Before Administration of Investigational Medicinal Product (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. 
The following procedures will be performed at visit 2 (week 0): 


 
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• 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 serum, 6 mL 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 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 
min) 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 reaction. 
• 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 
min) 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 
min) 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 serum, 6 mL 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 substudy. 
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 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 important 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 monitors 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: 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 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. 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 test IMP (fremanezumab) and placebo IMP 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 center may supply or administer IMPs. All IMPs must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labeled storage conditions or appropriate instructions with access limited to the investigator and 
authorized staff at the investigational center. 
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for IMP accountability, reconciliation, and record maintenance (ie, receipt, 
reconciliation, and final disposition records). 
A record of IMP accountability (ie, IMP and other study materials received, used, retained, 
returned, or destroyed) must be prepared and signed by the principal investigator or designee, 
with an account given for any discrepancies. Empty 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 prefilled 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. 
Botox will not be a stable concomitant preventive medication for cluster headaches. If the 
patients were treated with Botox for the prevention of migraine, they should have had at least 
2 cycles of Botox within 10 days of a new cluster cycle prior to screening. 
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 used systemic steroids to treat the current CH 
cycle or for any other indication to treat the current CH cycle within ≤7 days of screening. 
Butalbital: 
Screening/run-in period: Disallowed if used more than 10 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 15 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 adverse event potentially being related to immunogenicity (eg, lack of 
efficacy). 
d Unless the patient declines testing or local regulations prohibit testing.  
ADA=antidrug antibody; 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-glutamyltranspeptidase; INR=international normalized ratio; RBC=red blood cell; WBC=white blood 
cell. 


 
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APPENDIX N. PHARMACOKINETICS SAMPLES 
Specimen Sampling and Handling 
For plasma collection, samples will be collected in anticoagulant tubes, inverted slowly 
6 to 8 times to mix the contents, and placed on water/ice (approximately 4°C). Blood samples 
will be centrifuged (1500 g, approximately 10 minutes, at 2 to 8°C) between 5 minutes and 
1 hour after sampling. If a refrigerated centrifuge is not available, samples should be chilled 
before centrifugation. Other measures should be taken as appropriate to prevent samples from 
heating significantly during centrifugation. Separated plasma will be transferred in 
approximately equal portions in 2 labeled 2 mL-polypropylene tubes (Sets A and B). 
Labels for samples should include study number, patient randomization number, nominal 
collection time (Visit number), Set A or B, and indication that they are pharmacokinetic samples. 
Samples will be stored at a temperature of –70ºC to -20°C (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 –70ºC until assayed. The central laboratory will 
be notified before the shipment of the samples and will be sent the shipping information when 
the samples are shipped. An electronic file containing sample demographics will be emailed to 
the bioanalytical laboratory and the sponsor’s representatives from bioanalytical departments for 
each shipment. 
Set A samples will be transported frozen, with a temperature data logger and with dry ice 
sufficient for 4 days, on a monthly basis to the central laboratory. Central laboratory will ship the 
Set A samples on a monthly basis to the bioanalytical laboratory with dry ice sufficient for 4 
days and with a temperature data logger.  
Set B samples will be sent to the same laboratory as that for Set A. Instructions as to the 
disposition of the Set B samples will be provided by the sponsor. Sample shipments should be 
sent no later in the week than Wednesday morning for next‑day delivery. Samples are not to 
arrive on the weekend. 
Samples will be analyzed using an appropriate validated method. Timing of the initiation of 
sample analysis will be determined by the sponsor’s representatives of bioanalytical departments 
responsible for the bioanalysis while keeping the study blinding, if any, intact. 


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


 
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APPENDIX P. EXPLORATORY BIOMARKERS SAMPLES 
Blood samples (8.5 mL serum, 6 mL plasma and 2.5 mL for RNA [PAXgene]) will be collected 
via venipuncture or indwelling catheter at the time points detailed in Table 2 for serum, plasma, 
and RNA biomarker measures. Urine will be collected in parallel with blood collection. In 
addition, a 6-mL whole blood sample will be collected at baseline (or a later visit) for DNA. 
Details for processing and handling of each type of biomarker sample will be outlined in the 
laboratory manual. 
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 stored at –70°C and sent to the 
central laboratory on dry ice, 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 –70°C 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 
Blood samples (6 mL) for pharmacogenomic assessments will be collected from all patients in 
the study who signed the ICF for the pharmacogenomic assessments at the time point detailed in 
Table 2. Pharmacogenomic assessment potentially includes the association of DNA variations in 
specific genes of interest with clinical responses to test IMP (eg, efficacy, pharmacokinetics, 
tolerability, and safety features or disease susceptibility and severity features). The current list of 
genes with polymorphisms associated with either calcitonin gene-related peptide target 
engagement or cluster headache mechanism of action includes CALCA, CALCB, CALCRL, 
CRCP, RAMP, PRDM16, AJAP1, TSPAN2, MEF2D, TRPM8, TGFBR2, PHACTR1, FHL5, 
C7orf10, MMP16, ASTN2, LRP1, APOA1BP, TBC1D7, FUT9, STAT6, ATP5B, and MTHFR 
(Anttila et al 2013). The final list of genes that might be investigated will be selected at a later 
stage before the analysis to allow updating with new scientific information. Genetic analysis 
could also include sequencing of the whole genome if required. 
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 IMPs. 
Details on processes for collection and shipment of these samples can be found in the procedural 
manual. 


 
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APPENDIX R. PRODUCT COMPLAINTS 
Clinical Product Complaints 
A clinical product complaint is defined as a problem or potential problem with the physical 
quality or characteristics of clinical 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 


 
Placebo-Controlled Study–Chronic Cluster Headache 
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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. 


 
Placebo-Controlled Study–Chronic Cluster Headache 
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Study TV48125-CNS-30057 
173 
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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Placebo-Controlled Study–Chronic Cluster Headache 
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SAP_001.pdf: 
Statistical Analysis Plan with Amendment 01 
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 Chronic Cluster Headache 
Study Number TV48125-CNS-30057 
NCT02964338 
Statistical Analysis Plan with Amendment 01 Approval Date: 19 September 2018 


Placebo-Controlled Study–Chronic Cluster Headache 
Statistical Analysis Plan Amendment 01 
Study TV48125-CNS-30057 
1 
 
 
 
 
Statistical Analysis Plan 
Study Number TV48125-CNS-30057 
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 Chronic Cluster Headache 
 
Phase 3 
 
 
IND number: 129606; 
 EudraCT number: 2016-003171-21 
 
 
Statistical Analysis Plan Approval Date: 08 January 2018 
Statistical Analysis Plan Amendment 01 Approval Date : 19 September 2018 
 
 
Sponsor 
Teva Branded Pharmaceutical  
Products R&D, Inc. 
41 Moores Road 
Frazer, Pennsylvania 19355 
United States 
 
 
 
 
 
Prepared by: 


Placebo-Controlled Study–Chronic Cluster Headache 
Statistical Analysis Plan Amendment 01 
Study TV48125-CNS-30057 
2 
STATISTICAL ANALYSIS PLAN APPROVAL 
 
Study No.: 
TV48125-CNS-30057 
 
Study Title: 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 Chronic Cluster Headache 
 
 
Statistical Analysis Plan for: 
 
 Interim Analysis  
 
 Integrated Summary of Efficacy 
 
 Final Analysis 
 
 
 Integrated Summary of Safety 
 
 
Amendment: 1 
Author: 
 
 
 
 
 


Placebo-Controlled Study–Chronic Cluster Headache 
Statistical Analysis Plan Amendment 01 
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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
STATISTICAL ANALYSIS PLAN APPROVAL ..........................................................................2 
AMENDMENT HISTORY .............................................................................................................9 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................10 
INTRODUCTION .........................................................................................................................12 
1. 
STUDY ENDPOINTS ................................................................................................13 
1.1. 
Primary Efficacy Endpoints ........................................................................................13 
1.2. 
Secondary Efficacy Endpoints ....................................................................................13 
1.3. 
Safety Endpoints .........................................................................................................13 
1.4. 
Immunogenicity Assessment Endpoints .....................................................................14 
1.5. 
Exploratory Endpoints ................................................................................................14 
1.6. 
Wearable Sensor Substudy Endpoints ........................................................................15 
2. 
STUDY DESIGN .......................................................................................................17 
2.1. 
General Design ...........................................................................................................17 
2.1.1. 
Wearable Sensor Substudy .........................................................................................18 
2.2. 
Randomization and Blinding ......................................................................................19 
2.3. 
Data Monitoring Committee .......................................................................................19 
2.4. 
Sample Size and Power Considerations .....................................................................19 
2.5. 
Sequence of Planned Analyses ...................................................................................20 
2.5.1. 
Planned Interim Analyses ...........................................................................................20 
2.5.2. 
Final Analyses and Reporting .....................................................................................20 
3. 
ANALYSIS SETS ......................................................................................................21 
3.1. 
Intent-to-Treat Analysis Set ........................................................................................21 
3.2. 
Safety Analysis Set .....................................................................................................21 
3.3. 
Full Analysis Set .........................................................................................................21 
3.4. 
Per-Protocol Analysis Set ...........................................................................................21 
4. 
GENERAL ISSUES FOR DATA ANALYSIS ..........................................................22 
4.1. 
General ........................................................................................................................22 
4.2. 
Specification of Baseline Values ................................................................................22 
4.3. 
Region of Pooled Countries ........................................................................................22 
4.4. 
Handling Withdrawals and Missing Data ...................................................................22 


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4.5. 
Study Days and Visits .................................................................................................22 
5. 
STUDY POPULATION .............................................................................................24 
5.1. 
General ........................................................................................................................24 
5.2. 
Patient Disposition ......................................................................................................24 
5.3. 
Demographics and Baseline Characteristics ...............................................................24 
5.4. 
Medical History ..........................................................................................................24 
5.5. 
Prior Therapy and Medication ....................................................................................24 
5.6. 
Childbearing Potential and Methods of Contraception ..............................................25 
5.7. 
Physical Examinations ................................................................................................25 
5.8. 
Study Protocol Deviations ..........................................................................................25 
6. 
EFFICACY ANALYSIS ............................................................................................26 
6.1. 
General ........................................................................................................................26 
6.1.1. 
Cluster Headache Attacks Data from E-diary ............................................................26 
6.1.2. 
Data Derivation ...........................................................................................................26 
6.1.3. 
Analysis Windows for E-diary Data ...........................................................................27 
6.1.4. 
Handling Missing E-diary Data ..................................................................................28 
6.1.4.1. 
Primary Efficacy Endpoint .........................................................................................29 
6.1.4.2. 
Analyses Based on Monthly and 12-week Window ...................................................29 
6.1.4.3. 
Analyses of Mean Change from Baseline Using MMRM Method Based on 
1-Week Window .........................................................................................................29 
6.2. 
Primary Efficacy Endpoint and Analysis ...................................................................30 
6.2.1. 
Definition ....................................................................................................................30 
6.2.2. 
Primary Efficacy Analysis ..........................................................................................30 
6.2.3. 
Sensitivity Analyses for the Primary Efficacy Endpoint ............................................30 
6.2.3.1. 
Analysis with Multiple Imputation Method ...............................................................31 
6.2.3.2. 
Mixed Model for Repeated Measures Analysis ..........................................................31 
6.2.4. 
Subgroup Analyses .....................................................................................................32 
6.3. 
Secondary Efficacy Endpoints and Analyses .............................................................33 
6.3.1. 
Proportion of Patients with a ≥50% Reduction from Baseline in the Monthly 
Average Number of CH Attacks During the 12-Week Period After the First 
Dose of the IMP ..........................................................................................................33 
6.3.2. 
Mean Change from Baseline in the Number of Cluster Headache Attacks ...............33 
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 


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Compounds) During the 12-Week Period After Administration of the First 
Dose of the IMP ..........................................................................................................34 
6.3.4. 
Mean Change from Baseline in the Weekly Average Number of Days 
Oxygen is Used to Treat Chronic Cluster Headaches During 12-week Period 
After Administration of the First Dose of the IMP.....................................................34 
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 ............................................................35 
6.4.1. 
Proportion of Patients with ≥50%, 75%, or 100% Reduction from Baseline 
in Number of CH Attacks During the 12-Week Period (First 3 Exploratory 
Efficacy Endpoints) ....................................................................................................35 
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 .........................36 
6.4.3. 
Mean Change from Baseline in the Number of CH Attacks During the 
8-Week Period (Weeks 0 to 8) After Administration of the First Dose of the 
IMP .............................................................................................................................36 
6.4.4. 
Mean Change from Baseline in the Number of CH Attacks During the 
4-Week Period (Weeks 4 to 8) After Administration of the Second Dose of 
the IMP .......................................................................................................................36 
6.4.5. 
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 ..............................................................36 
6.4.6. 
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 ..............................................................37 
6.4.7. 
Cumulative Proportion of Responders Analysis .........................................................37 
6.4.8. 
Mean Change from Baseline in the Monthly Average Number of CH Attacks 
of at Least Severe Severity During the 12-Week Period After Administration 
of the First Dose of the IMP .......................................................................................39 
6.4.9. 
Changes from Baseline in Responses to Questionnaires That Measure 
Quality of Life, Satisfaction with Treatment, and Health Status ................................39 
6.4.9.1. 
Change from Baseline in EuroQol-5 Dimension Questionnaire ................................39 
6.4.9.2. 
Hospital Anxiety and Depression Scale .....................................................................39 
6.4.9.3. 
12-Item Short-Form Health Survey ............................................................................40 
6.4.9.4. 
Impact on Partner and Family Questionnaire .............................................................41 
6.4.9.5. 
Work Productivity and Activity Impairment Questionnaire: General Health 
V2.0 ............................................................................................................................41 
6.4.9.6. 
Patient Global Impression of Change Scale ...............................................................42 


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7. 
MULTIPLE COMPARISONS AND MULTIPLICITY ............................................43 
8. 
SAFETY ANALYSIS ................................................................................................44 
8.1. 
General ........................................................................................................................44 
8.2. 
Duration of Exposure to Study Drug ..........................................................................44 
8.3. 
Adverse Events ...........................................................................................................44 
8.4. 
Injection Site Assessments .........................................................................................45 
8.5. 
Hypersensitivity/Anaphylaxis .....................................................................................45 
8.6. 
Electronic Columbia Suicide Severity Rating Scale ..................................................45 
8.7. 
Deaths .........................................................................................................................46 
8.8. 
Clinical Laboratory Tests ...........................................................................................46 
8.8.1. 
Laboratory Values Meeting Hy’s Law Criteria ..........................................................48 
8.9. 
Physical Examinations ................................................................................................48 
8.10. 
Vital Signs ..................................................................................................................48 
8.11. 
Electrocardiography ....................................................................................................49 
8.12. 
Concomitant Medications or Therapies ......................................................................49 
9. 
TOLERABILITY VARIABLES AND ANALYSIS..................................................50 
10. 
PHARMACOKINETIC ANALYSIS .........................................................................51 
11. 
PHARMACOGENOMIC ANALYSIS ......................................................................52 
12. 
BIOMARKER ANALYSIS........................................................................................53 
13. 
IMMUNOGENICITY ANALYSIS ............................................................................54 
14. 
ANCILLARY STUDY ANALYSIS – WEARABLE SENSOR SUBSTUDY .........55 
15. 
PLANNED INTERIM ANALYSIS ...........................................................................56 
15.1. 
Statistical Methods ......................................................................................................56 
15.2. 
Timing and Data .........................................................................................................56 
15.3. 
Result Dissemination ..................................................................................................57 
15.4. 
Decision Rules ............................................................................................................57 
16. 
STATISTICAL SOFTWARE ....................................................................................58 
17. 
CHANGES TO ANALYSES SPECIFIED IN THE STUDY PROTOCOL ..............59 
18. 
REFERENCES ...........................................................................................................60 
APPENDIX A. E-DIARY QUESTIONNAIRE ..........................................................................61 
APPENDIX B. LOGICS FOR CLUSTER HEADACHE DERIVATION .................................64 
APPENDIX C. EUROQOL-5 DIMENSION QUESTIONNAIRE (EQ-5D) .............................65 
APPENDIX D. HOSPITAL ANXIETY AND DEPRESSION SCALE (HADS) ......................67 


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APPENDIX E. 12-ITEM SHORT-FORM HEALTH SURVEY (SF-12) ..................................69 
APPENDIX F. IMPACT ON PARTNER AND FAMILY QUESTIONNAIRE - 
PATIENTS .................................................................................................................71 
APPENDIX G. IMPACT ON PARTNER AND FAMILY QUESTIONNAIRE - 
PARTNERS ................................................................................................................73 
APPENDIX H. WORK PRODUCTIVITY AND ACTIVITY IMPAIRMENT 
QUESTIONNAIRE: GENERAL HEALTH V2.0(WPAI:GH) ..................................75 
 


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LIST OF TABLES 
Table 1: 
Study Visits .................................................................................................................23 
Table 2: 
Criteria for Potentially Clinically Significant Laboratory Values ..............................47 
Table 3: 
Criteria for Potentially Clinically Significant Vital Signs ..........................................48 


Placebo-Controlled Study–Chronic Cluster Headache 
Statistical Analysis Plan Amendment 01 
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AMENDMENT HISTORY 
The Statistical Analysis Plan for study TV48125-CNS-30057 (study protocol with amendment 02 dated 01 
May 2017) has been amended and reissued as follows: 
Date 
Summary of changes 
Reason for 
amendment 
01 May 2018 
Section 6.4.5 
New: 
∑𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝐶𝐶𝐶𝐶 𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎 𝑝𝑝𝑝𝑝𝑝𝑝 𝑑𝑑𝑑𝑑𝑑𝑑 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑎𝑎 𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤   
𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁 𝑜𝑜𝑜𝑜 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑤𝑤𝑤𝑤𝑤𝑤ℎ 𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎 𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟 𝑖𝑖𝑖𝑖 𝑡𝑡ℎ𝑒𝑒 𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑎𝑎 𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤 
 
Old: 
∑𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝐶𝐶𝐶𝐶 𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎 𝑝𝑝𝑝𝑝𝑝𝑝 𝑑𝑑𝑑𝑑𝑑𝑑 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑎𝑎 𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤   
𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁 𝑜𝑜𝑜𝑜 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑤𝑤𝑤𝑤𝑤𝑤ℎ 𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎 𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟 𝑖𝑖𝑖𝑖 𝑡𝑡ℎ𝑒𝑒 𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑎𝑎 𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤
×  7   
 
Correction 
30 March 2018 
Section 15.1, last paragraph  
Old: “….in the weekly average number of CH attacks during the 4-week 
period after administration of the IMP.”   
New: “….in the monthly average number of CH attacks during the 12-
week period after administration of the IMP.” 
Correction to typo 
13 August 2018 
Section 6.4.9.3, 3rd paragraph and last paragraph:  
Deleted wording for “Computed raw scores for 8 domains” and 
“Computed raw scores”. 
The software does 
not output 
computed raw 
scores 


Placebo-Controlled Study–Chronic Cluster Headache 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS  
Abbreviation 
Term 
ADA 
antidrug antibodies 
ANCOVA 
analysis of covariance 
ANOVA 
analysis of variance 
β-HCG 
beta-human chorionic gonadotropin 
CGRP 
calcitonin gene-related peptide 
CCH 
chronic cluster headache  
CH 
cluster headache  
CMH 
Cochran-Mantel-Haenszel 
CNS 
central nervous system 
CP 
conditional power 
CPRA 
cumulative proportion of responder’s analysis 
CRF 
case report form 
CV 
coefficient of variation 
e-diary  
electronic diary 
ECG 
electrocardiogram/electrocardiography 
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 
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 
PCS 
Physical Composite Scores 
PGIC 
Global Impression of Change 
PP 
per-protocol 


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Abbreviation 
Term 
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 


Placebo-Controlled Study–Chronic Cluster Headache 
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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-30057, (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 chronic 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. 


Placebo-Controlled Study–Chronic Cluster Headache 
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Study TV48125-CNS-30057 
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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 monthly average number of cluster headache (CH) attacks during the 12-week period after 
administration of the first dose of the investigational medicinal product (IMP), ie, based on 
week 0 to 12 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 
monthly average number of CH attacks over the 12-week period after the 
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 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 
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 chronic cluster headache (CCH) 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. 
• 12-lead electrocardiogram (ECG) findings at screening, baseline, and week 12 


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• 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: 
• proportion of patients with ≥50% reduction from baseline (run-in period) in the 
weekly average 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  
• proportion of patients with ≥75% reduction from baseline (run-in period) in the 
weekly average 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  
• proportion of patients reaching 100% reduction 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 
• mean change from baseline (run-in period) in the number of CH attacks during 
weeks 1, 2, 3, 4, 8, and 12, after administration of the first dose of the IMP 
• mean change from baseline (run-in period) in the number of CH attacks during the 
8-week period after administration of the first dose of the IMP, ie, based on week 0 to 
8 data 
• mean change from baseline (run-in period) in the number of CH attacks during the 
4-week period after administration of the second dose of the IMP, ie, based on week 4 
to 8 data 
• change from baseline (run-in period) 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  
• mean change from baseline (run-in period) 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, ie, based on week 0 to 12 data  


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• total cumulative distribution of percent reduction (≥0%, ≥10%, ≥20%, ≥30%, ≥40%, 
≥50%, ≥60%, ≥70%, or ≥80%) from baseline (run-in period) in the monthly average 
number of CH attacks during the 12-week period after the first dose of the IMP, ie, 
based on week 0 to 12 data 
• cumulative distribution function plot of percent reduction (≥0%, ≥10%, ≥20%, ≥30%, 
≥40%, ≥50%, ≥60%, ≥70%, or ≥80%) from baseline (run-in period) in the monthly 
average number of CH attacks during the 12-week period after the first dose of the 
IMP, ie, based on week 0 to 12 data 
• mean change from baseline (run-in period) in the monthly average number of CH 
attacks of at least severe severity during the 12-week period after administration of 
the first dose of the IMP, ie, based on week 0 to 12 data 
• changes from baseline (day 0) in responses to questionnaires that measure quality of 
life, satisfaction with treatment, and health status  
• the relationship between biofluid biomarkers and fremanezumab concentrations 
• the relationship between specific genetic polymorphisms within the calcitonin 
gene-related peptide (CGRP) receptor-ligand complex and headache-associated genes 
versus headache response, specific CH attack clinical features (eg. severity, IMP 
effects, IMP efficacy), and/or safety (eg, adverse events to IMP) 
• the relationship between baseline levels and/or mean changes in levels from baseline 
(day 0) in biofluid biomarkers versus treatment, CH response status (onset/duration), 
and response status (ie, responders versus nonresponders) 
1.6. 
Wearable Sensor Substudy Endpoints 
Wearable sensor substudy exploratory endpoints are the following: 
• change in total sleep time, sleep onset latency, wake after sleep onset, and sleep 
efficiency on days with and without CH attacks 
• the change in the total time of sedentary, light, moderate, and vigorous activity before 
(6-hour period), during, and after (6-hour period) CH attack relative to days free of 
attacks 
• the correlation between total time in sedentary, light, moderate, and vigorous activity; 
total sleep time; sleep onset latency; wake after sleep onset; and sleep efficiency and 
the frequency of CH attacks 
• the correlation between total time in sedentary, light, moderate, and vigorous activity; 
total sleep time; sleep onset latency; wake after sleep onset; and sleep efficiency and 
headache intensity during CH attacks 
• the correlation between total time in sedentary, light, moderate, and vigorous activity; 
total sleep time; sleep onset latency; wake after sleep onset; and sleep efficiency and 
headache duration during CH attacks 


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• the average total time in sedentary, light, moderate, and vigorous activity; total sleep 
time; sleep onset latency; wake after sleep onset; and sleep efficiency in patients with 
CCH 
• the correlation between the total time in sedentary, light, moderate and vigorous 
activity; total sleep time; sleep onset latency; wake after sleep onset; and sleep 
efficiency and the genetic and biomarker profiles 
• detection of time-dependent patterns composed of lower- and higher-level activity 
metrics (eg, activity score and sleep/wake patterns) 
• cross-correlation between the time-dependent activity patterns and CH attacks 
• prediction model for the coming CH attack, intensity, and duration. The input to the 
prediction model (ie, features) will be selected from the measurements collected by 
the digital wearable devices, information collected by the self-reporting devices, and 
aggregated information provided by the calculated endpoints (ie, various statistics) 


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2. 
STUDY DESIGN 
2.1. 
General Design 
This is a 16-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 CCH. The study will consist of a screening 
visit, a run-in period lasting approximately 4 weeks (+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 4 weeks (+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 have 
at least 10 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 (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 Patient 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 approximately 24 months from Q4/2016 to Q3/2018. 


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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 
 
CCH=chronic 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 3 placebo sc injections at visit 2 (week 0) and fremanezumab at 
225 mg administered as single sc injections at visits 3 and 4 (weeks 4 and 8, respectively). Patients randomized to 
the 675-mg sc loading dose group will receive placebo administered via an approximately 1-hour iv infusion and 
fremanezumab at 675 mg administered as 3 sc injections (225 mg/1.5 mL) at visit 2 (week 0) and fremanezumab at 
225 mg administered as single sc injections at visits 3 and 4 (weeks 4 and 8, respectively). Patients randomized to 
the placebo group will receive placebo as an approximately 1-hour iv infusion followed by placebo administered as 
3 placebo sc injections at visit 2 (week 0) and placebo as single sc injections at visits 3 and 4 (weeks 4 and 8, 
respectively).  
2.1.1. 
Wearable Sensor Substudy 
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). 
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 


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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 an approximately 1-hour iv infusion and 3 placebo 
subcutaneous (sc) injections 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 loading dose group: placebo administered via an 
approximately 1-hour iv infusion and fremanezumab at 675 mg administered as 3 sc 
injections (225 mg/1.5 mL) 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) 
• placebo group: placebo administered via an approximately 1-hour iv infusion and 3 
placebo 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) 
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 
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 4 CH attacks in the monthly 
average (assuming a common standard deviation [SD] of 8 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. 


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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 12-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 Section 15. 
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. 
Details are provided in Section 15. 
The study will not be unblinded until the final database lock and finalization of the SAP.  


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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 12-week 
on the primary endpoint. 
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.  
The efficacy analysis for the primary and secondary endpoints will be repeated for the 
per-protocol analysis set. 


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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 28 days if the number of days in the run-in period is not equal to 
28. 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. 
Dates that have incomplete information, such as only the month and year or just the year, will be 
estimated for the purpose of calculating variables that are dependent on time if necessary. Day 
will be estimated as the first day (01) of the month (if month and year of partial date are 
available) or middle (July 1) of the year (if only year is available), month will be estimated as 
July if year and day are available, unless otherwise noted. The imputations for partial dates are 
only for calculation purpose. Original date variables will not be imputed. Listings will list dates 
as collected. 
Patients’ date of birth will be collected by IRT. IRT will record the date of birth as the first day 
of the first month (January first) when only year is captured, and the first day of the selected 
month when month and year are captured. 
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 early, 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/monthly 
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. For continuous variables, treatment groups will 
be compared using an analysis of variance (ANOVA) with treatment group as a factor. For 
categorical variables, treatment groups will be compared using a Pearson’s chi-square (or 
Fisher’s exact test if cell sizes are too small). 
Baseline characteristics including years since first CCH 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. 
The years since first CCH diagnosis will be calculated as (date of informed consent - first date of 
CCH diagnosis + 1)/365.25. Rules for handling partial CCH diagnosis date are in Section 4.4. 
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 in by-visit or 
by-analysis-window summaries. 
6.1.1. 
Cluster Headache Attacks Data from E-diary 
CH attacks will be recorded in the e-diary daily. Corresponding CH attack questions are in 
Appendix A (questions A1, A2, and B1 through B15). Patients will record headache(s) occurred 
during last 48 hours. The recording window on e-diary device is “Yesterday morning 6:00 am to 
today at 5:59 am” or “The day before yesterday morning 6:00 am to yesterday at 5:59 am”; a 
maximum of 48 hours of recall time will be accepted to record CH attacks for the day before 
yesterday. 
The derivation logics for CH attacks are in Appendix B. A CH attack will be endorsed if required 
criteria in Appendix B are met.  
Baseline and postbaseline average number of CH attacks for a patient within an analysis window 
will be calculated based on data available and prorated to 28 days using formula [1A] as the 
monthly average for analyses based on monthly windows or prorated to 7 days using formula 
[1B] as the weekly average or weekly value for analyses based on weekly average or weekly 
windows. 
6.1.2. 
Data Derivation  
The monthly average of an efficacy variable will be calculated and prorated to 28 days as 
follows: 


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∑𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒 𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑡𝑡ℎ𝑒𝑒 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝  
𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁 𝑜𝑜𝑜𝑜 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝑤𝑤𝑤𝑤𝑤𝑤ℎ 𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎 𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟 𝑖𝑖𝑖𝑖 𝑡𝑡ℎ𝑒𝑒 𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑡𝑡ℎ𝑒𝑒 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 × 28   [1A] 
The weekly average or weekly value of an efficacy variable will be calculated and prorated to 7 
days as follows: 
∑𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒 𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑡𝑡ℎ𝑒𝑒 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝  
𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁 𝑜𝑜𝑜𝑜 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝑤𝑤𝑤𝑤𝑤𝑤ℎ 𝑎𝑎𝑎𝑎𝑎𝑎𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒 𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟 𝑖𝑖𝑖𝑖 𝑡𝑡ℎ𝑒𝑒 𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑡𝑡ℎ𝑒𝑒 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 × 7    [1B] 
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 
CCH”, or “days with use of any headache medication”, etc. 
The period will be the run-in period (including days from 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. 
The percentage of reduction from baseline in the monthly average number of CH attacks will be 
calculated as follows: 
𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏 𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣−𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣
𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏 𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣
× 100%   [2] 
where baseline value and postbaseline value are the monthly average calculated using [1A]. 
Note, the calculation of a proportion based on the weekly average or monthly average would 
yield the same results. Therefore to be consistent, all proportions will be calculated based on the 
monthly average number of CH attacks. 
6.1.3. 
Analysis Windows for E-diary Data 
Baseline window is the run-in period and includes days from the informed consent up to the day 
prior to the first dose of the IMP administration. The baseline average value for an efficacy 
variable will be calculated based on data recorded in the run-in period and prorated to 28 days 
using formula equation [1A] as the monthly average for analyses based on monthly windows or 
prorated to 7 days using formula [1B] as the weekly average or weekly value for analyses based 
on weekly average or weekly windows. 
Note, per eligibility checks at visit 2, patients with more than 28+3 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 31 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 28 days for the monthly average or 7 days for the 
weekly average. 
Postbaseline 4-week (monthly) analysis windows will be determined based on the actual 
dosing date as follows: 
• weeks 1 to 4: from the first dose of the IMP administration to the day before IMP 
administration at visit 3 (week 4); for endpoints based on week 0 to 4 data  
• weeks 5 to 8: from the IMP administration at visit 3 to the day before the IMP 
administration at visit 4 (week 8); for endpoints based on week 4 to 8 data 


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• weeks 9 to 12: from the IMP administration at visit 4 to the day before the EOT visit 
(visit 5/week 12); for endpoints based on week 8 to 12 data  
Notes:  
There will be no IMP administration at visit 5, and patients will return the e-diary at the 
visit; for patients who withdraw from the study early, the end day for the last window 
will be the day before EOT/early withdrawal visit; a 4-week analysis window may 
contain <28, 28, or >28 days. 
The monthly average of an efficacy variable for each analysis window will be calculated based 
on data recorded in the e-diary and prorated to 28 days using formula [1A]. Missing data 
handling methods are provided in Section 6.1.4. 
Postbaseline 1-week (weekly) analysis windows will be determined based on days in the 
4-week analysis windows (derived based on the actual dosing date as described above) as 
follows: 
• week 1 = day 1 to day 7 
• week 2 = day 8 to day 14 
• week 3 = day 15 to day 21 
• week 4 = day 22 to day 28*  
• week 5 = day 1 to day 7 
• week 6 = day 8 to day 14  
• week 7 = day 15 to day 21 
• week 8 = day 22 to day 28* 
• week 9 = day 1 to day 7  
• week 10 = day 8 to day 14  
• week 11 = day 15 to day 21 
• week 12 = day 22 to day 28* 
* This analysis window may contain <7, 7, or >7 days. 
For patients who withdraw from the study early, the last analysis window may be <7 days. 
The weekly value of an efficacy variable for each analysis window will be calculated based on 
data recorded in the e-diary and prorated to 7 days using formula [1B] if applicable. Missing data 
handling methods are provided in Section 6.1.4. 
6.1.4. 
Handling Missing E-diary Data 
This section includes missing data handling for e-diary data. For other type of data, the missing 
data handling methods are provided in the analysis section for the endpoint if applicable. 
of analysis window weeks 1 to 4 
(Month 1; Dose 1 to Dose 2) 
of analysis window weeks 5 to 8 
(Month 2; Dose 2 to Dose 3) 
of analysis window weeks 9 to 12 
(Month 3; Dose 3 to EOT) 


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6.1.4.1. 
Primary Efficacy Endpoint  
The monthly average number of CH attacks during 12-week period will be calculated based on 
data available and prorated to 28 days using formula [1A]. Note, patients who have < 10 days of 
e-diary data 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. 
6.1.4.2. 
Analyses Based on Monthly and 12-week Window 
In analyses using analysis of covariance (ANCOVA) based on 12-week window, the monthly 
average of an efficacy variable will be calculated based on data available and prorated to 28 days 
using formula [1A]; the weekly average of an efficacy variable will be calculated based on data 
available and prorated to 7 days using formula [1B]. 
Note, patients who have < 10 days of e-diary data will be excluded from the FAS and PP 
analysis set (Section 3). 
In analyses using MMRM based on monthly analysis windows  
• for patients who have ≥10 days of e-diary data in an analysis window, the monthly 
average number of CH attacks will be calculated based on data available in that 
analysis window and prorated to 28 days using formula [1A]; 
• for patients who have <10 days of e-diary data in an analysis window, the monthly 
average number of CH attacks for the analysis window will be considered as missing.  
In analyses based on proportion based on weeks 0 to 12, the average number of CH attacks 
will be calculated based on data available and prorated to 28 days using formula [1A] as the 
monthly average. Response status will be determined based on the prorated average using 
formula [2]. 
6.1.4.3. 
Analyses of Mean Change from Baseline Using MMRM Method Based on 
1-Week Window  
For analyses of mean change from baseline using an MMRM method based on 1-week analysis 
window, missing data will be handled as follows:  
• For patients who have ≥3 days of e-diary data in a week, the weekly value of an 
efficacy variable will be calculated based on data available and prorated to 7 days 
using formula [1B]. 
• Otherwise the weekly value of an efficacy variable will set to missing. 


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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 monthly average number of CH attacks during the 12-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 12-week 
period is the period from administration of the first dose of the IMP to the EOT/early withdrawal 
visit. 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 monthly average number 
of CH attacks for the fremanezumab treatment group and the placebo group, respectively. To 
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 loading dose 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 sets. 
Example SAS code for ANCOVA 
PROC MIXED DATA=<name>;  
     CLASS TRTP SEX REGION BPMU;  
     MODEL CHG= BASE BPMU SEX REGION TRTP /S ;  
     LSMEANS TRTP /DIFF=CONTROL(“Placebo”) CL ALPHA=0.05;  
     ODS OUTPUT LSMEANS= <name>  DIFFS= < name> ; 
RUN; 
Where TRTP denotes the planned treatment group; BPMU denotes the baseline preventive 
medication use (yes or no); CHG denotes the change from baseline; and BASE denotes the 
baseline number of CH attacks. In bold are the SAS key words. 
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. 
2
1
2
1
:
:
δ
δ
δ
δ
≠
=
a
o
H
vs
H
1δ
2
δ


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6.2.3.1. 
Analysis with Multiple Imputation Method  
An MI method will be utilized to impute the monthly missing data. Monthly analysis windows 
will be derived using the algorithm described in Section 6.1.3. The number of CH attacks within 
each monthly analysis window will be calculated and prorated to 28 days using formula [1A]. 
Data with the monthly average number of CH attacks will be processed using the following 
steps: 
• For patients with partial e-diary data (ie, have <10 days of data) in a monthly 
window, the number of CH attacks in that monthly window will be reset to missing 
before the MI procedure. 
• For patients in the active treatment groups who withdraw from the study early with 
reasons of adverse event or lack of efficacy, missing values will be imputed using 
data from the placebo-treated patients by assigning these patients to the placebo group 
for data imputation purpose. 
• Run SAS PROC MI procedure to create 10 sets of data.  
• Within each imputed data set, for patients with partial e-diary data in a monthly 
window (ie, <10 days of data), the number of CH attacks in the monthly window will 
be replaced by  
∑(observed 𝐶𝐶𝐶𝐶 𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑎𝑎 𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚ℎ𝑙𝑙𝑙𝑙 𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤 ) + (28 −𝑋𝑋) ∗𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖 𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣
28
 
Where X denotes the number of days with e-diary within a monthly window. 
• The monthly average number of CH attacks during the 12-week period after the first 
dose of the IMP will be the average of the values from 3 monthly analysis windows.  
Each set of imputed data will be analyzed using an ANCOVA method in a manner analogous to 
the primary endpoint as described in Section 6.2.2. The LS means and SEs from each analysis 
will be output to a SAS data set. 
The SAS MIANALYZE procedure will be used to generate the final LS means and SE for the 
treatment groups and the treatment differences (fremanezumab - placebo) as well as p-values 
associated with treatment differences. The 95% confidence intervals for the treatment differences 
will also be constructed. 
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 monthly 
average number of CH attacks during the 12-week period after administration of the first dose of 
the IMP.  
Postbaseline data will include data from three monthly analysis windows derived using the 
algorithm described in Section 6.1.3. Missing data will be handled as described in 
Section 6.1.4.2.  
The MMRM will include baseline preventive medication use (yes or no), gender, region 
(US/Canada or other), treatment, month (months 1 to 3), and month-by-treatment interaction as 


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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 months 1 to 3 will be presented to support the primary 
analysis. 
Example SAS codes for MMRM analysis: 
PROC MIXED DATA=<name> METHOD=REML; 
      CLASS USUBJID SEX BPMU REGION ATPTN TRTP;  
      MODEL CHG=BASE BPMU SEX REGION TRTP ATPTN TRTP*ATPTN/S; 
      REPEATED ATPTN/ SUB=USUBJID TYPE=UN; 
      LSMEANS TRTP TRTP*ATPTN/ DIFF CL ALPHA=0.05; 
      ODS OUTPUT LSMEANS= <name> DIFFS= < name>; 
RUN; 
Where TRTP denotes the planned treatment group; BPMU denotes the baseline preventive 
medication use (yes or no); CHG denotes the change from baseline; BASE denotes the baseline 
number of CH attacks; and ATPTN denotes the month or the analysis window. 
The analysis will be performed on the FAS. 
6.2.4. 
Subgroup Analyses 
The following subgroup analyses will be performed for primary endpoint and selected secondary 
endpoints (mean change from baseline in the number of CH attacks [the 2nd and 3rd secondary 
endpoints]; mean change from baseline in the number of days with use of cluster-specific acute 
headache medication [the 4th secondary endpoint]; mean change from baseline in the number of 
days oxygen is used [the 5th secondary endpoint]): 
• Age group (< 40 and ≥40 years old) 
• Race group (white and other) 
• Sex (male and female) 
• Baseline preventive medication use (yes and no) 
• Region (US/Canada and other) 
Data will be analyzed in a manner analogous to the method described in the section for each of 
these endpoints. 
Modification to SAS codes: adding a ‘by’ statement for the subgroup variable; If the subgroup 
variable is in MODEL statement, remove the subgroup variable from MODEL statement 
accordingly. 
The subgroup analyses will be performed on the FAS. 


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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 set. 
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. 
6.3.1. 
Proportion of Patients with a ≥50% Reduction from Baseline in the Monthly 
Average Number of CH Attacks During the 12-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. 
The 12-week period is the period from administration of the first dose of the IMP to the 
EOT/early withdrawal visit. CH attacks within the 12-week period will be derived from the 
e-diary data as described in Section 6.1.1 and prorated to 28. 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.  
Example SAS code for CMH: 
PROC FREQ DATA=<name>; 
     TABLES BPMU*TRTP*AVALC / CMH;  
     OUTPUT OUT=<name> CMH; 
RUN; 
Where TRTP denotes the planned treatment group; BPMU denotes the baseline preventive 
medication use (yes or no); and AVALC denotes the responses with yes for responders (with 
≥50% CH attacks reduction) and no for non-responders (with <50% CH attacks 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 based on the monthly 
average number of CH attacks using an MMRM method in a manner analogous to the analysis as 
described in Section 6.2.3.2. 
• the 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 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. Data will be 


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prorated to 28 days as the monthly average. CH attacks within each analysis window will be 
derived from the e-diary data as described in Section 6.1.1. Missing data handling methods are 
provided in Section 6.1.4.2 
The analysis will be based on data from all three 4-week (monthly) analysis windows. Results 
for each endpoint will be subsetted from PROC MIXED outputs. For the 2nd secondary endpoint, 
the results from the first analysis window (weeks 1 to 4) will be presented; for the 3rd secondary 
endpoint, the results from the last analysis window (weeks 9 to 12) 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 [1B]. 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. 
6.3.4. 
Mean Change from Baseline in the Weekly Average Number of Days Oxygen is 
Used to Treat Chronic 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 [1B]. 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. 
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 


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• 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. 
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. Analyses will be based on the FAS. 
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. 
6.4.1. 
Proportion of Patients with ≥50%, 75%, or 100% Reduction from Baseline in 
Number of CH Attacks During the 12-Week Period (First 3 Exploratory 
Efficacy Endpoints)  
The following exploratory efficacy endpoint will not be analyzed since the result would be the 
same as these from the first secondary endpoint (≥50 reduction in monthly average). Note, the 
calculation of a proportion based on the weekly average or monthly average would yield the 
same result.  
• proportion of patients with ≥50% reduction from baseline (run-in period) in the 
weekly average 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 following exploratory efficacy endpoints will be analyzed using a CMH method in a manner 
analogous to the first secondary endpoint as described in Section 6.3.1. The proportion of 
reductions will be calculated based on monthly average number of CH attacks to be consistent 
with the calculation of the first secondary endpoint. 
• proportion of patients with ≥75% reduction from baseline (run-in period) in the 
weekly average 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  
• proportion of patients reaching 100% reduction 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 12-week period is the period from administration of the first dose of the IMP to the 
EOT/early withdrawal visit. CH attacks within the 12-week period will be derived from the 
e-diary data as described in Section 6.1.1 and prorated to 28 days using formula [1A]. Missing 
data handling methods are provided in Section 6.1.4.2. 


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The proportion of reduction for a patient will be calculated using formula [2]. Responders will be 
those with ≥75% or 100% reduction, respectively. 
The monthly analyses will be presented. 
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 
This exploratory efficacy endpoint will be analyzed using an MMRM in a manner analogous to 
the analysis as described in Section 6.2.3.2.  
Postbaseline data will include data from twelve 1-week analysis windows derived using the 
algorithm described in Section 6.1.3. Missing data handling methods are provided in 
Section 6.1.4.3. If days with e-diary data in a 1-week analysis window are more than 7, CH 
attacks for the analysis window will be prorated to 7 days using formula [1B]. 
Analyses will be based on data from all 12 analysis windows. Results for weeks 1, 2, 3, 4, 8, or 
12 will be subsetted from PROC MIXED outputs afterwards. 
LSMEANS statement in PROC MIXED will be changed to: 
      LSMEANS TRTP*ATPTN/ DIFF CL ALPHA=0.05; 
6.4.3. 
Mean Change from Baseline in the Number of CH Attacks During the 8-Week 
Period (Weeks 0 to 8) After Administration of the First Dose of the IMP 
This exploratory efficacy endpoint will be analyzed using an MMRM in a manner analogous to 
the analysis as described in Section 6.2.3.2. 
Postbaseline data will include data from analysis windows of weeks 1 to 4 and weeks 5 to 8 
derived using the algorithm described in Section 6.1.3. Missing data handling methods are 
provided in Section 6.1.4.2. The overall results from PROC MIXED will be presented. 
LSMEANS statement in PROC MIXED will be changed to: 
      LSMEANS TRTP / DIFF CL ALPHA=0.05; 
6.4.4. 
Mean Change from Baseline in the Number of CH Attacks During the 4-Week 
Period (Weeks 4 to 8) After Administration of the Second Dose of the IMP 
The exploratory efficacy endpoints will be analyzed based on the monthly average number of 
CH attacks using an MMRM method in a manner analogous to the analysis as described in 
Section 6.3.2. 
The analysis will be done in the same PROC MIXED procedure as described in Section 6.3.2. 
The results from the second analysis window (weeks 5 to 8) will be subsetted from the output of 
the PROC MIXED and will be presented. 
6.4.5. 
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  
Pain severity for each CH attack will be recorded in the e-diary as follows:  


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1 = Mild  
2 = Moderate  
3 = Severe  
4 = Very Severe  
The analysis will be based on daily average derived from the numerical rating (1, 2, 3, or 4). If 
there is more than 1 CH attack for a day, the worst severity of CH attacks for that day will be 
used for the analysis. For patients who do not have CH attacks in a day, the severity rating for 
that day will be set to 0. 
The weekly average severity of CH attacks will be calculated as follows: 
∑𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝐶𝐶𝐶𝐶 𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎 𝑝𝑝𝑝𝑝𝑝𝑝 𝑑𝑑𝑑𝑑𝑦𝑦 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑎𝑎 𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤   
𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁 𝑜𝑜𝑜𝑜 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑤𝑤𝑤𝑤𝑤𝑤ℎ 𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎 𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟 𝑖𝑖𝑖𝑖 𝑡𝑡ℎ𝑒𝑒 𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑎𝑎 𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤   
Change from baseline in the severity of CH attacks will be analyzed based on the calculated 
weekly average severity rating using an MMRM in a manner analogous to the analysis as 
described in Section 6.2.3.2. Postbaseline data will include data from all twelve 1-week analysis 
windows. 
Analyses will be based on data from all 12 weekly analysis windows. Results for weeks 1, 2, 3, 
4, 8, or 12 will be subsetted from PROC MIXED outputs afterwards. 
LSMEANS statement in PROC MIXED will be changed to: 
      LSMEANS TRTP*ATPTN/ DIFF CL ALPHA=0.05; 
6.4.6. 
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  
Use of any acute headache medication 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 any acute headache medication (triptan, ergot, 
opioids, or butalbital) for CH within the 12-week period for a patient will be calculated and 
prorated to 7 days using formula [1B]. The missing data handling method for analysis of mean 
change from baseline 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. 
6.4.7. 
Cumulative Proportion of Responders Analysis 
• total cumulative distribution of percent reduction (≥0%, ≥10%, ≥20%, ≥30%, ≥40%, 
≥50%, ≥60%, ≥70%, or ≥80%) from baseline (run-in period) in the monthly average 
number of CH attacks during the 12-week period after the first dose of the IMP, 
ie, based on week 0 to 12 data 


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• cumulative distribution function plot of percent reduction (≥0%, ≥10%, ≥20%, ≥30%, 
≥40%, ≥50%, ≥60%, ≥70%, or ≥80%) from baseline (run-in period) in the monthly 
average number of CH attacks during the 12-week period after the first dose of the 
IMP, ie, based on week 0 to 12 data 
The 12-week period is the period from administration of the first dose of the IMP to the 
EOT/early withdrawal visit. CH attacks within the 12-week period will be derived from the 
e-diary data as described in Section 6.1.1 and prorated to 28. Missing data handling methods are 
provided in Section 6.1.4.2. The percentage of reduction from baseline will be calculated using 
formula [2]. 
A cumulative proportion of responder’s analysis (CPRA) will be provided for the percent 
reduction from baseline in the monthly average number of CH attacks during the 12-week 
period. This technique is a special case of the empirical cumulative distribution function, which 
requires that the data be specified as the cumulative proportion of patients who have values 
above all specified cut-off values of interest (0%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 
80%). 
Let Yki denote the percent reduction from baseline in the monthly average number of CH attacks 
during the 12-week period for patient i in treatment group k, where k = 1,2,3 and i = 1, …, nk, nk 
is the total number of patients in treatment group k. 
Let Cj denote the jth cut-off value of interest, where j = 1, …, J. For the cut-off value ranges from 
0% to 80% by 10, C1 = 0, C2 =10,…, C9 = 80. 
The cumulative proportion of responders will be calculated as follows: 
 
 
 
 
 
 
 
Summary statistics for total cumulative reduction at ≥ 0%, ≥10%, ≥20%, ≥30%, ≥40%, ≥50%, 
≥60%, ≥70%, or ≥80% will be presented. 
The CPRA graph will place responder levels of interest (0%, 10%, 20%, 30%, 40%, 50%, 60%, 
70%, or 80%) on the x-axis and graph the associated proportion of patients calculated for that 
response level on the y-axis for each treatment group. A 2-dimensional graph will display data 
by plotting Pkj (y-axis) verse Cj (x-axis), with k overlaid curves representing k treatment groups. 
I (Yki ≥ Cj), 
nk 
Pkj   = 
∑ 
i=1 
nk 
    I (Yki > Cj) = 
 1 
1, if Yki ≥ Cj 
0, if Yki < Cj or if Yki  is missing 
where   


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6.4.8. 
Mean Change from Baseline in the Monthly Average Number of CH Attacks of 
at Least Severe Severity During the 12-Week Period After Administration of the 
First Dose of the IMP 
The mean change from baseline in the monthly average number of CH attacks of at least severity 
will be analyzed using an ANCOVA in a manner analogous to the endpoints in Section 6.2.2.  
The derivation of input data for this analysis is the same as the primary analysis except only 
counting CH attacks with severity of severe or very severe. 
6.4.9. 
Changes from Baseline in Responses to Questionnaires That Measure Quality of 
Life, Satisfaction with Treatment, and Health Status  
These will include analyses based on the quality of life, satisfaction with treatment, and health 
status measured by the EQ-5D questionnaire, HADS, SF-12, Impact on Partner and Family 
questionnaire, WPAI questionnaire, and PGIC scale. 
6.4.9.1. 
Change from Baseline in EuroQol-5 Dimension Questionnaire  
The 5-level EQ-5D questionnaire (Appendix C) is a standardized questionnaire that assesses 
overall state of health. The EQ-5D questionnaire consists of 2 parts. In part 1, patients will rate 
their health in 5 domains: mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression using a scale of 1 to 5 as follows: 
1=no problems 
2=slight problems 
3=moderate problems 
4=severe problems 
5= extreme or unable to 
In part 2, patients will rate their health state on a 0 to 100 mm visual analog scale; a rating of 0 means 
the worst imaginable health state, and a rating of 100 means the best imaginable health state. Data will 
be collected in the investigational site tablet at visit 2, 3, and 5. 
Part 1 data will be summarized using descriptive statistics by domain and visit. A missing 
category will be presented if applicable.  
For part 2 data, change from baseline at visit 3 and 5 in the health status (visual analog scale) 
will be analyzed using an MMRM in a manner analogous to the analysis as described in 
Section 6.2.3.2. Postbaseline data will include data from visits 3 and 5. Results from overall and 
each visit will be presented. 
6.4.9.2. 
Hospital Anxiety and Depression Scale 
The HADS is a 14-item scale developed to measure anxiety (7 items) and depression (7 items). 
Each item is scored on a 4-point scale from 0 to 3. Total scores for depression and anxiety range 
from 0 to 21; a total score of 0 to 7 is normal, 8 to 10 is borderline abnormal, and 11 to 21 is 
abnormal. Scoring details are provided in Appendix D. 


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Patients will complete the HADS in the investigational site tablet at visits 2, 3, and 5. Total score 
for each sub-scale (depression or anxiety) will be calculated by summation of raw scores from 
the 7 items for each sub-scale. Categorical score level (normal, borderline abnormal, and 
abnormal) will be derived accordingly based on the total scores for each sub-scale. 
For total score calculations of each sub-scale, missing score(s) will be handled as follows: 
• If having scores for at least 4 items, the missing score will be inferred using the mean 
score of the remaining items for the patient. The total score for the sub-scale will be 
calculated as follows: 
∑ 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓 𝑁𝑁 𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖    
𝑁𝑁
×  7   
Where N (≤7 and ≥4) is the number of non-missing items for a sub-scale. 
• If missing score for more than 4 items, the total score for that sub-scale will be 
invalid (missing). 
Change from baseline at visits 3 and 5 in total score for each sub-scale (depression and anxiety) 
will be analyzed using an MMRM in a manner analogous to the analysis as described in 
Section 6.2.3.2. Postbaseline data will include data from visits 3 and 5. Results from overall and 
each visit will be presented. 
Raw data and total scores for each sub-scale (depression and anxiety; numerical and categorical 
level) will also be summarized using descriptive statistics by visit. A missing category will be 
presented if applicable. 
For summaries with the total scores, a footnote will be added indicating 0-7 = Normal; 8-10 = 
Borderline abnormal; 11-21 = Abnormal. 
6.4.9.3. 
12-Item Short-Form Health Survey  
The 12-Item Short-Form Health Survey version 2 (SF-12v2) is a generic health survey 
containing 12 items (questions) to measure functional health and well-being rated in 8 health 
domains:  
• general health (1 item) 
• physical functioning (2 items) 
• role functioning - physical (2 items) 
• role functioning - emotional (2 items) 
• bodily pain (1 item) 
• mental health (2 items) 
• vitality (1 item) 
• social functioning (1 item) 
Detail descriptions of each item are provided in Appendix E. Patients will complete the SF-12 in 
the investigational site tablet at visits 2, 3 and 5. 


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Physical Composite Scores (PCS-12) and Mental Health Composite Scores (MCS-12) will be 
computed using scoring software (Scoring Software v5.0).  
Change from baseline at visits 3 and 5 in PCS-12 and MCS-12 will be analyzed using an 
MMRM in a manner analogous to the analysis as described in Section 6.2.3.2. Postbaseline data 
will include data from visits 3 and 5. Results from overall and each visit will be presented. 
Raw data will be summarized using descriptive statistics by visit. 
6.4.9.4. 
Impact on Partner and Family Questionnaire 
The patients and partners/family members of patients participating in the study, if applicable, 
will complete an Impact on Partner and Family questionnaire at visits 2, 3, and 5. Responses will 
be recorded in the investigational site tablet. The questionnaire for patients is provided in 
Appendix F; for partners in Appendix G. 
Patients and partners/family members of patients will respond the questions based on impact of 
CH “during the last 12 weeks” at baseline visit and impact of CH “since last assessment” at 
postbaseline visits. 
Raw data will be summarized using descriptive statistics. 
6.4.9.5. 
Work Productivity and Activity Impairment Questionnaire: General Health 
V2.0  
The generic version of the Work Productivity and Activity Impairment: General Health 
(WPAI: GH; Appendix H) 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. Patients will complete the WPAI questionnaire in the investigational site tablet at 
visits 2, 3, and 5. 
The scores for the following 4 domains will be derived based on the WPAI: GH questionnaire. 
Derived scores will be multiplied by 100 to express in percentages. Higher percentages indicate 
greater impairment. 
1. Percent work item missed due to health: 
𝑄𝑄2
𝑄𝑄2+𝑄𝑄4 
2. Percent impairment while working due to health:  
𝑄𝑄5
10 
3. Percent overall work impairment due to health: 
𝑄𝑄2
𝑄𝑄2+𝑄𝑄4 + ቂቀ1 −
𝑄𝑄2
𝑄𝑄2+𝑄𝑄4ቁ×
𝑄𝑄5
10ቃ 
4. Percent activity impairment due to health: 
𝑄𝑄6
10 
Change from baseline at visits 3 and 5 in above calculated domain scores will be analyzed using 
an MMRM in a manner analogous to the analysis as described in Section 6.2.3.2. Postbaseline 
data will include data from visits 3 and 5. The results for overall and visits 3 and 5 will be 
presented. 
Raw data will be summarized using descriptive statistics by visit. 


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6.4.9.6. 
Patient Global Impression of Change Scale 
The PGIC is a validated generic tool for the assessment of overall change in the severity of 
illness following treatment. Patients will be asked to rate the change in their overall health and 
well-being since the study start (the time after patient received the first IMP dose) on a 7-point 
scale as the follows: 
• 1 = Much worse 
• 2 = Moderately worse 
• 3 = Slightly worse 
• 4 = Stayed the same 
• 5 = A little better 
• 6 = Moderately better 
• 7 = Much better 
Patients will record responses to the PGIC scale in the electronic diary device at home at week 1 (day 7) 
and in the investigational site tablet at visits 3, 4, and 5. 
For analysis purpose, a dichotomous scale of Yes or No will be derived. A favorable change is 
score of 5-7, which means there is improvement (Yes) with the treatment. If the response is 1-4, 
it is considered no improvement (No). 
The percentage of patients’ dichotomous scale of Yes or No rated by PGIC assessments at each 
visit will be analyzed using a CMH method in a manner analogous to the first secondary 
endpoint as described in Section 6.3.1. 
Raw data will be summarized using descriptive statistics for each visit. Missing category will be 
presented if applicable. 


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7. 
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 loading dose 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: 
1. 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. 
2. If the resulting 2-sided p-value from 1 of comparisons is >0.05 (fail to reject the null 
hypothesis) and other resulting 2-sided p-value is ≤0.025 (
𝛼𝛼
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 further comparisons will be interpreted inferentially. 
3. If the resulting 2-sided p-value from both comparisons are >0.05 (fail to reject both null 
hypotheses), then no statistical significant 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 1.2. The same 
testing rules as described above will be 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 >0.05, the testing process stops. No further comparisons will be interpreted 
inferentially. 
For the last secondary endpoint (PPSI assessments), only the assessment at week 12 will be 
included in the multiple comparisons. 


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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) for a patient is defined as the number of days a patient is 
in the double-blind treatment period and calculated as date of EOT visit - first date of the IMP 
+ 1. For patients who are lost to follow-up, the date of EOT visit is defined as the date of last 
IMP administration + 27. Duration of iv infusion (minutes) will be calculated for the infusion as 
stop date/time of infusion - start date/time of infusion. Dosing visit interval (days) is defined as 
the number of days between dosing visit (dose 1 and dose 2; dose 2 and dose 3) and calculated as 
date of next dosing - date of current dosing. 
Duration of the 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. 
Summaries for injection site and infusion-related adverse events and protocol-defined adverse 
events of special interest will be presented (overall and by severity). 


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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 µmol/L 
Bilirubin (total) 
≥34.2 µmol/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 


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Height will be measured at screening visit, and data will be listed in the vital sign listing. 
8.11. 
Electrocardiography 
Triplicate 12-lead ECGs will be collected at 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 
multimodal the algorithms to monitor physiological activity, sleep/wake activity, and treatment 
responses. Results will be reported separately. 
These analyses will include data from both pivotal studies and the long-term safety study and are 
not included in this SAP. A separate analysis plan will be provided. 


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15. 
PLANNED INTERIM ANALYSIS 
An interim analysis for futility will be performed once 50% of patients (the first 150 patients) 
have completed 12-week assessments during the double-blind study period or have withdrawn 
from the study early. The futility will be assessed using conditional power (CP). The study may 
be terminated if the CP is less than 25%. An independent statistician from a third party will 
perform the analysis. 
15.1. 
Statistical Methods 
The independent statistician may consider using the normal distribution based z-test as an 
approximation to calculate the CP for the interim analysis. Using the z-test approximation, the 
CP calculation can be simplified as: 








−
+
∆
−
+
∆
−
Φ
−
=
−
)
)
(
2
2
)
(
1
(
1
α)
 
N,
 
CP(n,
2
2
1
2
/
1
σ
σ
α
n
N
n
n
N
n
z
c
 
 
Where 
2
2
2
1
)
(
*
)
(
*
σ
σ
σ
n
N
n
N
n
c
−
−
+
=
 
Z1-α/2 is the critical value from the standard normal distribution; N is the total number of patients 
planned for each treatment group and n is the number of patients in each treatment group at 
interim analysis. Δ1 and σ1 are the observed treatment difference and common SD in the interim 
analysis, respectively. Δ and σ are the unknown treatment difference and common SD of the 
future data, respectively. 
Under the condition of n=N-n, Δ=Δ1 and σ=σ1 the CP can be determined by the effect size Δ/σ as 








−
+
∆
−
+
∆
−
Φ
−
=
−
)
)
(
2
2
)
(
1
(
2
1
α)
 
N,
 
CP(n,
2
2
1
2
/
1
σ
σ
α
n
N
n
n
N
n
z
 






∆
−
Φ
−
=
−
)
1
1
(
2
1
α)
 
N,
 
CP(n,
2
/
1
σ
α
n
z
 
The critical variable for the interim analysis is the primary efficacy variable in this study: mean 
change from baseline in the monthly average number of CH attacks during the 12-week period 
after administration of the IMP. Observed treatment difference and SD and will be calculated 
using ANOVA. 
15.2. 
Timing and Data 
The interim analysis will be performed once 50% of patients (the first 150 patients, 50 patients 
per treatment group) have completed 12-week assessments or withdrawn from study early. 
Data for the interim analysis futility will be 100% clean. Analysis dataset(s) for CH attacks will 
be provided to the independent statistician. 


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The Teva statistician will request to have a copy of the randomization code sent to the 
independent statistician prior to the interim analysis while all persons who are involved in the 
study will remain blinded. The production and execution of the analysis and the randomization 
code will be conducted and kept in a secure location by the independent statistician. 
15.3. 
Result Dissemination  
The report of the interim analysis will only include binary results (yes or no) to indicate whether 
or not the CP for an active treatment group is less than 25%. 
15.4. 
Decision Rules 
Decision of whether or not to continue the study will be based on CPs from the 2 comparisons 
(fremanezumab 900-mg iv loading dose group versus placebo or fremanezumab 675-mg sc 
loading dose group versus placebo). 
If both comparisons satisfy the stopping criterion (CP <25%), this study may be considered to be 
terminated. 
If the CP for 1 of the 2 comparisons is ≥25%, the study will continue without changes. 


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


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


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18. 
REFERENCES 
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. E-DIARY QUESTIONNAIRE 
The recording window on e-diary device is “Yesterday morning 6:00 AM to today at 5:59 AM” or “The 
day before yesterday morning 6:00 AM to yesterday at 5:59 AM”. A maximum of 48 hours of recall 
time will be accepted. 
A1 
Did you have any Headache? 
  
A2 
How many episodes of headache did you have?  
NUMBER 
Questions to be asked for each attack 
B1 
At what approximate time did the attack begin? 
TIME 
B2 
At what approximate time did the attack end? 
TIME 
B3 
 
How bad was your headache (head pain) when it was 
at its worst 
 
MILD 
MODERATE 
SEVERE 
VERY SEVERE 
B4 
 
  
Was the headache restricted to one side of your head? 
Yes, my headache was restricted to the left 
side of my head 
Yes, my headache was restricted to the right 
side of my head 
No, my headache happened in both sides 
During any time of your headache, did you experience the following in the same side of you headache?  
B5 
Red eye and/or tearing (lacrimation)? 
  
B6 
Stuffy nose (nasal congestion) and/or runny nose? 
  
B7 
Swelling around your eyes (eyelid or palpabrea 
edema)? 
  
B8 
Sweating on your forehead or face? 
  
B9 
Did your forehead or face become red (flushing)? 
  
B10 
Sensation of full ear (fullness of your ear)? 
  
B11 
Dropping of the upper eyelid (ptosis) 
  
B12 
On the side of pain, your pupil became smaller than 
on the other side (miosis)? 
  
B13 
Did you become agitated or restless (walking around 
the room, bending your head, etc.)? 
  
B14 
Did you use oxygen at any time during the attack? 
  
B15 
Did you take any medications during the attack? 
GO MED CHEST 
Comparing this attack with typical attacks that you experienced BEFORE THIS STUDY, would you say 
that: 


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C1 
The severity of this attack was  
SAME as before study 
MORE SEVERE than before study 
LESS SEVERE than before study 
C2 
The duration of this attack was 
SAME as before study 
LONGER than before study 
SHORTER than before study 
D1 
How many hours did you sleep? 
NUMBER 
D2 
How rested/recovered did you feel when you wake 
up? 
Totally rested 
Somewhat rested;  
not rested at all 
D3 
How much time did you have trouble concentrating on 
activities that you needed to do? 
NONE OF THE TIME 
SOME OF THE TIME 
MOST OF THE TIME 
ALL TIME 
D4 
How interested (motivated, energized) were you in 
doing daily activities? 
VERY INTERESTED 
SOMEWHAT INTERESTED 
NOT INTERESTED 
In general how was your day? 
It was a good day 
Neutral (not good or bad) 
It was a bad day 
D5 
Which of the following situations best describe your 
work/school performance, when you did not have a 
headache? (select only one) 
I worked/studied normally 
My working/studying ability 
was impaired by less than 50% 
My work/studying ability was 
impaired by 50% or more 
I missed work/school 
D6 
During your work or school day, approximately how 
much of the time did you feel that you were working 
more slowly or taking longer to complete tasks than 
usual or expected? (select only one) 
None of the time 
Some of the time 
About half of the time or more 
D7 
On average, how much of the time were you very 
tired, asleep, or feeling drained? (select only one) 
None of the time 
Some of the time 
Most of the time 
All of the time 


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D8 
Which of the following situations best describe your 
ability to perform household chores, when you did not 
have a headache? (select only one) 
I performed household 
activities normally 
My ability to perform 
household chores was 
impaired by less than 50% 
My ability to perform 
household chores was 
impaired by 50% or more 
I could not perform household 
chores 
Not applicable 
D9 
How engaged were you with your partner's or 
children's activities, when you didn't have a headache? 
(select only one) 
Very engaged 
Somewhat engaged 
Not engaged 
Not applicable 


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APPENDIX B. LOGICS FOR CLUSTER HEADACHE DERIVATION 
 
CLUSTER HEADACHE ATTACK 
  
OPTION 1  
A1 
YES 
B3  
SEVERE, VERY SEVERE 
B4 
RESTRICTED TO LEFT OR RIGHT  
AND 
  
B5-B12 
YES TO AT LEAST ONE 
OR 
  
B13 
YES 
OPTION 2 
A1 
YES 
B3  
MILD, MODERATE, SEVERE, VERY SEVERE 
B4 
RESTRICTED TO LEFT OR RIGHT  
AND 
  
B14 
YES 
OR 
  
B15 
YES TO USE OF ACUTE MEDICATION (TRIPTAN OR ERGOT 
OR OPIOIDS OR BUTALBITAL) 
AND 
  
B5-B12 
YES TO AT LEAST ONE 
OR 
  
B13 
YES 
 


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APPENDIX C. EUROQOL-5 DIMENSION QUESTIONNAIRE (EQ-5D) 


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APPENDIX D. HOSPITAL ANXIETY AND DEPRESSION SCALE 
(HADS) 


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APPENDIX E. 12-ITEM SHORT-FORM HEALTH SURVEY (SF-12) 


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APPENDIX F. IMPACT ON PARTNER AND FAMILY 
QUESTIONNAIRE - PATIENTS 


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APPENDIX G. IMPACT ON PARTNER AND FAMILY 
QUESTIONNAIRE - PARTNERS 


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


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