Clinical trial NCT02629861
Conditions: Migraine
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc.
Start date: 2016-03-23; Completion date: 2017-04-10
Enrollment: 875 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study is being conducted to evaluate two doses of TEV-48125 in adult patients with episodic migraine

Detailed description:

Arms: arm 1: Matching Placebo arm 2: Participants randomized to receive fremanezumab 675 mg/placebo/placebo received 675 mg of fremanezumab as 3 injections (225 mg/1.5 mL) on Day 0, and placebo as a single 1.5-mL injection on Days 28 and 56. arm 3: Participants randomized to receive fremanezumab 225/225/225 mg received 1 active injection (225 mg/1.5 mL) on Days 0, 28 and 56.
Interventions: intervention 1: Fremanezumab intervention 2: Placebo
Intervention descriptions: intervention 1: Fremanezumab was provided as a sterile, unpreserved, aqueous solution for injection, 225 mg/1.5 mL pre-filled syringe for single-use administration.

The 675 mg dose was given as 3 injections; doses of 225 mg were given as a single injection. Study drug was administered at the clinical site. intervention 2: Placebo 1.5 mL pre-filled syringes identical in appearance to active intervention. Study drug was administered at the clinical site.

Protocol documents:
Prot_000.pdf: 
Clinical Study Protocol with Amendment 01
A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study
Comparing the Efficacy and Safety of 2 Dose Regimens of Subcutaneous 
Administration of TEV-48125 Versus Placebo
for the Preventive Treatment of Episodic Migraine
Study Number TV48125-CNS-30050
NCT02629861
Protocol with Amendment 01 Approval Date: 30 March 2016


Placebo-Controlled Study–Episodic Migraine
Clinical Study Protocol with Amendment 01
Study TV48125-CNS-30050
1
 
Clinical Study Protocol with Amendment 01
Study Number TV48125-CNS-30050
A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study 
Comparing the Efficacy and Safety of 2 Dose Regimens of Subcutaneous Administration of 
TEV-48125 Versus Placebo for the Preventive Treatment of Episodic Migraine
Phase 3
IND number: 106,533
EudraCT number: 2015-004598-34
Protocol Approval Date: 30 March 2016
Sponsor
Monitors
Teva Branded Pharmaceutical 
Products R&D, Inc.
41 Moores Road
Frazer, Pennsylvania 19355
United States
NCGS, Inc.
288 Meeting Street
Suite 400
Charleston, South Carolina 29401
United States
PRA
4130 Parklake Avenue
Suite 400
Raleigh, NC 27612
Authorized Representative
Teva Branded Pharmaceutical Products R&D, Inc.
Sponsor’s Medical Expert
Sponsor’s Safety Representative
Teva Pharmaceuticals
ratiopharm GmbH
Confidentiality Statement
This clinical study will be conducted in accordance with current Good Clinical Practice (GCP), as directed by the 
provisions of the International Conference on Harmonisation (ICH); United States (US) Code of Federal 
Regulations (CFR) and European Union (EU) Directives (as applicable in the region of the study); local country 
regulations; 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.
© 2016 Teva Branded Pharmaceutical Products R&D, Inc. All rights reserved.


Placebo-Controlled Study–Episodic Migraine
Clinical Study Protocol with Amendment 01
Study TV48125-CNS-30050
2
AMENDMENT HISTORY
The protocol for Study TV48125-CNS-30050 (dated 21 October 2015) has been amended and 
reissued as follows:
Amendment 01
30 March 2016
3 patients enrolled to date
Administrative Letter 02:
Suspected Anaphylaxis
01 March 2016
0 patients enrolled to date
Administrative Letter 01:
Drug Administration, Patient-
Reported Outcome Measures, 
and Laboratory Tests 
22 January 2016
0 patients enrolled to date
Details about the changes and reason/justification for each change are provided in Section 17.


Placebo-Controlled Study–Episodic Migraine
Clinical Study Protocol with Amendment 01
Study TV48125-CNS-30050
INVESTIGATOR AGREEMENT
Clinical Study Protocol with Amendment 01
Original Protocol Dated 21 October 2015
IND number: 106,533
EudraCT number: 2015-004598-34
A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study 
Comparing the Efficacy and Safety of 2 Dose Regimens of Subcutaneous Administration of 
TEV-48125 Versus Placebo for the Preventive Treatment of Episodic Migraine
Phase 3
Principal Investigator: __________________________________________
Title: _________________________________________________
Address of Investigational Center: __________________________________
__________________________________
__________________________________
Tel: ______________
I have read the protocol with Amendment 01 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 or local legal and regulatory requirements and applicable regulations and guidelines.
I will make available the protocol and all information on the drug that were furnished to me by 
the sponsor to all physicians and other study personnel responsible to me who participate in this 
study and will discuss this material with them to ensure that they are fully informed regarding the 
drug and the conduct of the study. I agree to keep records on all patient information, study drug 
shipment and return forms, and all other information collected during the study, in accordance 
with national and local Good Clinical Practice (GCP) regulations.
Principal Investigator
Signature
Date
SPONSOR PROTOCOL APPROVAL


Placebo-Controlled Study–Episodic Migraine
Clinical Study Protocol with Amendment 01
Study TV48125-CNS-30050
4
COORDINATING INVESTIGATOR AGREEMENT


Placebo-Controlled Study–Episodic Migraine
Clinical Study Protocol with Amendment 01
Study TV48125-CNS-30050
5
CLINICAL LABORATORY AND OTHER DEPARTMENTS AND 
INSTITUTIONS
Central Institutional Review Board
Central Clinical Laboratory
PPD Global Central Laboratories 
2 Tesseneer Drive
Highland Heights, KY 41076
Electronic Data Capture
Medidata Rave
Data Management
PRA
4130 Parklake Avenue
Suite 400
Raleigh, NC 27612
Electronic Clinical Outcome Assessment
eResearch Technology, Inc.
1818 Market Street
Philadelphia, PA 19103
Central Electrocardiogram Evaluation
eResearch Technology, Inc.
1818 Market Street
Philadelphia, PA 19103
Web and Phone Integrated Interactive Response Technology
Y-Prime


Placebo-Controlled Study–Episodic Migraine
Clinical Study Protocol with Amendment 01
Study TV48125-CNS-30050
6
Bioanalytical Pharmacokinetics Evaluation 
(bioanalytical analysis)
Teva Branded Pharmaceuticals R&D, Inc.
 (pharmacokinetics evaluation)
Teva Branded Pharmaceuticals R&D, Inc.
Bioanalytical Immunogenicity Evaluation 
Teva Branded Pharmaceuticals R&D, Inc.
Biomarker Evaluation
Teva Branded Pharmaceuticals R&D, Inc.
Pharmacogenomic and Biomarker Sample Storage
BioStorage Technologies, Inc. 
2910 Fortune Circle West, Suite E 
Indianapolis, IN 46241 USA
BioStorage Technologies, GmbH 
Im Leuschnerpark 1b 
64347 Griesheim Germany


Placebo-Controlled Study–Episodic Migraine
Clinical Study Protocol with Amendment 01
Study TV48125-CNS-30050
7
CLINICAL STUDY PERSONNEL CONTACT INFORMATION
For medical issues, contact the physician listed below: 
 Teva Branded Pharmaceuticals 
R&D, Inc.
Study Director
For operational issues, contact the operational leads listed below:
 Teva Branded Pharmaceuticals R&D, Inc.
For serious adverse events:
Send by e-mail to the local safety officer/contract research organization (LSO/CRO). The email 
address will be provided in the serious adverse event form. In the event of difficulty transmitting 
the form, contact the sponsor’s study personnel identified above for further instruction.


Placebo-Controlled Study–Episodic Migraine
Clinical Study Protocol with Amendment 01
Study TV48125-CNS-30050
8
CLINICAL STUDY PROTOCOL SYNOPSIS
Study TV48125-CNS-30050
Title of Study: A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study Comparing 
the Efficacy and Safety of 2 Dose Regimens of Subcutaneous Administration of TEV-48125 Versus Placebo for the 
Preventive Treatment of Episodic Migraine
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc.
IND Number: 106,533
EudraCT Number: 2015-004598-34
Name of Active Ingredient: Humanized anti-calcitonin gene-related peptide (CGRP) monoclonal antibody
Name of Investigational Product: TEV-48125
Phase of Clinical Development: 3
Number of Investigational Centers Planned: Approximately 140
Countries Planned: Approximately 15
Planned Study Period: 1Q/2016 (first patient in) to 3Q/2017 (last patient last visit)
Number of Patients Planned: A total of 768 patients (256 patients per treatment group) are planned to be enrolled
in this study to have 675 completers (225 completers per treatment group); a 12% drop-out rate is anticipated. 
Patients will be randomized 1:1:1 to the following treatment groups:

monthly subcutaneous (sc) administration of TEV-48125 at 225 mg

sc administration of TEV-48125 at 675 mg followed by monthly sc placebo

monthly sc administration of placebo
(Note: For this study, monthly dosing refers to dosing approximately every 4 weeks [28 days].)
Study Population: The study population will be composed of female and male patients, aged 18 to 70 years,
inclusive, with a history of migraine (as defined by International Classification of Headache Disorders, 3rd revision 
[ICHD-3] criteria [Classification Committee of the IHS, 2013]) for at least 12 months prior to screening and 
episodic migraine (EM) prospectively documented via a review of headache data recorded daily in an electronic 
daily headache diary device during a 28-day run-in period.
Because headache consortium guidelines recommend preventive therapies for patients with EM occurring on 4 or 
more days per month due to the frequency of headaches and high degree of disability, patients using no more than 
1 preventive medication at the time of study enrollment will be allowed to remain on the medication if the 
medication has at least moderate evidence of efficacy for migraine (Silberstein et al 2012). Patients on concomitant 
preventive medications must be on a stable dose for at least 2 months of consecutive use prior to study entry (ie, 
before the run-in period), without anticipated changes during the study. A list of preventive medications is presented 
in Appendix A. The total number of patients receiving concomitant preventive medication during the study will not 
exceed 30% of the total sample size of the study. This subset will be randomized independently.


Placebo-Controlled Study–Episodic Migraine
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Primary Objectives: The primary objectives of this study are as follows:

to demonstrate the efficacy 2 dose regimens of TEV-48125, as assessed by the decrease in the monthly 
average number of migraine days during 12-week period after the 1st dose of study drug relative to the 
baseline period

to evaluate the safety and tolerability of 2 dose regimens TEV-48125 in the preventive treatment of 
EM
Secondary Objectives: The secondary objectives of the study are as follows:

to evaluate the proportion of patients reaching at least 50% reduction in the monthly average number 
of migraine days with TEV-48125 during the 12-week period after the 1st dose of study drug relative to 
the baseline period

to demonstrate the efficacy of TEV-48125, as assessed by the reduction in the monthly average 
number of days of use of any acute headache medications during the 12-week period after the 1st dose 
of study drug relative to the baseline period

to demonstrate the efficacy of TEV-48125, as assessed by the reduction of the number of migraine 
days during the 4-week period after the 1st dose of study drug relative to the baseline period

to demonstrate the efficacy of TEV-48125, as assessed by the reduction in the monthly average 
number of migraine days during the 12-week period after the 1st dose of study drug relative to the 
baseline period in patients not receiving concomitant migraine preventive medications at baseline

to demonstrate the efficacy of TEV-48125, as assessed by the reduction of migraine-related disability 
as measured by the Migraine Disability Assessment (MIDAS) questionnaire, at 4 weeks after the last 
(3rd) dose of study drug relative to baseline

to evaluate the immunogenicity of TEV-48125 and the impact of antidrug antibodies (ADAs) on 
efficacy and safety during 12 weeks of treatment with TEV-48125
Exploratory Objectives: The exploratory objectives of the study are as follows:

to demonstrate the efficacy of TEV-48125, as assessed by the decrease in the monthly average number 
of headache days of at least moderate severity during the 12-week period after the 1st dose of study 
drug relative to the baseline period

to evaluate the proportion of patients reaching at least 75% reduction and total (100%) reduction in the 
monthly average number of migraine days during the 12-week period after the 1st dose of study drug

to evaluate the proportion of patients reaching at least 50% reduction and at least 75% reduction in the 
number of migraine days during the 4-week period after the 1st dose of study drug relative to the 
baseline period who sustain this level of response over the 12-week period after the 1st dose of study 
drug

to demonstrate the efficacy of TEV-48125 in patients who previously used topiramate for migraine, 
but discontinued, as assessed by the reduction of the monthly average number of migraine days during 
the 12-week period after the 1st dose of study drug relative to the baseline period

to demonstrate the efficacy of TEV-48125 in patients who previously used onabotulinumtoxinA for 
migraine, but discontinued, as assessed by the reduction of the monthly average number of migraine 
days during the 12-week period after the 1st dose of study drug relative to the baseline period


Placebo-Controlled Study–Episodic Migraine
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
to demonstrate the efficacy of TEV-48125, as assessed by the reduction of the number of migraine 
days during the 4-week period after the 2nd dose of study drug and the 4-week period after the last (3rd) 
dose of study drug relative to the baseline period

to demonstrate the efficacy of TEV-48125, as assessed by the reduction of the monthly average 
number of headache days of any severity during the 12-week period after the 1st dose of study drug 
relative to the baseline period

to demonstrate the efficacy of TEV-48125, as assessed by the reduction in the number of headache 
days of at least moderate severity during the 4-week period after each dose of study drug relative to the 
baseline period

to evaluate the proportion of patients reaching at least 50% reduction, at least 75% reduction, and total 
(100%) reduction in the monthly average number of headache days of at least moderate severity during 
the 12-week period after the 1st dose of study drug

to evaluate the proportion of patients reaching at least 50% reduction and at least 75% reduction in the 
number of headache days of at least moderate severity during the 4-week period after the 1st dose of 
study drug for whom this level of effect is sustained throughout the 12-week period after the 1st dose of 
study drug

to demonstrate the efficacy of TEV-48125, as assessed by the reduction in the number of headache 
days of at least moderate severity during the 12-week period after the 1st dose of study drug for patients 
not receiving concomitant preventive migraine medications relative to the baseline period

to demonstrate the efficacy of TEV-48125, as assessed by the reduction in the number of headache 
days of at least moderate severity during the 12-week period after the 1st dose of study drug for patients 
who used topiramate for migraine in the past relative to the baseline period

to demonstrate the efficacy of TEV-48125, as assessed by the reduction in the number of headache 
days of at least moderate severity during the 12-week period after the 1st dose of study drug for patients 
who used onabotulinumtoxinA for migraine in the past relative to the baseline period

to demonstrate the efficacy of TEV-48125, as assessed by the reduction in the monthly average 
number of headache hours of any severity during the 12-week period after the 1st dose of study drug
relative to the baseline period

to demonstrate the efficacy of TEV-48125, as assessed by the reduction in the monthly average 
number of headache hours of at least moderate severity during the 12-week period after the 1st dose of 
study drug relative to the baseline period

to demonstrate the efficacy of TEV-48125, as assessed by the reduction of the monthly average 
number of days of the use of migraine-specific acute headache medications (triptans and ergot 
compounds) during the 12-week period after the 1st dose of study drug relative to the baseline period

to demonstrate the efficacy of TEV-48125, as assessed by the reduction of the monthly average 
number of days with nausea or vomiting during the 12-week period after the 1st dose of study drug 
relative to the baseline period

to demonstrate the efficacy of TEV-48125, as assessed by the reduction of the monthly average 
number of days with photophobia and phonophobia during the 12-week period after the 1st dose of 
study drug relative to the baseline period


Placebo-Controlled Study–Episodic Migraine
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Study TV48125-CNS-30050
11

to demonstrate the efficacy of TEV-48125, as assessed by a change in quality of life at 4 weeks after 
the last (3rd) dose of study drug relative to baseline

to explore the correlation between pharmacokinetic parameters and drug efficacy

to explore the relationship between genetic polymorphisms within the CGRP receptor-ligand complex 
(eg, CALCA, CALCB, CALCRL, CRCP, and RAMP) and migraine-associated genes (eg, PRDM16, 
AJAP1, TSPAN2, MEF2D, TRPM8, TGFBR2, PHACTR1, FHL5, C7orf10, MMP16, ASTN2, LRP1, 
APOA1BP, TBC1D7, FUT9, STAT6, ATP5B, and MTHFR) and mode-of-action-related pathways
versus hypertension, migraine severity, and safety and efficacy responses

to explore the relationship between biofluid bone, angiogenic, and inflammatory biomarkers with 
TEV-48125 concentrations and efficacy responses
Study Endpoints 
Primary Endpoint: The primary endpoint is the mean change from baseline (28-day run-in period) in the monthly 
average number of migraine days during the 12-week period after the 1st dose of study drug.
Secondary Endpoints: The secondary endpoints are as follows:

proportion of patients reaching at least 50% reduction in the monthly average number of migraine days 
during the 12-week period after the 1st dose of study drug

mean change from baseline (28-day run-in period) in the monthly average number of days of use of 
any acute headache medications during the 12-week period after the 1st dose of study drug

mean change from baseline (28-day run-in period) in the number of migraine days during the 4-week 
period after the 1st dose of the study drug

mean change from baseline (28-day run-in period) in the monthly average number of migraine days 
during the 12-week period after the 1st dose of study drug in patients not receiving concomitant 
migraine preventive medications

mean change from baseline (day 0) in disability score, as measured by the MIDAS questionnaire, at 
4 weeks after administration of the last (3rd) dose of study drug
Exploratory Endpoints: The exploratory endpoints are as follows:

mean change from baseline (28-day run-in period) in the number of headache days of at least moderate 
severity during the 12-week period after the 1st dose of study drug

proportion of patients reaching at least 75% reduction and total (100%) reduction in the monthly 
average number of migraine days during the 12-week period after the 1st dose of study drug

proportion of patients reaching at least 50% reduction and at least 75% reduction in the number of 
migraine days during the 4-week period after the 1st dose of study drug for whom this level of effect is 
sustained throughout the 12-week period after the 1st dose of study drug

mean change from baseline (28-day run-in period) in the monthly average number of migraine days 
during the 12-week period after the 1st dose of study drug in patients who used topiramate for migraine 
in the past


Placebo-Controlled Study–Episodic Migraine
Clinical Study Protocol with Amendment 01
Study TV48125-CNS-30050
12

mean change from baseline (28-day run-in period) in the number of migraine days during the 12-week 
period after the 1st dose of study drug for patients who used onabotulinumtoxinA for migraine in the 
past

mean change from baseline (28-day run-in period) in the number of migraine days during the 4-week 
period after the 2nd dose of the study drug

mean change from baseline (28-day run-in period) in the number of migraine days during the 4-week 
period after the last (3rd) dose of the study drug

mean change from baseline (28-day run-in period) in the monthly average number of headache days of 
any severity during the 12-week period after the 1st dose of study drug

mean change from baseline (28-day run-in period) in the number of headache days of at least moderate 
severity during the 4-week period after each dose of study drug

proportion of patients reaching at least 50% reduction, at least 75% reduction, and total (100%) 
reduction in the monthly average number of headache days of at least moderate severity during the 
12-week period after the 1st dose of study drug

proportion of patients reaching at least 50% reduction and at least 75% reduction in the number of 
headache days of at least moderate severity during the 4-week period after the 1st dose of study drug 
for whom this level of effect is sustained throughout the 12-week period after the 1st dose of study drug

mean change from baseline (28-day run-in period) in the number of headache days of at least moderate 
severity during the 12-week period after the 1st dose of study drug for patients not receiving 
concomitant preventive migraine medications

mean change from baseline (28-day run-in period) in the number of headache days of at least moderate 
severity during the 12-week period after the 1st dose of study drug for patients who used topiramate for 
migraine in the past

mean change from baseline (28-day run-in period) in the number of headache days of at least moderate 
severity during the 12-week period after the 1st dose of study drug for patients who used 
onabotulinumtoxinA for migraine in the past

mean change from baseline (28-day run-in period) in the monthly average number of headache hours 
of any severity during the 12-week period after the 1st dose of study drug

mean change from baseline (28-day run-in period) in the monthly average number of headache hours 
of at least moderate severity during the 12-week period after the 1st dose of study drug

mean change from baseline (28-day run-in period) in the monthly average number of days of use of 
migraine-specific acute headache medications (triptans and ergot compounds) during the 12-week 
period after the 1st dose of study drug

mean change from baseline (28-day run-in period) in the monthly average number of days with nausea 
or vomiting during the 12-week period after the 1st dose of study drug

mean change from baseline (28-day run-in period) in the monthly average number of days with 
photophobia and phonophobia during the 12-week period after the 1st dose of study drug

mean change from baseline (day 0) in quality of life, as measured by the Migraine-Specific Quality of 
Life (MSQOL) questionnaire, at 4 weeks after administration of the last (3rd) dose of study drug


Placebo-Controlled Study–Episodic Migraine
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Study TV48125-CNS-30050
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
mean change from baseline (day 0) in the health status, as measured by the EuroQol-5 Dimension, 5 
response level version (EQ-5D-5L) questionnaire at 4 weeks after administration of the last (3rd) dose 
of study drug

mean change from baseline (day 0) in patient depression status, as measured by the 2-item Patient 
Health Questionnaire (PHQ-2) and 9-item Patient Health Questionnaire (PHQ-9), at 4 weeks after 
administration of the last (3rd) dose of study drug

mean change from baseline (day 0) in patient work productivity and activity impairment, as measured 
by the Work Productivity and Activity Impairment (WPAI) questionnaire, at 4 weeks after 
administration of the last (3rd) dose of study drug

assessment of patient satisfaction, as measured by the Patient Global Impression of Change (PGIC)
scale, at 4 weeks after administration of the 1st dose of study drug, at 4 weeks after the 2nd dose of 
study drug, and at 4 weeks after the last (3rd) dose of study drug

exploratory correlation of specific genetic polymorphisms and headache response, specific migraine 
clinical features, and adverse events to medication

mean change from baseline in exploratory biofluid biomarkers versus treatment, migraine 
onset/severity, and response status (ie, responders versus nonresponders)

correlation of exploratory biofluid biomarkers with TEV-48125 concentrations
General Design and Methodology: This is a 16-week, multicenter, randomized, double-blind, placebo-controlled, 
parallel-group study to compare the safety, tolerability, and efficacy of 2 dose regimens of sc TEV-48125 and
placebo. 

monthly sc administration of TEV-48125 at 225 mg

sc administration of 675 mg of TEV-48125 at visit 2 followed by monthly sc placebo 

monthly sc administration of placebo 
Randomization will be performed using electronic interactive response technology (IRT). Patients will be stratified 
based on gender, country, and baseline preventive migraine medication use (yes, no) to ensure balance for the 
covariates (treatment group, preventive medication use, country, and gender).
Blinded treatment will be administered sc once monthly (approximately every 4 weeks) for a total of 3 doses. First
treatment administration will occur at visit 2 (day 0), and additional doses will be administered at visits 3 and 4. 
Final study assessments will be performed at visit 5 (end-of-treatment [EOT] visit), approximately 4 weeks after 
administration of the 3rd and final dose of study drug. Upon completion of the final study assessments, patients may 
enter a long-term safety and efficacy study (Study TV48125-CNS-30051), consisting of a 12-month double-blind 
treatment period and a 6.5-month follow-up period. In the long-term safety extension study, patients receiving active 
study drug in the current study will continue receiving the same treatment (ie, monthly sc TEV-48125 at 225 mg or 
quarterly sc TEV-48125 at 675 mg), and patients receiving placebo in the current study will be randomized in a 1:1 
ratio to receive monthly sc TEV-48125 at 225 mg or quarterly sc TEV-48125 at 675 mg during the long-term safety 
and efficacy study. Patients who do not enroll in the long-term safety and efficacy study for any reason will be 
offered to enter the long-term safety extension for the purpose of evaluating ADA approximately 7.5 months
(225 days[the approximate equivalent of 5 half-lives]) after receiving the last dose of study drug in this study.
Method of Blinding and Randomization: The sponsor, investigators, study staff (except for staff involved in 
bioanalytical analyses), and patients will be blinded to treatment assignment. A computer-generated master 


Placebo-Controlled Study–Episodic Migraine
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randomization list will be provided to drug packaging facilities. Packaging vendor(s) will package active and 
placebo into single-visit kits according to Good Manufacturing Practice procedures. Kits will be identical in 
appearance and contain 1 prefilled syringe with active drug or placebo. Adequate kit supply for upcoming study 
visits will be managed by IRT and kept (refrigerated at 2°C to 8°C) on site.
This is a randomized study with stratification based on gender, country, and baseline preventive medication use (yes, 
no). Each patient will undergo randomization in a 1:1:1 ratio within the stratum to which he or she belongs to 
receive 1 of the 2 TEV-48125 dose regimens or placebo, as assigned by the IRT. The IRT will manage initial drug 
supply, maintenance of adequate study drug supplies on site, and study randomization centrally. At the time of each 
study visit, the IRT will be queried, and site personnel will retrieve and administer a 1.5-mL volume from each
syringe contained in the appropriately numbered kit(s).
The total number of patients receiving concomitant preventive medication during the study will not exceed 30% of 
the total sample size of the study.
Study Drug Dose, Mode of Administration, and Administration Rate: Prefilled syringes (active or placebo) will 
be contained in uniquely numbered kits and stored (refrigerated at 2°C to 8°C) on site. Active syringes will contain 
150 mg/mL of TEV-48125, and placebo syringes will contain the same vehicle and excipients as those for active 
injections. Each kit will contain 1 prefilled syringe.
Study drug will be administered by qualified study personnel as sc injections approximately every 4 weeks (28 days)
for a total of 3 doses, as follows:

Patients randomized to receive TEV-48125 at 225 mg will receive 225 mg of TEV-48125 as 1 active 
injection (225 mg/1.5 mL) and two 1.5-mL placebo injections at visit 2 and 225 mg of TEV-48125 as 
1 active injection (225 mg/1.5 mL) at visits 3 and 4.

Patients randomized to receive TEV-48125 675 mg/placebo will receive 675 mg of TEV-48125 as 
3 active injections (225 mg/1.5 mL) at visit 2 and placebo as single 1.5-mL injection at visits 3 and 4.

Patients randomized to receive placebo will receive three 1.5-mL placebo injections at visit 2 and 
single 1.5-mL placebo injection at visits 3 and 4.
The recommended sc injection sites follow the National Institutes of Health Patient Education Guidelines of 
June 2012, which are available in Appendix C and at 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. Each of 
the injections at visit 2 should be given in a different location (eg, not in precisely the same place), and study staff 
member(s) responsible for administration of injections should inspect previous injection sites to ensure that they are 
free of bruising and tenderness and that proper rotation of sites is performed.
The total number of sc injections and their locations will be recorded for each dosing visit (visits 2, 3, and 4). A 
1.5-mL volume from each syringe in each visit’s kit(s) must be injected sc for dosing to be considered complete.
Investigational Product: TEV-48125
Reference Therapy: 
Placebo: Same vehicle and excipients as those for active injection
Comparison Drug: Not applicable
Duration of Patient Participation: Patient participation will last for approximately 4 months (including a 28-day 
run-in period and a 12-week, double-blind treatment period); after which, patients may enter into a double-blind, 
long-term safety and efficacy study. Patients who do not enroll in the double-blind, long-term safety and efficacy 
study for any reason will be offered to enter the long-term safety extension for the purpose of evaluating ADA 


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approximately 7.5 months (225 days [the approximate equivalent of 5 half-lives]) after receiving the last dose of 
study drug in this study. Thus, patient participation for these patients will last approximately 10.5 months.
The end of the study is defined as the date the last patient attends the EOT/early withdrawal visit (visit 5).
Criteria for Inclusion: Patients may be included in the study only if they meet all of the following criteria:
a.
Males or females aged 18 to 70 years, inclusive, with migraine onset at ≤50 years of age
b.
Patient signs and dates the informed consent document
c.
Patient has history of migraine (according to ICHD-3 criteria [Classification Committee of the 
IHS, 2013]) or clinical judgement suggests a migraine diagnosis (not better accounted for by another 
ICHD-3 diagnosis) for ≥12 months prior to screening.
d.
Patient fulfills the following criteria for EM in prospectively collected baseline information during the 
28-day run-in period:

headache occurring on ≥6 and ≤14 days 

on ≥4 days, fulfilling any of the following:
o
ICHD-3 diagnostic criteria C and D for 1.1 Migraine without aura (Appendix D)
o
ICHD-3 criteria B and C for 1.2 Migraine with aura (Appendix D)
o
Probable migraine (a migraine subtype where only 1 migraine criterion is missing)
o
The patient used a triptan or ergot derivative to treat an established headache
e.
Not using preventive medications (presented in Appendix B) (ie, at least 5 half-lives have passed since 
last use) or using no more than 1 preventive medication (presented in Appendix A) for migraine or 
other medical conditions (eg, propranolol used for hypertension) if the dose and regimen have been 
stable for at least 2 months prior to beginning the 28-day run-in period.
f.
Body mass index of 17.5 to 37.5 kg/m2 and a total body weight between 45 and 120 kg, inclusive
g.
All patients must be of nonchildbearing potential, defined as:

women surgically sterile by documented complete hysterectomy, bilateral oophorectomy, or 
bitubal ligations or confirmed to be postmenopausal (at least 1 year since last menses and 
follicle-stimulating hormone above 35 U/L)

men surgically sterile by documented vasectomy
or
if of childbearing potential, patients must meet any of the following criteria:

Patients must simultaneously use 2 forms of highly effective contraception methods (defined in 
Section 5.2) with their partners during the entire study period and for 7.5 months after the last dose 
of study drug.

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 
subject. 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.


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h.
Female patients of childbearing potential must have negative a serum beta-human chorionic 
gonadotropin (β-HCG) pregnancy test at screening (confirmed by urine dipstick β-HCG pregnancy test 
at baseline).
i.
The patient demonstrated compliance with the electronic headache diary during the run-in period by 
entry of headache data on a minimum of 24 out of 28 days (~85% diary compliance).
j.
The patient is in good health as determined by a medical and psychiatric history, medical examination, 
12-lead electrocardiogram (ECG), serum chemistry, hematology, coagulation, and urinalysis.
k.
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 evaluation, as 
specified in this protocol.
Criteria for Exclusion: Patients will be excluded from participating in this study if they meet any of the following 
criteria: 
a.
Patient has received onabotulinumtoxinA (Botox®, Allergan, Inc.) for migraine or for any medical or 
cosmetic reasons requiring injections in the head, face, or neck during the 4 months before screening.
b.
Patient is using medications containing opioids (including codeine) or barbiturates (including 
butalbital/aspirin/caffeine, butalbital/paracetamol/caffeine, or any other combination containing 
butalbital) on more than 4 days per month for the treatment of migraine or for any other reason.
c.
Patients who have previously failed (lack of efficacy) 2 or more of the clusters of the following 
medications for treatment of EM or chronic migraine after adequate therapeutic trial defined as use for 
at least 3 months at accepted migraine therapeutic doses:

cluster A: divalproex sodium and sodium valproate

cluster B: flunarizine and pizotifen

cluster C: amitriptyline, nortriptyline, venlafaxine, and duloxetine

cluster D: atenolol, nadolol, metoprolol, propranolol, and timolol
d.
Patient has used an intervention/device (eg, scheduled nerve blocks and transcranial magnetic 
stimulation) for migraine during the last 2 months prior to screening.
e.
Clinically significant hematological, cardiac, renal, endocrine, pulmonary, gastrointestinal, 
genitourinary, neurologic, hepatic, or ocular disease, at the discretion of the investigator
f.
Evidence or medical history of clinically significant psychiatric issues, including any suicide attempt in 
the past, or suicidal ideation with a specific plan in the past 2 years.
g.
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
h.
Known infection or history of human immunodeficiency virus, tuberculosis, or chronic hepatitis B or C
infection
i.
Past or current history of cancer in the past 5 years, except for appropriately treated nonmelanoma skin 
carcinoma


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j.
Pregnant or nursing females
k.
History of hypersensitivity reactions to injected proteins, including monoclonal antibodies
l.
Participation in a clinical study of a new chemical entity or a prescription medicine within 2 months 
before study drug administration or 5 half-lives, whichever is longer
m. Any prior exposure to a monoclonal antibody targeting the CGRP pathway (AMG 334, ALD304, 
LY2951742, or TEV-48125)
n.
Any finding in the baseline 12-lead ECG considered clinically significant in the judgment of the 
investigator
o.
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)
p.
Hepatic enzymes (alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase) 
>1.5 × the upper limit of the normal range (ULN) after confirmation in a repeat test or suspected 
hepatocellular damage that fulfills criteria for Hy’s law at screening
q.
Serum creatinine >1.5 × the ULN, clinically significant proteinuria, or evidence of renal disease at 
screening
r.
History of alcohol or drug abuse during the past 2 years, or alcohol or drug dependence during the past 
5 years
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 guardianship, or institutionalized

unable to be contacted in case of emergency

has any other condition, which, in the opinion of the investigator, makes the patient inappropriate 
for inclusion in the study
t.
The patient is a study center or sponsor employee who is directly involved in the study or the relative 
of such an employee.
Measures and Time Points:
Primary Efficacy Measure and Time Point: The primary efficacy endpoint for this study will be derived from 
headache data (ie, occurrence of headache, duration of headache, maximum severity of headache, and acute
migraine-specific medication use) collected daily using an electronic headache diary device.
Eligible patients will receive training on the use of the electronic headache diary device and will be informed of 
compliance requirements at screening. Patients will complete electronic headache diary entries with questions 
about the previous day daily, beginning on day –27 (the day after the screening visit) through the EOT/early 
withdrawal visit. The electronic headache diary device will allow entry of headache information for up to 
48 hours after a given day.
Secondary Efficacy Measures and Time Points: Secondary efficacy endpoints will be derived from headache 
data (ie, occurrence of headache, duration of headache, maximum severity of headache, and acute 


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migraine-specific medication use) collected daily using an electronic headache diary device. In addition, 
migraine-related disability will be assessed using the MIDAS, completed at time points specified in Table 1.
Exploratory Efficacy Measures and Time Points: The following exploratory efficacy measures will be 
assessed at time points specified in Table 1: 

exploratory efficacy endpoints derived from headache data (ie, occurrence of headache, duration of 
headache, maximum severity of headache, and acute migraine-specific medication use), which are
collected daily using an electronic headache diary device

PHQ-2/PHQ-9 (Note: Patients will first respond to the PHQ-2. They will respond to questions 3 
through 9 [unique questions] of the PHQ-9 only if the PHQ-2 is positive.)

MSQOL questionnaire 

EQ-5D-5L questionnaire

PGIC scale

WPAI questionnaire
Safety and Tolerability Measures and Time Points: Safety and tolerability will be assessed at time points 
specified in Table 1 using the following measures:

inquiries about adverse events 

inquiries about concomitant medication usage 

safety laboratory tests (serum chemistry, hematology, coagulation, and urinalysis)

serum/urine β-HCG test (women of childbearing potential only)

12-lead ECGs

vital signs measurements (systolic and diastolic blood pressure, pulse, temperature, and respiratory 
rate)

physical examinations, including body weight

injection site reaction (ie, erythema, induration, ecchymosis, and pain) assessments 

electronic Columbia-Suicide Severity Rating Scale (eC-SSRS)
Pharmacokinetics/Biomarkers/Immunogenicity Measures and Time Points:
Pharmacokinetic Measures and Time Points: Blood samples for pharmacokinetics analysis of TEV-48125 will 
be collected from all patients at the time points specified in Table 1 for the purpose of 
pharmacokinetic/pharmacodynamic relationship assessment. The pharmacodynamic parameters will be the 
efficacy responses.
The actual date and time of each blood sample, as well as the date and time of the last study drug dose prior to 
each sample, will be recorded in the case report form.
TEV-48125 plasma concentration will be measured using a validated assay.


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Immunogenicity Measures and Time Points: Blood samples for immunogenicity will be collected at the time 
points specified in Table 1.
Biomarker Measures and Time Points: Biomarker blood and urine samples will be collected from all patients at 
the time points specified in Table 1, and a blood sample will be collected from patients who consent to 
pharmacogenomic analysis at visit 2 or any visit thereafter.
Allowed and Disallowed Medications Before and During the Study:
Prior Medications and Therapeutic Failures of Migraine Preventives: Details regarding excluded prior migraine 
preventive treatments and therapeutic failures of migraine preventives are described in the exclusion criteria.
Concomitant (Current) Therapy: Up to 30% of patients will be allowed to remain on stable doses of no more than 
1 preventive migraine medication for the duration of the study provided the medication has at least moderate 
evidence of efficacy as defined by guidelines (Silberstein et al 2012) and presented in Appendix A. Patients on 
preventive medication must be on a stable dose for at least 2 months of consecutive use prior to study entry. 
Alternatively, patients must have discontinued the preventive medication at least 5 half-lives prior to screening.
Patients will be allowed to use acute medications to treat acute migraine attacks as needed.
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 clinic visit.
Statistical Considerations:
Sample Size Rationale: A sample size of 675 randomized (ie, 225 evaluable patients completing the study per 
treatment group) is needed for 90% power to show a 1.6 difference in migraine days (assuming a common standard 
deviation [SD] of 5.2 days) at an alpha level of 0.05. Assuming a 12% discontinuation rate, 256 patients per 
treatment group will be randomized.
Efficacy Analysis: For the purpose of this study, a migraine day is endorsed when at least 1 of the following 
situations occur:

a calendar day (0:00 to 23:59) demonstrating at least 2 consecutive hours of a headache meeting 
criteria for migraine with or without aura

a calendar day (0:00 to 23:59) demonstrating at least 2 consecutive hours of a headache meeting 
criteria for probable migraine, a migraine subtype where only 1 migraine criterion is missing

a calendar day (0:00 to 23:59) demonstrating a headache of any duration that was treated with 
migraine-specific medications (triptans and ergot compounds)


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Analysis of Primary Efficacy Endpoint: The primary efficacy endpoint, the mean change from baseline (28-day 
run-in period) in the monthly average number of migraine days during the 12-week period after the 1st dose of study 
drug, will be analyzed using an analysis of covariance method. The model will include treatment, gender, country, 
and baseline preventive medication use as fixed effects, and baseline number of migraine days and years since onset 
of migraines as covariates. Ninety-five percent confidence intervals will be constructed for the least squares mean
differences between each TEV-48125 group and the placebo group.
Analysis of Secondary and Exploratory Efficacy Endpoints: The same analysis used for the primary efficacy 
endpoint will be performed for the continuous secondary and exploratory efficacy endpoints. For the proportion of 
responders, defined as 50% or more reduction from baseline in the monthly average number of migraine days, 
Cochran-Mantel-Haenszel test will be used.
Multiple Comparisons and Multiplicity: A fixed-sequence (hierarchical) testing procedure will be implemented to 
control the type 1 error rate at 0.05. The sequence of comparisons will be described in detail in the statistical 
analysis plan.
Safety and Tolerability 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 study drug (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.
Local tolerability findings will be listed and summarized descriptively.
Changes in laboratory 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.
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 study drug.
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.
Pharmacokinetic Analysis: Pharmacokinetic plasma concentration results (TEV-48125) will be tabulated 
descriptively at each planned sampling time point by treatment group.
Pharmacokinetic/Pharmacodynamic Analysis: The pharmacokinetic/pharmacodynamic relationship will be 
estimated by compartmental techniques. The pharmacokinetic parameters will be based on TEV-48125 
measurements. The pharmacodynamic will be the efficacy responses. 
The pharmacokinetic/pharmacodynamic relationship will be estimated using the most appropriate model after 
comparing different candidate models for their quality of fit. Covariates that may affect the 
pharmacokinetic/pharmacodynamic relationship will be tested for inclusion in the model. This analysis will be 
reported separately.


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Immunogenicity Analysis: Summary of immunogenicity results will be provided, and the incidence of 
immunogenicity will be calculated. The impact of immunogenicity on the pharmacokinetic profile, drug efficacy, 
and clinical safety will be evaluated. This impact analysis will be reported separately.
Biomarker Analysis: Biomarker analysis will include logistic regression, receiver operating characteristic curves, 
and summary statistics. Results will be reported separately. 


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TABLE OF CONTENTS
TITLE PAGE...................................................................................................................................1
AMENDMENT HISTORY .............................................................................................................2
INVESTIGATOR AGREEMENT...................................................................................................3
COORDINATING INVESTIGATOR AGREEMENT...................................................................4
CLINICAL LABORATORY AND OTHER DEPARTMENTS AND INSTITUTIONS ..............5
CLINICAL STUDY PERSONNEL CONTACT INFORMATION ...............................................7
CLINICAL STUDY PROTOCOL SYNOPSIS...............................................................................8
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS................................................31
1.
BACKGROUND INFORMATION...........................................................................33
1.1.
Introduction.................................................................................................................33
1.2.
Name and Description of Investigational Product......................................................34
1.3.
Findings from Nonclinical and Clinical Studies.........................................................34
1.3.1.
Nonclinical Studies.....................................................................................................34
1.3.2.
Clinical Studies...........................................................................................................35
1.3.2.1.
Clinical Pharmacology Studies...................................................................................35
1.3.2.2.
Clinical Safety and Efficacy Studies ..........................................................................36
1.4.
Known and Potential Risks and Benefits to Human Patients.....................................37
1.4.1.
Known and Potential Risks and Benefits of TEV-48125...........................................37
1.4.1.1.
Risks of TEV-48125...................................................................................................37
1.4.1.2.
Benefits of TEV-48125...............................................................................................37
1.4.2.
Overall Risk and Benefit Assessment for This Study ................................................38
1.5.
Selection of Drugs and Dosages.................................................................................38
1.5.1.
Justification for Dosage of Active Drug.....................................................................38
1.5.2.
Justification for Use of Placebo..................................................................................39
1.6.
Compliance Statement................................................................................................39
1.7.
Population to be Studied and Justification..................................................................39
1.8.
Location and Timing of Study....................................................................................40
2.
PURPOSE OF THE STUDY AND STUDY OBJECTIVES.....................................41
2.1.
Purpose of the Study...................................................................................................41
2.2.
Study Objectives.........................................................................................................41
2.2.1.
Primary Objectives .....................................................................................................41


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2.2.2.
Secondary Objectives .................................................................................................41
2.2.3.
Exploratory Objectives ...............................................................................................42
2.3.
Study Endpoints..........................................................................................................44
2.3.1.
Primary Efficacy Endpoint .........................................................................................44
2.3.2.
Secondary Efficacy Endpoints....................................................................................44
2.3.3.
Exploratory Efficacy Endpoints .................................................................................44
2.3.4.
Safety and Tolerability Endpoints ..............................................................................46
2.3.5.
Pharmacokinetic/Immunogenicity/Biomarker Endpoints ..........................................46
2.3.5.1.
Pharmacokinetic Endpoints ........................................................................................46
2.3.5.2.
Immunogenicity Endpoint ..........................................................................................46
2.3.5.3.
Biomarker Endpoints..................................................................................................47
3.
STUDY DESIGN .......................................................................................................48
3.1.
General Design and Study Schema.............................................................................48
3.2.
Justification for Study Design ....................................................................................50
3.3.
Primary and Secondary Efficacy Measures and Time Points.....................................51
3.3.1.
Primary Efficacy Measure and Time Points...............................................................51
3.3.2.
Secondary Efficacy Measure and Time Points...........................................................51
3.4.
Safety and Tolerability Measures and Time Points....................................................51
3.5.
Pharmacokinetic, Biomarker, and Immunogenicity Measures and Time 
Points ..........................................................................................................................52
3.5.1.
Pharmacokinetic Measures and Time Points..............................................................52
3.5.2.
Immunogenicity Measures and Time Points ..............................................................52
3.5.3.
Biomarker Measures and Time Points........................................................................52
3.6.
Exploratory/Other Efficacy Measures and Time Points.............................................52
3.7.
Randomization and Blinding......................................................................................52
3.8.
Maintenance of Randomization and Blinding............................................................53
3.8.1.
Randomization............................................................................................................53
3.8.2.
Blinding/Unblinding...................................................................................................53
3.8.3.
Data Monitoring Committee.......................................................................................54
3.9.
Drugs Used in the Study.............................................................................................54
3.9.1.
Investigational Product ...............................................................................................54
3.9.2.
Placebo........................................................................................................................54
3.10.
Drug Supply and Accountability ................................................................................54


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3.10.1.
Drug Storage and Security..........................................................................................54
3.10.2.
Drug Accountability ...................................................................................................54
3.11.
Duration of Patient Participation and Justification.....................................................55
3.12.
Stopping Rules and Discontinuation Criteria .............................................................55
3.13.
Source Data Recorded on the Case Report Form.......................................................56
3.14.
Study Procedures ........................................................................................................56
3.14.1.
Procedures for Screening (Visit 1[Day –28]).............................................................60
3.14.2.
Procedures Before Study Drug Treatment..................................................................61
3.14.2.1.
28-Day Run-In Period (Days –28 Through –1)..........................................................61
3.14.2.2.
Baseline (Visit 2 [Day 0 (±3 Days)])..........................................................................61
3.14.3.
Procedures During Study Drug Treatment .................................................................62
3.14.3.1.
Double-Blind Treatment Period (Visits 2 Through 5 [Day 0 Through Day 84 
±3 Days]) ....................................................................................................................62
3.14.4.
Procedures After Study Drug Treatment ....................................................................64
3.14.5.
Unscheduled Visits .....................................................................................................64
4.
SELECTION AND WITHDRAWAL OF PATIENTS..............................................66
4.1.
Patient Inclusion Criteria ............................................................................................66
4.2.
Patient Exclusion Criteria...........................................................................................67
4.3.
Justification for Key Inclusion and Exclusion Criteria...............................................69
4.4.
Withdrawal Criteria and Procedures...........................................................................69
5.
TREATMENT OF PATIENTS..................................................................................71
5.1.
Drugs Administered During the Study .......................................................................71
5.2.
Restrictions .................................................................................................................72
5.3.
Prior and Concomitant Therapy or Medication..........................................................72
5.3.1.
Prior Medications and Therapeutic Failures of Migraine Preventives:......................72
5.3.2.
Concomitant Therapies and Medications ...................................................................72
5.4.
Procedures for Monitoring Patient Compliance .........................................................73
5.5.
Total Blood Volume ...................................................................................................73
6.
ASSESSMENT OF EFFICACY ................................................................................74
6.1.
Primary Efficacy Measure and Justification...............................................................74
6.2.
Migraine Disability Assessment.................................................................................74
6.3.
Two-Item Patient Health Questionnaire/9-Item Patient Health Questionnaire ..........75
6.4.
Migraine-Specific Quality of Life Questionnaire.......................................................75


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6.5.
EuroQol-5 Dimension Questionnaire .........................................................................75
6.6.
Patient Global Impression of Change Scale ...............................................................75
6.7.
Work Productivity and Activity Impairment Questionnaire ......................................76
7.
ASSESSMENT OF SAFETY.....................................................................................77
7.1.
Adverse Events ...........................................................................................................77
7.1.1.
Definition of an Adverse Event..................................................................................77
7.1.2.
Recording and Reporting Adverse Events..................................................................78
7.1.3.
Severity of an Adverse Event .....................................................................................79
7.1.4.
Relationship of an Adverse Event to the Study Drug.................................................79
7.1.5.
Serious Adverse Events..............................................................................................80
7.1.5.1.
Definition of a Serious Adverse Event .......................................................................80
7.1.5.2.
Expectedness...............................................................................................................80
7.1.5.3.
Reporting a Serious Adverse Event............................................................................81
7.1.6.
Protocol-Defined Adverse Events of Special Interest ................................................82
7.1.7.
Withdrawal Due to an Adverse Event ........................................................................83
7.1.8.
Overdose of Study Drug .............................................................................................83
7.1.9.
Protocol Deviations Because of an Adverse Event ....................................................83
7.2.
Pregnancy ...................................................................................................................84
7.3.
Clinical Laboratory Tests ...........................................................................................84
7.3.1.
Serum Chemistry ........................................................................................................85
7.3.2.
Hematology.................................................................................................................85
7.3.3.
Coagulation.................................................................................................................86
7.3.4.
Urinalysis....................................................................................................................86
7.3.5.
Other Clinical Laboratory Tests .................................................................................87
7.3.5.1.
Human Chorionic Gonadotropin Tests.......................................................................87
7.3.5.2.
Follicle-Stimulating Hormone Tests...........................................................................87
7.4.
Vital Signs ..................................................................................................................87
7.5.
Electrocardiography....................................................................................................87
7.6.
Physical Examinations................................................................................................88
7.7.
Electronic Columbia-Suicide Severity Rating Scale..................................................88
7.8.
Concomitant Therapy or Medication..........................................................................88
7.9.
Immunogenicity..........................................................................................................88
7.10.
Injection Site Assessments .........................................................................................89


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7.11.
Methods and Timing of Assessing, Recording, and Analyzing Safety Data..............89
8.
ASSESSMENT OF PHARMACOKINETICS/ BIOMARKERS/ 
IMMUNOGENICITY ................................................................................................90
8.1.
Pharmacokinetic Variables.........................................................................................90
8.1.1.
Specimen Sampling and Handling..............................................................................90
8.1.2.
Shipment and Analysis of Samples ............................................................................90
8.2.
Immunogenicity Testing.............................................................................................91
8.2.1.
Blood Sampling and Handling....................................................................................91
8.2.2.
Shipment and Analysis of Samples ............................................................................91
8.3.
Assessment of Exploratory Biofluid Biomarkers.......................................................91
8.3.1.
Pharmacogenomic Assessment...................................................................................92
8.3.2.
Specimen Sampling and Handling..............................................................................92
8.3.3.
Shipment and Analysis of Samples ............................................................................93
8.4.
Methods and Timing of Assessing, Recording, and Analyzing Clinical 
Pharmacology Data.....................................................................................................93
9.
STATISTICS ..............................................................................................................94
9.1.
Sample Size and Power Considerations .....................................................................94
9.2.
Analysis Sets...............................................................................................................94
9.2.1.
Intent-to-Treat Analysis Set........................................................................................94
9.2.2.
Safety Analysis Set.....................................................................................................94
9.2.3.
Full Analysis Set.........................................................................................................94
9.2.4.
Additional Analysis Sets.............................................................................................94
9.3.
Data Handling Conventions........................................................................................94
9.4.
Study Population.........................................................................................................95
9.4.1.
Patient Disposition......................................................................................................95
9.4.2.
Demographic and Baseline Characteristics ................................................................95
9.5.
Efficacy Analysis........................................................................................................95
9.5.1.
Primary Endpoint........................................................................................................95
9.5.2.
Secondary Endpoints ..................................................................................................96
9.5.3.
Exploratory Endpoints................................................................................................96
9.5.4.
Planned Method of Analysis.......................................................................................98
9.5.4.1.
Primary Efficacy Analysis..........................................................................................98
9.5.4.2.
Sensitivity Analysis ....................................................................................................98


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9.5.4.3.
Secondary Efficacy Analysis......................................................................................98
9.5.4.4.
Exploratory Efficacy Analysis....................................................................................98
9.6.
Multiple Comparisons and Multiplicity......................................................................98
9.7.
Safety and Tolerability Endpoints and Analysis ........................................................98
9.7.1.
Safety and Tolerability Endpoints ..............................................................................99
9.7.2.
Safety Analysis ...........................................................................................................99
9.8.
Pharmacokinetic Analysis ........................................................................................100
9.9.
Biomarker Analysis ..................................................................................................100
9.10.
Pharmacokinetic/Pharmacodynamic Analysis..........................................................100
9.11.
Immunogenicity Analysis.........................................................................................100
9.12.
Planned Interim Analysis..........................................................................................100
9.13.
Reporting Deviations from the Statistical Plan ........................................................100
10.
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.......................................101
11.
QUALITY CONTROL AND QUALITY ASSURANCE .......................................102
11.1.
Protocol Amendments and Protocol Deviations and Violations ..............................102
11.1.1.
Protocol Amendments ..............................................................................................102
11.1.2.
Protocol Violations...................................................................................................102
11.2.
Information to Study Personnel................................................................................102
11.3.
Study Monitoring......................................................................................................103
11.4.
Clinical Product Complaints.....................................................................................103
11.4.1.
Product Complaint Information Needed from the Investigational Center................104
11.4.2.
Handling the Study Drug at the Investigational Center............................................104
11.4.3.
Adverse Events or Serious Adverse Events Associated with a Product 
Complaint .................................................................................................................105
11.4.4.
Documenting a Product Complaint ..........................................................................105
11.5.
Audit and Inspection.................................................................................................105
12.
ETHICS ....................................................................................................................106
12.1.
Informed Consent .....................................................................................................106
12.2.
Health Authorities and Independent Ethics Committees/Institutional Review 
Boards.......................................................................................................................106
12.3.
Confidentiality Regarding Study Patients ................................................................106
12.4.
Declaration of the End of the Clinical Study............................................................107
12.5.
Registration of the Clinical Study.............................................................................107


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13.
DATA HANDLING, DATA QUALITY CONTROL, AND RECORD 
KEEPING .................................................................................................................108
13.1.
Data Collection.........................................................................................................108
13.2.
Data Quality Control.................................................................................................108
13.3.
Archiving of Case Report Forms and Source Documents........................................109
13.3.1.
Sponsor Responsibilities...........................................................................................109
13.3.2.
Investigator Responsibilities.....................................................................................109
14.
FINANCING AND INSURANCE...........................................................................111
15.
REPORTING AND PUBLICATION OF RESULTS..............................................112
16.
REFERENCES .........................................................................................................113
17.
SUMMARY OF CHANGES TO PROTOCOL TV48125-CNS-30049 ..................116
17.1.
Amendment 01 Dated 30 March 2016......................................................................116
17.2.
Administrative Letter Dated 01 March 2016............................................................149
17.3.
Administrative Letter Dated 22 January 2016..........................................................151
APPENDIX A.
PREVENTIVE MEDICATIONS ALLOWED FOR THE DURATION 
OF THE STUDY......................................................................................................152
APPENDIX B.
DISALLOWED MEDICATIONS FOR THE DURATION OF THE 
STUDY.....................................................................................................................153
APPENDIX C.
NATIONAL INSTITUTES OF HEALTH PATIENT EDUCATION 
GUIDELINES OF JUNE 2012.................................................................................154
APPENDIX D.
ICHD-3 DIAGNOSTIC CRITERIA ...............................................................161
APPENDIX E.
GUIDANCE ON SAFETY MONITORING...................................................162
APPENDIX F.
CLINICAL CRITERIA FOR DIAGNOSING ANAPHYLAXIS ...................165


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LIST OF TABLES
Table 1:
Study Procedures and Assessments............................................................................57
Table 2:
Blood Volumes...........................................................................................................73
Table 3:
Severity of Pain Scale for Injection Site Assessments ...............................................89
Table 4:
Changes to the Protocol............................................................................................117


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LIST OF FIGURES
Figure 1:
Overall Study Schema ................................................................................................50


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Table of Abbreviations
Abbreviation
Term
β-HCG
beta-human chorionic gonadotropin
ADA
antidrug antibody
ALP
alkaline phosphatase 
ALT
alanine aminotransferase 
AST
aspartate aminotransferase 
BP
blood pressure
CBC
complete blood count
CDMS
clinical data management system 
CFR
Code of Federal Regulations (US)
CGRP
calcitonin gene-related peptide
CM
chronic migraine
Cmax
maximum observed plasma drug concentration
CRF
case report form (refers to any media used to collect study data [ie, paper or 
electronic])
CRO
contract research organization
DNA
deoxyribonucleic acid
ECG
electrocardiography/electrocardiogram
EDTA
ethylenediaminetetraacetic acid 
EM
episodic migraine
EOT
end of treatment (visit)
EQ-5D-5L
EuroQol-5 Dimension, 5 response level version
EU
European Union
FAS
full analysis set
FDA
Food and Drug Administration (US)
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GGT
gamma-glutamyl transpeptidase
ICH
International Conference on Harmonisation
ICHD
International Classification of Headache Disorders


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Abbreviation
Term
IEC
Independent Ethics Committee
IgG
immunoglobulin G
IgM
immunoglobulin M
IHS
International Headache Society
INR
international normalized ratio 
IRB
Institutional Review Board
ITT
intent-to-treat 
iv
intravenous(ly)
IRT
interactive response technology
LSO
local safety officer
MIDAS
Migraine Disability Assessment
MSQOL
Migraine-Specific Quality of Life 
NOAEL
no-observed-adverse-effect level
PBO
placebo
PEF
peak expiratory flow
PGIC
Patient Global Impression of Change
PHQ-2
2-item Patient Health Questionnaire
PHQ-9
9-item Patient Health Questionnaire
QC
quality control
RBC
red blood cell
RNA
ribonucleic acid
sc
subcutaneous(ly)
SD
standard deviation
SOP
standard operating procedure
SUSAR
suspected unexpected serious adverse reaction
t½
terminal elimination half-life
tmax
time to maximum observed drug concentration
ULN
upper limit of the normal range
US(A)
United States (of America)
V
visit
WBC
white blood cell
WPAI
Work Productivity and Activity Impairment


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1.
BACKGROUND INFORMATION
1.1.
Introduction
Migraine is a prevalent condition characterized by attacks of headache and associated symptoms 
(such as nausea, photophobia, or phonophobia). The 2 most common forms of migraine, 
migraine without aura and migraine with aura, occur on less than 15 days per month and are 
referred to as episodic forms of migraine (ie, EM) (Lipton et al 2007). However, approximately
3% of individuals with EM evolve, in any given year, to a significantly more disabling condition 
called CM (Bigal et al 2008, Lipton et al 2007,Scher et al 2003). Individuals with CM present 
with headaches of any severity on 15 or more days per month and have full-blown migraine on at 
least 8 days per month (Classification Committee of the International Headache Society [IHS],
2013). A sizable proportion of individuals with CM experiences daily headaches and, therefore, 
faces considerable disability (Bigal and Lipton 2008).
The pathophysiology of migraine involves central and peripheral events. Activation of structures 
in the brainstem are involved in the modulation of sensory activity, which is impaired during 
migraine attacks. Chronic dysfunction in these structures predisposes migraineurs not only to 
migraine attacks, but to increased headache frequency (Goadsby and Hargreaves 2008). 
Furthermore, the activation of these structures is also associated with inflammation and protein 
extravasation at the level of the meningeal blood vessels, muscles and other structures innervated 
by the trigeminal nerve. This combination of peripheral insults (inflammation and plasma protein 
extravasation) with impairment of the inhibitory pain mechanisms at the level of brainstem is 
paramount to frequent migraines (Goadsby et al 2002).
Calcitonin gene-related peptide (CGRP) is a well-studied neuropeptide found at the centers of 
the migraine processes, both centrally and peripherally (Eftekhari and Edvinsson 2010). Its role 
in migraine pathophysiology was suggested more than 20 years ago (Edvinsson and Goadsby 
1990, Goadsby et al 1990). Jugular levels of CGRP are increased during migraine attacks, and 
intravenous (iv) CGRP administration induces migraine-like headache in most individuals with 
migraine (Ashina et al 2000, Hansen et al 2010). Calcitonin gene-related peptide is therefore 
involved in the pathophysiology of migraine at all levels, peripherally (vasodilation, 
inflammation and protein extravasation), at the trigeminal ganglion, and inside the brain (Ho et al 
2010). Inhibition of CGRP has demonstrated efficacy in the treatment of EM (Hewitt et al 2011,
Ho et al 2008, Olesen et al 2004).
The goals of migraine treatment are to relieve pain, restore function, reduce headache frequency, 
and to prevent progression of EM to CM. Pharmacological interventions for the treatment of 
migraine include acute (symptomatic) treatments and daily preventive medications. The latter is 
indicated for patients with CM and may be appropriate patients with EM who have significant 
disability with migraine attacks (>3 days per month with headache-related disability), 
contraindications to triptans or other vasoactive medications, significant adverse effects from 
triptans, and patients with severe or prolonged attacks (Lipton and Silberstein 2015). Currently 
available drug therapies for preventive treatment of migraine include antiepileptic drugs, 
beta-blockers, triptans, antidepressants, angiotensin receptor blockers, angiotensin-converting 
enzyme inhibitors, serotonergic agents, calcium channel blockers, nonsteroidal 
anti-inflammatory drugs, opioids, and direct vascular smooth muscle relaxants. Although there 


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are more than 40 medications within these classes of drugs that are used with varying response 
rates to prevent migraine, only 5 marketed drugs are approved by the Food and Drug 
Administration (FDA) in the United States (US) for the preventive treatment of migraine; 4 of 
them are approved for the prophylaxis of migraine: propranolol, timolol maleate, divalproex 
sodium, and topiramate. The clinical trials (Brandes et al 2004, Klapper 1997, Mathew et al 
1995, Nadelmann et al 1986, Silberstein et al 2004) that supported registration of these drugs for 
this indication were conducted before the establishment of CM as a single entity and generally 
included patients with headaches on less than 15 days per month. Only 1 medication, 
onabotulinumtoxinA, is approved for prophylaxis of CM (Lipton and Silberstein 2015).
TEV-48125 (also known as PF-04427429, RN307, or LBR-101) is a fully humanized 
immunoglobulin G (IgG) 2a/kappa monoclonal antibody derived from a murine precursor. 
TEV-48125 is a potent, selective CGRP binder and blocks both CGRP isoforms (α- and 
β-CGRP) from binding to the CGRP receptor. TEV-48125 is specific for CGRP and does not 
bind to the closely related family members amylin, calcitonin, or adrenomedullin peptides. Two 
mutations were introduced into the constant region of the TEV-48125 heavy chain to limit 
antibody effector functions. This loss of function prevents TEV-48125 from stimulating 
antibody-dependent cell mediated cytotoxicity and triggering complement-mediated lysis; these 
activities can lead to unwanted consequences such as cell lysis, opsonization, and cytokine 
release and inflammation (Armour et al 1999, Zeller et al 2008).
The pharmacokinetics and tolerability of TEV-48125 (iv doses ranging from 0.2 to 2000 mg and 
subcutaneous [sc] doses of 225 mg and 900 mg) has been well-characterized in the Phase 1 
development program (see Section 1.3.2.1). Furthermore, the safety and effectiveness of 
TEV-48125 has been demonstrated in a randomized double-blind, placebo controlled Phase 2 
study of 2 sc dosing regimens of TEV-48125 (monthly TEV-48125 at 900 mg or TEV-48125 at 
675 mg followed by monthly TEV-48125 at 225 mg) in patients with CM and a randomized, 
double-blind, placebo-controlled Phase 2 study of 2 sc dosing regimens of TEV-48125 (monthly 
TEV-48125 at 675 or 225 mg) in patients with EM (see Section 1.3.2.2). The acceptable 
tolerability, long terminal elimination half-life (t½, approximately 45 days) and ability to 
administer sc make TEV-48125 an attractive therapeutic candidate for the preventive treatment 
of CM and EM.
1.2.
Name and Description of Investigational Product
TEV-48125 (formerly LBR-101, PF-04427429, or RN307) is a fully humanized IgG2a/kappa 
monoclonal antibody derived from a murine precursor. TEV-48125 is being developed for 
administration by the sc route. A more detailed description of the product is given in Section 3.9.
1.3.
Findings from Nonclinical and Clinical Studies
1.3.1.
Nonclinical Studies
In vivo pharmacology studies of TEV-48125 in animal models indicate that TEV-48125 
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.


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Safety pharmacology parameters of TEV-48125 were assessed in the pivotal toxicology studies 
in Sprague Dawley rats and cynomolgus monkeys and a separate cardiovascular safety 
pharmacology study in male cynomolgus monkeys. There were no treatment-related changes in 
electrocardiograms (ECGs) and heart rates in the 1- and 3-month toxicity studies, and a single iv
dose of TEV-48125 at 100 mg/kg did not result in changes in cardiovascular parameters or body 
temperature in monkeys. Additionally, no target organ toxicity was identified. In these 
referenced studies, the no-observed-adverse-effect level (NOAEL) ranged from 100 to 
300 mg/kg dosed either iv or sc. In a 3-month monkey study, perivascular inflammation of the 
ciliary artery was observed in a few animals at doses ≥100 mg/kg. The inflammation was 
suspected to be the result of immune complex formation/deposition from the monkeys’ 
immunogenic response to the drug (TEV-48125). In the pivotal 6-month chronic toxicity study in 
monkeys following once-weekly sc dosing at dosage levels of up to 300 mg/kg/week, achieving 
high exposure throughout the study, no microscopic findings were noted in any of the organs, 
including the ciliary vessels of the eyes, and the NOAEL of the chronic toxicity study was 
determined to be the highest dose tested, 300 mg/kg/week. Thus, it is believed that in view of the 
low frequency (ie, observed in very few animals) and minimal severity, the finding (perivascular 
inflammation) that was only recorded in the 3-month toxicity study, and had been resolved 
during the recovery period, is an incidental finding.
The pharmacokinetics of TEV-48125 in animals (rats and monkeys) is typical of a humanized 
IgG2 molecule, with low mean plasma clearance, low volume of distribution at steady state, and 
a long t½. Exposure as defined by the maximum observed plasma drug concentration (Cmax) and 
the area under the plasma concentration-time curve increased linearly across doses following 
single and repeated once-weekly dosing. No gender differences in exposure were observed in 
rats or monkeys.
Additionally, pivotal reproductive and developmental toxicity studies in rabbits and rats with 
TEV-48125 were conducted and completed. Preliminary data suggest that weekly dosing with 
TEV-48125 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.
Overall, no toxicological concerns were identified following up to 6 months of dosing to the 
experimental animals.
Further details may be found in the current Investigator’s Brochure.
1.3.2.
Clinical Studies
To date, TEV-48125 has been studied in 6 Phase 1 studies in healthy volunteers and 
2 Phase 2b studies in migraine patients. In total, 484 subjects (118 healthy volunteers and 
366 migraine patients) received at least 1 dose of TEV-48125 via iv or sc administration.
A brief summary of clinical pharmacology and clinical safety and efficacy studies of TEV-48125 
follows. Further details may be found in the current Investigator’s Brochure.
1.3.2.1.
Clinical Pharmacology Studies
A total of 118 subjects received at least 1 dose of TEV-48125 across 6 completed Phase 1 studies 
at doses ranging from 0.2 through 2000 mg. Studies included 2 single-dose-escalation 
pharmacokinetic and pharmacodynamic studies in healthy men (Studies B0141001 and 


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B0141002); a 2-cohort, placebo-controlled, cross-over study to examine the acute effects 
administration of TEV-48125 on capsaicin flare response in healthy men (Study B0141006); a 
parallel-group, repeat-dose study of TEV-48125 in healthy men and women (Study B0141007); 
a single-dose study evaluating the safety, tolerability, and pharmacokinetics of doses up to 
2000 mg administered to healthy women (Study LBR-101-008); and a single-dose study 
comparing the safety, tolerability, absolute bioavailability, and pharmacokinetics if sc and iv 
TEV-48125 in healthy men and women (Study LBR-101-011).
Based on noncompartmental analysis, TEV-48125 exposure increases with dose in an 
approximately dose-proportional manner from 225 to 900 mg following sc administration and 
over the dose range from 100 to 2000 mg following iv infusion. The Cmax occurred near the end 
of the iv infusion (median time to Cmax [tmax] of 1 to 5 hours after the start of the infusion), and 
Cmax was prolonged as indicated by the delayed tmax (median tmax 96 to 108 hours postdose) after 
sc administration. The mean t½ following sc administration was similar to that observed after iv 
administration for each dose level. The t½ ranged from approximately 642 to 770 hours 
(approximately 27 to 32 days) at the 225-mg dose level, and the t½ ranged from approximately 
1140 to 1200 hours (approximately 48 to 50 days) at the 900-mg dose level. Absolute 
bioavailability of the sc dose was approximately 55%.
TEV-48125 was well tolerated with favorable safety profile. The treatment-emergent adverse 
events reported in the Phase 1 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 
TEV-48125 has not been identified, nor has a maximally tolerated dose been identified. The 
most common treatment-emergent adverse events reported were headache, nasopharyngitis, 
gastroenteritis, and back pain. There were no deaths. One serious adverse event reported as 
“thoracic aortic aneurysm aggravated” in an individual receiving a single iv 300-mg TEV-48125 
dose resolved.
TEV-48125 does not appear to be associated with any clinically relevant patterns of change in 
vital signs (systolic and diastolic blood pressure, temperature and heart rate) or cardiac 
conduction and repolarization (P-R interval, QT interval corrected for heart rate using Bazett’s 
and Fridericia’s formulas) measured by frequent 12-lead ECGs. No changes in liver function 
tests (aspartate aminotransferase [AST], alanine aminotransferase [ALT], total bilirubin, and 
alkaline phosphatase [ALP]) or differences between TEV-48125 and placebo in hematological 
parameters, tests assessing renal function, electrolytes, or urinalysis has been observed in any of 
the Phase 1 studies.
1.3.2.2.
Clinical Safety and Efficacy Studies
The safety, tolerability, and efficacy of TEV-48125 was evaluated in migraine patients in 
2 Phase 2b studies. The first study was a multicenter, randomized, double-blind, 
placebo-controlled, parallel-group study comparing the efficacy, safety, tolerability, and 
pharmacokinetics of 2 doses of TEV-48125 with placebo in 264 patients with CM 
(Study LBR-101-021). Following a 28-day run-in period, participants were randomized and 
treated sc once monthly for 3 months. One active group received a 1st dose of 675 mg followed 
by 225 mg on the subsequent 2 months. The other active group received 900 mg per month. The 
mean change in headache hours relative to baseline for each TEV-48125 dose arm was 
significantly different from the placebo arm at 3 months (primary endpoint), and the study was 


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also positive at 2 and 1 months. Both doses were also superior to placebo for the secondary 
endpoint (decrease in the number of days with moderate or severe headache at 3 months). At the 
doses tested, TEV-48125 was well tolerated, and no serious treatment-related adverse events 
were reported. Most adverse events were mild to moderate. No safety signals were observed in 
the clinical laboratory tests, vital signs, physical examination, or ECGs.
The second study was a multicenter, randomized, double-blind, placebo-controlled, 
parallel-group study comparing the efficacy, safety, tolerability, and pharmacokinetics of 2 doses 
of TEV-48125 with placebo in 297 patients with EM (Study LBR-101-022). Following a 28-day 
run-in period, participants were randomized and treated sc once monthly for 3 months. Two 
active doses were tested, 225 mg given monthly for 3 months and 675 mg given monthly for 
3 months. The mean change in number of migraine days at month 3 relative to baseline for both 
TEV-48125 dose arms was significantly different from placebo at 3 (primary endpoint), 2, and 
1 months. Secondary and exploratory endpoints were also positive for the duration of the study. 
Both doses were well tolerated, and no serious treatment-related adverse events were reported. 
Most adverse events were mild to moderate and the lowest dose had a numerically lower number 
of adverse events relatively to placebo. No safety signals were observed in the clinical laboratory 
tests, vital signs, physical examination, or ECGs.
1.4.
Known and Potential Risks and Benefits to Human Patients 
1.4.1.
Known and Potential Risks and Benefits of TEV-48125 
Information regarding risks and benefits of TEV-48125 to human patients may be found in the 
current Investigator’s Brochure.
1.4.1.1.
Risks of TEV-48125
Identified risks (adverse drug reactions) of TEV-48125 include injection site erythema, 
administration site pain, injection site pain, injection site pruritus, injection site dermatitis, 
infusion-related reaction, and drug hypersensitivity. None of the identified risks are considered 
important risks.
Potential risks for TEV-48125 are 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.
As described in Section 1.3.2.2, sc TEV-48125 has generally been well tolerated over the ranges 
of doses evaluated (single doses of 0.02 to 2000 mg in healthy volunteers, multiple doses of 
30 to 300 mg in healthy volunteers, and multiple doses of 225 to 900 mg in migraine patients). 
The most common treatment-emergent adverse events 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.
1.4.1.2.
Benefits of TEV-48125
As described in Section 1.3.2.2, results from Phase 2 clinical studies have demonstrated 
statistically significant reductions in mean headache hours after 1, 2, and 3 months of 
TEV-48125 treatment in patients with CM and statistically significant reductions in monthly 


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migraine days after 1, 2, and 3 months of TEV-48125 treatment in patients with EM. Results for 
several secondary/exploratory endpoints also showed TEV-48125 to be superior to placebo.
1.4.2.
Overall Risk and Benefit Assessment for This Study
Based on the current safety profile and the demonstrated efficacy of the sc TEV-48125 dosage 
form, the overall risk and benefit assessment for this study is favorable.
1.5.
Selection of Drugs and Dosages
A detailed description of study drug administration is presented in Section 5.1.
1.5.1.
Justification for Dosage of Active Drug
The TEV-48125 doses and dosing regimens to be evaluated in this double-blind study were 
selected on the basis of animal pharmacodynamic and pharmacokinetic data, 
6 pharmacokinetic/safety studies in healthy volunteers, 2 safety/efficacy study in patients with 
migraine, and population pharmacokinetic and pharmacokinetic/pharmacodynamic modeling and 
simulations.
The pharmacodynamics of TEV-48125 were examined in animal models by characterization of 
the ability of TEV-48125 to block CGRP functions in vivo (see Section 1.3.1). Specifically,
neurogenic vasodilation by capsaicin application on the skin was used to induce a 
CGRP-mediated increase in vasodilatation or skin blood flow in cynomolgus monkeys. In this 
study, TEV-48125 (dosed as a single iv bolus at 1, 10, or 100 mg/kg) produced a dose-dependent 
inhibition of the capsaicin-induced skin flare response. The magnitude and duration of the 
inhibition produced by TEV-48125 were dose-dependent, with the 10 and 100 mg/kg doses 
showing inhibition out to 56 days postdose. Based on body surface area conversion, these doses 
are equivalent to single doses of approximately 225 and 2000 mg, respectively, in patients with 
migraine. Therefore, the 225-mg dose was considered to be a reasonable and pragmatic choice 
for the lowest dose with potential for effectiveness.
Based on data from the pharmacokinetic and pharmacodynamic studies in animal models and the 
pharmacokinetics, safety, and tolerability of TEV-48125 from Phase 1 studies in healthy 
volunteers, 2 dose regimens were selected for sc administration in the Phase 2b study in patients 
with EM for a treatment period of 3 months. The 2 active arms were 225 and 675 mg 
administered monthly. The results of the Phase 2b study demonstrated that both dose regimens 
are effective, safe, and well tolerated by EM patients. The mean change in number of migraine 
days relative to baseline for both TEV-48125 dose arms were significantly different from the 
placebo arm at 3 months (primary endpoint), and the study was also strikingly positive at 
2 months and 1 month. Although a maximum tolerated dose was not reached in the Phase 2b 
study, and doses up to 2000 mg were observed to be safe in healthy volunteers, it is considered 
best practice to select the lowest effective dose known for administration. Therefore, the lowest 
dose from the Phase 2b study, 225 mg TEV-48125 administered monthly, was preserved for the 
Phase 3 study in patients with EM. A 2nd active treatment group will receive TEV-48125 at 
675 mg quarterly to examine the potential for loss of efficacy within a 3-month treatment period 
following a single sc administration. In a simulation, a low dose of 225 mg once in 3 months was 
evaluated and found to be with limited efficacy. Thus, the next supported higher dose of 675 mg 
was selected for this regimen.


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1.5.2.
Justification for Use of Placebo
A placebo-controlled design is appropriate given the purpose and objectives of this clinical 
study. Inclusion of a placebo control group is consistent with Classification Committee of the 
IHS guidelines for controlled trials of drugs in migraine, 3rd edition (Tfelt-Hansen et al 2012).
1.6.
Compliance Statement
This study will be conducted in full accordance with the International Conference on 
Harmonisation (ICH) Good Clinical Practice (GCP) Consolidated Guideline (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, European Union [EU] Directive 2001/20/EC 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 studies on medicinal products 
for human use). Any episode of noncompliance will be documented.
The investigator is responsible for performing the 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 study in 
accordance with the protocol will be documented in separate study agreements with the sponsor 
and other forms as required by national 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 study and must ensure that trained personnel are immediately available in the event 
of a medical emergency. The investigator and the applicable study staff must be familiar with the 
background to, and requirements of, the study and with the properties of the study drug(s) as 
described in the Investigator’s Brochure or prescribing information.
The principal investigator at each investigational center has the overall responsibility for the 
conduct and administration of the study at that center and for contacts with study management, 
with the Independent Ethics Committee (IEC)/Institutional Review Board (IRB), and with local 
authorities.
1.7.
Population to be Studied and Justification
The study population will be composed of female and male patients, aged 18 to 70 years,
inclusive, with a history of migraine (as defined by International Classification of Headache 
Disorders, 3rd revision [ICHD-3] criteria [Classification Committee of the IHS, 2013]) for at least 
12 months prior to screening and EM prospectively documented via a review of headache data 
recorded daily during a 28-day run-in period in an electronic headache diary device.
Because headache consortium guidelines recommend preventive therapies for patients with EM 
occurring on 4 or more days per month due to the frequency of headaches and high degree of 
disability, patients using no more than 1 preventive medication at the time of study enrollment 
will be allowed to remain on the medication if the medication has at least moderate evidence of 
efficacy for migraine (Silberstein et al 2012). Patients must be on a stable dose and regimen of 
the preventive medication for at least 2 months prior to study entry (ie, before the run-in period), 
and they cannot change the dose and regimen during the study. The total number of patients 


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receiving concomitant preventive medication during the study will not exceed 30% of the total 
sample size of the study.
Episodic migraine is a highly prevalent condition and a significant cause of disability, especially 
in patients with high frequency EM. Furthermore, 3% to 6% of patients with EM evolve in any 
given year to CM, which is significantly more disabling (Scher et al 2003). Risk factors for 
evolution from EM to CM include high headache frequency and the use of specific classes of 
acute medication, including barbiturates and opiates (Bigal et al 2008).
Aside from limiting migraine-associated disability, it is expected that effective preventive 
migraine medications should decrease the likelihood that a patient with EM will evolve to CM. 
However, available preventive medications have variable response rates and are associated 
adverse effects. In addition, only 4 are approved for preventive treatment of EM (Lipton and 
Silberstein 2015, Shamiliyan et al 2013).
1.8.
Location and Timing of Study 
This study is planned to be conducted in approximately 15 countries, including North and South 
America, the European Union, and Asia Pacific, at approximately 140 centers. It is expected to 
start in in 1Q 2016 and have a duration of approximately 21 months. Additional centers will be 
added, if needed. Expected duration of the study may also be extended dependent on enrollment 
speed and other factors.


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2.
PURPOSE OF THE STUDY AND STUDY OBJECTIVES
2.1.
Purpose of the Study
The study is being conducted to evaluate the efficacy, safety, and immunogenicity of 
TEV-48125 treatment in adult patients with EM. Results of this study may contribute to the 
registration of TEV-48125 for this indication.
2.2.
Study Objectives
2.2.1.
Primary Objectives
The primary objectives of this study are as follows:

to demonstrate the efficacy 2 dose regimens of TEV-48125, as assessed by the 
decrease in the monthly average number of migraine days during 12-week period 
after the 1st dose of study drug relative to the baseline period

to evaluate the safety and tolerability of 2 dose regimens TEV-48125 in the 
preventive treatment of EM
2.2.2.
Secondary Objectives
The secondary objectives of the study are as follows:

to evaluate the proportion of patients reaching at least 50% reduction in the monthly 
average number of migraine days with TEV-48125 during the 12-week period after 
the 1st dose of study drug relative to the baseline period

to demonstrate the efficacy of TEV-48125, as assessed by the reduction in the 
monthly average number of days of use of any acute headache medications during the 
12-week period after the 1st dose of study drug relative to the baseline period

to demonstrate the efficacy of TEV-48125, as assessed by the reduction of the 
number of migraine days during the 4-week period after the 1st dose of study drug 
relative to the baseline period

to demonstrate the efficacy of TEV-48125, as assessed by the reduction in the 
monthly average number of migraine days during the 12-week period after the 
1st dose of study drug relative to the baseline period in patients not receiving 
concomitant migraine preventive medications at baseline

to demonstrate the efficacy of TEV-48125, as assessed by the reduction of 
migraine-related disability as measured by the Migraine Disability Assessment 
(MIDAS) questionnaire, at 4 weeks after the last (3rd) dose of study drug relative to 
baseline

to evaluate the immunogenicity of TEV-48125 and the impact of antidrug antibodies 
(ADAs) on efficacy and safety during 12 weeks of treatment with TEV-48125


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2.2.3.
Exploratory Objectives
The exploratory objectives of the study are as follows:

to demonstrate the efficacy of TEV-48125, as assessed by the decrease in the monthly 
average number of headache days of at least moderate severity during the 12-week 
period after the 1st dose of study drug relative to the baseline period

to evaluate the proportion of patients reaching at least 75% reduction and total 
(100%) reduction in the monthly average number of migraine days during the 
12-week period after the 1st dose of study drug

to evaluate the proportion of patients reaching at least 50% reduction and at least 75% 
reduction in the number of migraine days during the 4-week period after the 1st dose 
of study drug relative to the baseline period who sustain this level of response over 
the 12-week period after the 1st dose of study drug

to demonstrate the efficacy of TEV-48125 in patients who previously used topiramate 
for migraine, but discontinued, as assessed by the reduction of the monthly average 
number of migraine days during the 12-week period after the 1st dose of study drug 
relative to the baseline period

to demonstrate the efficacy of TEV-48125 in patients who previously used 
onabotulinumtoxinA for migraine, but discontinued, as assessed by the reduction of 
the monthly average number of migraine days during the 12-week period after the 1st
dose of study drug relative to the baseline period

to demonstrate the efficacy of TEV-48125, as assessed by the reduction of the 
number of migraine days during the 4-week period after the 2nd dose of study drug 
and the 4-week period after the last (3rd) dose of study drug relative to the baseline 
period

to demonstrate the efficacy of TEV-48125, as assessed by the reduction of the 
monthly average number of headache days of any severity during the 12-week period 
after the 1st dose of study drug relative to the baseline period

to demonstrate the efficacy of TEV-48125, as assessed by the reduction in the number 
of headache days of at least moderate severity during the 4-week period after each 
dose of study drug relative to the baseline period

to evaluate the proportion of patients reaching at least 50% reduction, at least 75% 
reduction, and total (100%) reduction in the monthly average number of headache 
days of at least moderate severity during the 12-week period after the 1st dose of study 
drug

to evaluate the proportion of patients reaching at least 50% reduction and at least 75% 
reduction in the number of headache days of at least moderate severity during the 
4-week period after the 1st dose of study drug for whom this level of effect is 
sustained throughout the 12-week period after the 1st dose of study drug

to demonstrate the efficacy of TEV-48125, as assessed by the reduction in the number 
of headache days of at least moderate severity during the 12-week period after the 


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1st dose of study drug for patients not receiving concomitant preventive migraine 
medications relative to the baseline period

to demonstrate the efficacy of TEV-48125, as assessed by the reduction in the number 
of headache days of at least moderate severity during the 12-week period after the 1st
dose of study drug for patients who used topiramate for migraine in the past relative 
to the baseline period

to demonstrate the efficacy of TEV-48125, as assessed by the reduction in the number 
of headache days of at least moderate severity during the 12-week period after the 1st
dose of study drug for patients who used onabotulinumtoxinA for migraine in the past
relative to the baseline period

to demonstrate the efficacy of TEV-48125, as assessed by the reduction in the 
monthly average number of headache hours of any severity during the 12-week 
period after the 1st dose of study drug relative to the baseline period

to demonstrate the efficacy of TEV-48125, as assessed by the reduction in the 
monthly average number of headache hours of at least moderate severity during the 
12-week period after the 1st dose of study drug relative to the baseline period

to demonstrate the efficacy of TEV-48125, as assessed by the reduction of the 
monthly average number of days of the use of migraine-specific acute headache 
medications (triptans and ergot compounds) during the 12-week period after the 
1st dose of study drug relative to the baseline period

to demonstrate the efficacy of TEV-48125, as assessed by the reduction of the 
monthly average number of days with nausea or vomiting during the 12-week period 
after the 1st dose of study drug relative to the baseline period

to demonstrate the efficacy of TEV-48125, as assessed by the reduction of the 
monthly average number of days with photophobia and phonophobia during the 
12-week period after the 1st dose of study drug relative to the baseline period

to demonstrate the efficacy of TEV-48125, as assessed by a change in quality of life 
at 4 weeks after the last (3rd) dose of study drug relative to baseline

to explore the correlation between pharmacokinetic parameters and drug efficacy

to explore the relationship between genetic polymorphisms within the CGRP 
receptor-ligand complex (eg, CALCA, CALCB, CALCRL, CRCP, and RAMP) and 
migraine-associated genes (eg, PRDM16, AJAP1, TSPAN2, MEF2D, TRPM8, 
TGFBR2, PHACTR1, FHL5, C7orf10, MMP16, ASTN2, LRP1, APOA1BP, 
TBC1D7, FUT9, STAT6, ATP5B, and MTHFR) and mode-of-action-related 
pathways versus hypertension, migraine severity, and safety and efficacy responses

to explore the relationship between biofluid bone, angiogenic, and inflammatory 
biomarkers with TEV-48125 concentrations and efficacy responses


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2.3.
Study Endpoints
2.3.1.
Primary Efficacy Endpoint
The primary efficacy endpoint is the mean change from baseline (28-day run-in period) in the 
monthly average number of migraine days during the 12-week period after the 1st dose of study
drug.
2.3.2.
Secondary Efficacy Endpoints
The secondary efficacy endpoints are as follows:

proportion of patients reaching at least 50% reduction in the monthly average number 
of migraine days during the 12-week period after the 1st dose of study drug

mean change from baseline (28-day run-in period) in the monthly average number of 
days of use of any acute headache medications during the 12-week period after the 
1st dose of study drug 

mean change from baseline (28-day run-in period) in the number of migraine days 
during the 4-week period after the 1st dose of the study drug

mean change from baseline (28-day run-in period) in the monthly average number of 
migraine days during the 12-week period after the 1st dose of study drug in patients 
not receiving concomitant migraine preventive medications 

mean change from baseline (day 0) in disability score, as measured by the MIDAS 
questionnaire, at 4 weeks after administration of the last (3rd) dose of study drug
2.3.3.
Exploratory Efficacy Endpoints
The exploratory efficacy endpoints are as follows:

mean change from baseline (28-day run-in period) in the number of headache days of 
at least moderate severity during the 12-week period after the 1st dose of study drug

proportion of patients reaching at least 75% reduction and total (100%) reduction in 
the monthly average number of migraine days during the 12-week period after the 
1st dose of study drug

proportion of patients reaching at least 50% reduction and at least 75% reduction in 
the number of migraine days during the 4-week period after the 1st dose of study drug 
for whom this level of effect is sustained throughout the 12-week period after the 1st
dose of study drug

mean change from baseline (28-day run-in period) in the monthly average number of 
migraine days during the 12-week period after the 1st dose of study drug in patients 
who used topiramate for migraine in the past

mean change from baseline (28-day run-in period) in the number of migraine days 
during the 12-week period after the 1st dose of study drug for patients who used 
onabotulinumtoxinA for migraine in the past


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
mean change from baseline (28-day run-in period) in the number of migraine days 
during the 4-week period after the 2nd dose of the study drug

mean change from baseline (28-day run-in period) in the number of migraine days 
during the 4-week period after the last (3rd) dose of the study drug

mean change from baseline (28-day run-in period) in the monthly average number of 
headache days of any severity during the 12-week period after the 1st dose of study 
drug

mean change from baseline (28-day run-in period) in the number of headache days of 
at least moderate severity during the 4-week period after each dose of study drug

proportion of patients reaching at least 50% reduction, at least 75% reduction, and 
total (100%) reduction in the monthly average number of headache days of at least 
moderate severity during the 12-week period after the 1st dose of study drug

proportion of patients reaching at least 50% reduction and at least 75% reduction in 
the number of headache days of at least moderate severity during the 4-week period 
after the 1st dose of study drug for whom this level of effect is sustained throughout 
the 12-week period after the 1st dose of study drug

mean change from baseline (28-day run-in period) in the number of headache days of 
at least moderate severity during the 12-week period after the 1st dose of study drug 
for patients not receiving concomitant preventive migraine medications

mean change from baseline (28-day run-in period) in the number of headache days of 
at least moderate severity during the 12-week period after the 1st dose of study drug 
for patients who used topiramate for migraine in the past

mean change from baseline (28-day run-in period) in the number of headache days of 
at least moderate severity during the 12-week period after the 1st dose of study drug 
for patients who used onabotulinumtoxinA for migraine in the past

mean change from baseline (28-day run-in period) in the monthly average number of 
headache hours of any severity during the 12-week period after the 1st dose of study 
drug

mean change from baseline (28-day run-in period) in the monthly average number of 
headache hours of at least moderate severity during the 12-week period after the 
1st dose of study drug

mean change from baseline (28-day run-in period) in the monthly average number of 
days of use of migraine-specific acute headache medications (triptans and ergot 
compounds) during the 12-week period after the 1st dose of study drug

mean change from baseline (28-day run-in period) in the monthly average number of 
days with nausea or vomiting during the 12-week period after the 1st dose of study 
drug

mean change from baseline (28-day run-in period) in the monthly average number of 
days with photophobia and phonophobia during the 12-week period after the 1st dose 
of study drug


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
mean change from baseline (day 0) in quality of life, as measured by the 
Migraine-Specific Quality of Life (MSQOL) questionnaire, at 4 weeks after 
administration of the last (3rd) dose of study drug

mean change from baseline (day 0) in the health status, as measured by the EuroQol-5 
Dimension, 5 response level version (EQ-5D-5L) questionnaire at 4 weeks after 
administration of the last (3rd) dose of study drug

mean change from baseline (day 0) in patient depression status, as measured by the 
2-item Patient Health Questionnaire (PHQ-2) and 9-item Patient Health 
Questionnaire (PHQ-9), at 4 weeks after administration of the last (3rd) dose of study 
drug

mean change from baseline (day 0) in patient work productivity and activity 
impairment, as measured by the Work Productivity and Activity Impairment (WPAI)
questionnaire, at 4 weeks after administration of the last (3rd) dose of study drug

assessment of patient satisfaction, as measured by the Patient Global Impression of 
Change (PGIC) scale, at 4 weeks after administration of the 1st dose of study drug, at 
4 weeks after the 2nd dose of study drug, and at 4 weeks after the last (3rd) dose of 
study drug
2.3.4.
Safety and Tolerability Endpoints
The safety and tolerability endpoints for this study are as follows:

occurrence of adverse events throughout the study

abnormal standard 12-lead ECG findings

changes from baseline in vital signs (systolic and diastolic blood pressure, pulse, 
temperature, and respiratory rate) measurements 

changes from baseline in clinical laboratory (serum chemistry, hematology,
coagulation, and urinalysis) test results

abnormal physical examination findings

abnormal local injection site tolerability findings (ie, erythema, induration, 
ecchymosis) and occurrence of injection site pain

suicidal ideation and behavior as suggested by the electronic Columbia-Suicide 
Severity Scale (eC-SSRS)
2.3.5.
Pharmacokinetic/Immunogenicity/Biomarker Endpoints
2.3.5.1.
Pharmacokinetic Endpoints
There are no prespecified pharmacokinetic endpoints.
2.3.5.2.
Immunogenicity Endpoint
There are no prespecified immunogenicity endpoints.


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2.3.5.3.
Biomarker Endpoints
The biomarker endpoints are as follows:

exploratory correlation of specific genetic polymorphisms and headache response, 
specific migraine clinical features, and adverse events to medication

mean change from baseline in exploratory biofluid biomarkers versus treatment, 
migraine onset/severity, and response status (ie, responders versus nonresponders)

correlation of exploratory biofluid biomarkers with TEV-48125 concentrations


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3.
STUDY DESIGN
3.1.
General Design and Study Schema
This is a 16-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group 
study to compare the safety, tolerability, and efficacy of 2 dose regimens of sc TEV-48125 and 
placebo in adults with EM. The study consists of a screening visit, a 28-day run-in period, and a 
12-week (84-day) treatment period, including a final evaluation at week 12 (end-of-treatment 
[EOT] visit, approximately 4 weeks [28 days] after the final dose of study drug).
The study population will be composed of female and male patients, aged 18 to 70 years, 
inclusive, with a history of migraine (as defined by ICHD-3 criteria [Classification Committee of 
the IHS, 2013]) for at least 12 months prior to screening and EM prospectively documented via a 
review of headache data recorded daily during a 28-day run-in period in an electronic headache 
diary device.
Patients using no more than 1 preventive medication at the time of study enrollment will be 
allowed to remain on the medication if the medication has at least moderate evidence of efficacy 
for migraine (Silberstein et al 2012). Patients should not be using concomitant preventive 
migraine medications (presented in Appendix B) at the time of the screening visit, and will not 
be allowed to initiate these medications after study start. A small subgroup of patients 
(approximately 30%) will be allowed to use concomitant migraine preventive medications 
(presented in Appendix A), and no changes in these medications will be allowed until the last
study assessments are complete. Patients will be allowed to use acute medications to treat acute 
migraine attacks as needed.
After completing the informed consent process (screening visit [visit 1]), patients will be 
screened for eligibility. Eligible patients will enter a 28-day run-in period. Headache information 
will be captured daily throughout study participation using the electronic headache diary device. 
After completing the run-in period, patients will be asked to return to the study center on day 0 
(visit 2). Patients who have confirmed EM with headache of any type on 6 to 14 days and 
migraine on at least 4 days and meet all other eligibility criteria (including electronic headache 
diary compliance criteria during the 28-day run-in period) will be randomly assigned in a 
1:1:1 ratio to 1 of 3 treatment groups:

monthly sc administration of TEV-48125 at 225 mg

sc administration of 675 mg of TEV-48125 at visit 2 followed by monthly sc placebo

monthly sc administration of placebo
(Note: For this study, monthly dosing refers to dosing approximately every 4 weeks [28 days].)
Randomization will be performed using electronic interactive response technology (IRT). 
Patients will be stratified based on gender, country, and baseline preventive migraine medication 
use (yes, no) to ensure balance for the covariates (treatment group, preventive migraine
medication use, country, and gender). The total number of patients receiving concomitant 
preventive medication during the study will not exceed 30% of the total sample size of the study.


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Blinded treatment will be administered sc once monthly (ie, approximately every 4 weeks) for a 
total of 3 doses. First treatment administration will occur at visit 2 (day 0), and additional doses 
will be administered at visits 3 and 4. Final study assessments will be performed at visit 5 (EOT 
visit), approximately 4 weeks after administration of the 3rd and final dose of study drug.
Headache information will be captured daily during the entire study using an electronic headache 
diary device. Assessments of migraine-related disability and change in quality of life (using the 
MIDAS questionnaire, PHQ-2/PHQ-9, MSQOL questionnaire, EQ-5D-5L questionnaire, and 
PGIC scale, and WPAI questionnaire); safety evaluations; blood draws for pharmacokinetic, 
immunogenicity, and biomarker analysis; and urine sampling for biomarker analysis will be 
performed throughout the study according to the schedule of assessments (Table 1). In addition, 
patients who consent to pharmacogenomic assessment will provide a blood sample for testing.
Upon completion of the final study assessments patients who complete all scheduled visits may 
be eligible to enter a long-term safety and efficacy study (Study TV48125-CNS-30051), 
consisting of a 12-month double-blind treatment period and a 6.5-month follow-up period. 
Patients receiving active study drug in the current study will continue receiving the same 
treatment (ie, monthly sc TEV-48125 at 225 mg or quarterly sc TEV-48125 at 675 mg), and 
patients receiving placebo in the current study will be randomized in a 1:1 ratio to receive 
monthly sc TEV-48125 at 225 mg or quarterly sc TEV-48125 at 675 mg during the long-term 
safety and efficacy study. This long-term safety and efficacy study is beyond the scope of this 
protocol. A separate protocol will be issued. Patients who withdraw from the study before 
completing the 12-week evaluation period will have EOT visit (visit 5) procedures and 
assessments performed on the last day they receive the study drug or as soon as possible 
thereafter. Those patients who do not enter the long-term safety and efficacy study for any reason 
will be offered to enter the long term safety extension for the purpose of evaluating ADA 
approximately 7.5 months (225 days [the approximate equivalent of 5 half-lives]) after 
administration of the last (3rd) dose of study drug in this study.
The assessments and procedures performed during each study visit are detailed in Table 1 and 
Section 3.14. The study schema is presented in Figure 1.
The end of the study is defined as the date the last patient attends the EOT/early withdrawal visit 
(visit 5).
A total of 768 patients are planned to be randomized in a 1:1:1 ratio (256 patients per treatment 
group) to receive 3 monthly sc doses of TEV-48125 at 225 mg, 1 monthly sc dose of TEV-48125 
at 675 mg followed by 2 monthly sc doses of matching placebo, or 3 monthly sc doses of 
matching placebo.


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Figure 1:
Overall Study Schema
PBO=placebo; V=visit.
Note: Baseline refers to the 28-day run-in period for headache variables and visit 2 (day 0) for all other variables.
3.2.
Justification for Study Design
A randomized, double-blind, placebo-controlled, parallel-group design is appropriate given the 
objectives of this study. Furthermore, this design is consistent with the recommendations of the 
Classification Committee of the IHS for controlled trials of preventive drugs in migraine (Tfelt-
Hansen et al 2012).
The dose planned for administration at visit 2 (1st dose) for patients randomized to receive 
TEV-48125 at 675 mg followed by monthly sc placebo requires administration of 3 × 1.5-mL 
injections. In order to blind the treatment arms based on both dose-volume and number of 
injections, each patient will receive three 1.5-mL sc injections at visit 2: three 1.5-mL sc 
injections of active drug, one 1.5-mL sc injection of active drug and two 1.5-mL injections of 
placebo, or three 1.5-mL injections of placebo. Each patient will receive a single 1.5-mL sc 
injection of active drug (225 mg) or placebo at visits 3 and 4 according to their randomized 
treatment.


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3.3.
Primary and Secondary Efficacy Measures and Time Points
A description of the efficacy measures is provided in Section 6.
3.3.1.
Primary Efficacy Measure and Time Points
The primary efficacy endpoint for this study will be derived from headache data (ie, occurrence 
of headache, duration of headache, maximum severity of headache, and acute migraine-specific 
medication use) collected daily using an electronic headache diary device. 
Eligible patients will receive training on the use of the electronic headache diary device and will 
be informed of compliance requirements at screening. Patients will complete electronic headache 
diary entries with questions about the previous day beginning on day -27 (the day after the 
screening visit) through the EOT/early withdrawal visit. The electronic headache diary device 
will allow entry of headache information for up to 48 hours after a given day.
3.3.2.
Secondary Efficacy Measure and Time Points
The secondary efficacy endpoints will be derived from headache data (ie, occurrence of 
headache, duration of headache, maximum severity of headache, and acute migraine-specific 
medication use) collected daily using an electronic headache diary device. In addition, 
migraine-related disability will be assessed using the MIDAS questionnaire, completed at time 
points specified in Table 1.
3.4.
Safety and Tolerability Measures and Time Points
Safety and tolerability will be assessed at time points specified in Table 1 using the following 
measures:

inquiries about adverse events

inquiries about concomitant medication usage

safety laboratory tests (serum chemistry, hematology, coagulation, and urinalysis)

serum/urine beta-human chorionic gonadotropin (β-HCG) test (women of 
childbearing potential only)

12-lead ECGs

vital signs measurements (systolic and diastolic blood pressure, pulse, temperature, 
and respiratory rate)

physical examinations, including body weight

injection site reaction (ie, erythema, induration, ecchymosis, and pain) assessments

eC-SSRS
A description of the safety measures is provided in Section 7.


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3.5.
Pharmacokinetic, Biomarker, and Immunogenicity Measures and 
Time Points
A description of the pharmacokinetic, biomarker, and immunogenicity measures is provided in 
Section 8.
3.5.1.
Pharmacokinetic Measures and Time Points
Blood samples for pharmacokinetics analysis of TEV-48125 will be collected from all patients at 
time points specified in Table 1 for the purpose of pharmacokinetic/pharmacodynamic 
relationship assessment. The pharmacodynamic parameters will be the efficacy responses.
The actual date and time of each blood sample, as well as the date and time of the last study drug 
dose prior to the sample, will be recorded in the case report form (CRF).
TEV-48125 plasma concentration will be measured using a validated assay.
3.5.2.
Immunogenicity Measures and Time Points
Blood samples for immunogenicity analysis will be collected at time points specified in Table 1.
3.5.3.
Biomarker Measures and Time Points
Biomarker blood and urine samples will be collected from all patients at time points specified in 
Table 1, and a blood sample will be collected from patients who consent to pharmacogenomic 
analysis at visit 2 or any visit thereafter.
3.6.
Exploratory/Other Efficacy Measures and Time Points
The following exploratory efficacy measures will be assessed at time points specified in Table 1:

exploratory efficacy endpoints derived from headache data (ie, occurrence of 
headache, duration of headache, maximum severity of headache, and acute 
migraine-specific medication use), which are collected daily using an electronic 
headache diary device

PHQ-2/PHQ-9 (Note: Patients will first respond to the PHQ-2. They will respond to 
questions 3 through 9 [unique questions] of the PHQ-9 only if the PHQ-2 is positive.)

MSQOL questionnaire

EQ-5D-5L questionnaire

PGIC scale completed

WPAI questionnaire
3.7.
Randomization and Blinding
The sponsor, investigators, study staff (except for staff involved in bioanalytical analyses), and 
patients will be blinded to treatment assignment. A computer-generated master randomization 
list will be provided to drug packaging facilities. Packaging vendor(s) will package active drug
and placebo into single-visit kits according to Good Manufacturing Practice procedures. Kits will 
be identical in appearance and contain 1 prefilled syringe with active drug or placebo. Adequate 


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kit supply for upcoming study visits will be managed by IRT and kept (refrigerated at 2°C to 
8°C) on site.
This is a randomized study with stratification based on gender, country, and baseline preventive 
medication use (yes, no). Each patient will undergo randomization in a 1:1:1 ratio within the 
stratum to which he or she belongs to receive 1 of the 2 TEV-48125 dose regimens or placebo, as 
assigned by the IRT. The IRT will manage initial drug supply, maintenance of adequate study 
drug supplies on site, and study randomization centrally. At the time of each study visit, the IRT 
will be queried, and site personnel will retrieve and administer a 1.5-mL volume from each 
syringe contained in the appropriately numbered kit(s).
3.8.
Maintenance of Randomization and Blinding
3.8.1.
Randomization
Patient randomization codes will be maintained in a secure location within Teva Global 
Biometrics or in a secure location with the vendor contracted to create the list. At the time of 
analysis, when treatment codes are needed, the Teva statistician assigned to the study will make 
a request to unblind and will receive the unblinded codes.
3.8.2.
Blinding/Unblinding
Pharmacokinetic data may be assessed during the study. Personnel responsible for bioanalysis 
will be provided with the randomization code in order to facilitate the analysis. However, the 
personnel responsible for bioanalysis 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 an individual patient’s concentration 
data).
For information about personnel who may be aware of treatment assignments, see Section 3.7. 
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 or pregnancy, or in cases when knowledge of the study drug 
assignment is needed to make treatment decisions, the investigator may unblind the patient’s 
drug assignment as deemed necessary, mainly in emergency situations. Individual treatment 
codes, indicating the treatment randomization for each randomized patient, will be available to 
the investigator(s) and/or pharmacist(s) at the study center via the IRT, both via telephone and 
internet. If possible, the sponsor should be notified of the event prior to breaking of the code. If 
this is not possible, the sponsor should be notified immediately afterwards, and the patient’s drug 
code assignment should not be revealed. Breaking of the treatment code can always be 
performed by the site without prior approval by the sponsor.
When a blind is broken, the patient will be withdrawn from the study, and the event will be 
recorded 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 adverse events that are defined as: 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 revealed (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, analysis, and reporting of the data.
3.8.3.
Data Monitoring Committee
This is not applicable.
3.9.
Drugs Used in the Study
A description of administration procedures is given in Section 5.1. Additional details may also be 
found in the current version of the Investigator’s Brochure for TEV-48125.
3.9.1.
Investigational Product
TEV-48125 will be provided as a sterile, unpreserved, colorless to slightly yellow, aqueous 
solution for injection, supplied in a 2.25-mL prefilled syringe for single-use administration, 
containing 150 mg/mL in 16±2.5 mM L-histidine, 0.2-mg/mL polysorbate 80, 84-mg/mL 
sucrose, and 0.136-mg/mL ethylenediaminetetraacetic acid (EDTA).
TEV-48125 will be administered sc at a dose of 225 mg at visit 2 (for patients randomized to 
both TEV-48125 dosing regimens), and TEV-48125 will be administered sc at a dose of 225 mg 
at visits 3 and 4 (for patients randomized to the monthly TEV-48125 at 225 mg dosing regimen). 
Each dose will be separated by approximately 28 days. A more detailed description of 
administration procedures is given in Section 5.1.
3.9.2.
Placebo
Placebo will be provided as a sterile solution of 16±2.5 mM L-histidine, 0.2-mg/mL 
polysorbate 80, 84-mg/mL sucrose, and 0.136-mg/mL EDTA, presented as 2.25 mL per syringe.
Placebo will be administered sc at visits 2, 3, and 4 (for patients randomized to the placebo 
treatment group) or visits 3 and 4 (for patients randomized to the TEV-48125 
675 mg/placebo/placebo dosing regimen). A more detailed description of administration 
procedures is given in Section 5.1.
3.10.
Drug Supply and Accountability
3.10.1.
Drug Storage and Security
The study drug (TEV-48125 and placebo) must be stored refrigerated at 2°C to 8°C (36°F to 
46°F), protected from light; the site should have a process for monitoring the drug storage 
temperature. TEV-48125 and placebo supplies must be kept in a secure area (eg, locked 
refrigerator). 
3.10.2.
Drug Accountability
Each study drug shipment will include a packing slip listing the contents of the shipment, drug 
return instructions, and any applicable forms.


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Each investigator is responsible for ensuring that deliveries of study drug and other study 
materials from Teva are correctly received, recorded, handled, stored, accounted for, and used in 
accordance with this protocol. In addition, each investigator is responsible for ensuring that study 
drug and other materials from Teva are correctly, safely, and properly disposed of in accordance 
with local regulations.
A record of study drug accountability (ie, study drug and other 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.
3.11.
Duration of Patient Participation and Justification
This study will consist of a screening visit, a 28-day run-in period, and a 12-week (84-day) 
double-blind treatment period. Patients are expected to participate in this study for approximately 
16 weeks. Patients completing this study may enroll in the double-blind, long-term safety and 
efficacy study (Study TV48125-CNS-30051). Those patients who do not enter the long-term 
safety and efficacy study for any reason will be offered to enter the long-term safety extension 
for the purpose of evaluating ADA approximately 7.5 months (225 days) after administration of 
the last (3rd) dose of study drug in this study. Thus, patient participation for these patients will 
last approximately 10.5 months.
See Section 12.4 for the definition of the end of the study.
The durations of the run-in and double-blind treatment periods align with Classification 
Committee of the IHS guidelines for controlled trials for the preventive treatment of migraine 
(Tfelt-Hansen et al 2012).
Patients who do not enroll in the long-term safety and efficacy study for any reason but who 
enter the long-term safety extension for the purpose of evaluating ADA will return 
approximately 7.5 months (225 days, the approximate equivalent of 5 half-lives) after the last 
dose of study drug. This is consistent with the 2009 FDA Guidance for Industry on Assay 
Development for Immunogenicity Testing of Therapeutic Proteins; a complete washout of the 
drug from the circulating blood is expected after approximately 7.5 months (≥5 half-lives), 
allowing a more precise evaluation of ADA.
3.12.
Stopping Rules and Discontinuation Criteria
There are no formal rules for early termination of this study. During the conduct of the study, 
serious adverse events will be reviewed (see Section 7.1.5) as they are reported from the 
investigational center to identify safety concerns. The study may be terminated by the sponsor at 
any time.
A patient may discontinue participation in the study at any time for any reason (eg, lack of 
efficacy, consent withdrawn, and adverse event). The investigator and/or sponsor can withdraw a 
patient from the study at any time for any reason (eg, protocol violation or deviation as defined 
in Section 11.1.2, noncompliance, or adverse event). In addition, patients with abnormal hepatic 
laboratory values (eg, ALT, AST, ALP, gamma-glutamyl transpeptidase [GGT], total bilirubin, 
or international normalized ratio [INR]) may meet criteria for discontinuation from the study 
drug as summarized in Appendix E.


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3.13.
Source Data Recorded on the Case Report Form
All patient data must have supportive original source documentation in the medical records, or 
equivalent, before they are transcribed onto the CRF. Data may not be recorded directly onto the 
CRF and considered as source data unless the sponsor provides written instructions specifying 
which data are permitted to be recorded directly onto the CRF.
Source data, including test results and/or assessments (eg, clinical laboratory, central ECG 
evaluation center, and electronic headache diary data) collected by other institutions outside of 
the study center, are sent to the investigational center where they are retained, but not entered 
into the CRF unless otherwise noted in the protocol. These data may also be sent electronically 
to the sponsor (or organization performing data management) for direct entry into the clinical 
database (see Section 13.1). All data from other institutions will be available to the investigator.
The CRFs are filed in the sponsor’s central file.
3.14.
Study Procedures
Study procedures and assessments with their timing are summarized in Table 1. Detailed by-visit 
information is provided in the sections following the table. Detailed descriptions of each 
assessment are provided in Section 6 (efficacy assessments), Section 6.2 (safety assessments), 
and Section 8 (pharmacokinetic and other assessments).


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Table 1:
Study Procedures and Assessments
Study period
Pretreatment 
period (incl. 
screening visit 
and run-in 
period)
Double-blind treatment period
Visit number
V1
V2
V3
V4
V5
Month number
Month -1
Month 0
Month 1
Month 2
Month 3
Procedures and assessments (completed before dosing, when applicable,
unless otherwise noted)
Screening
days -28 to -1
Baseline 
dose 1
day 0
(+3 days)
Dose 2
day 28 
(±3 days)
Dose 3
day 56 
(±3 days)
EOT or early 
withdrawal
day 84 
(±3 days)
Informed consent
X
Medical and psychiatric history
X
Prior medication history
X
Record demographic characteristics
X
Inclusion and exclusion criteria
X
X
Randomization
X
Physical examination, including weight and heighta
X
X
X
Triplicate 12-lead ECGb,c
X
X
X
Vital signs measurementb
X
X
X
X
X
Adverse eventsd
X
X
X
X
X
Concomitant medication inquiry
X
X
X
X
X
Clinical laboratory testse
X
X
X
X
X
Serum β-HCG testf
X
Urine β-HCG testf
X
X
X
X
FSHg
X


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Study period
Pretreatment 
period (incl. 
screening visit 
and run-in 
period)
Double-blind treatment period
Visit number
V1
V2
V3
V4
V5
Month number
Month -1
Month 0
Month 1
Month 2
Month 3
Procedures and assessments (completed before dosing, when applicable,
unless otherwise noted)
Screening
days -28 to -1
Baseline 
dose 1
day 0
(+3 days)
Dose 2
day 28 
(±3 days)
Dose 3
day 56 
(±3 days)
EOT or early 
withdrawal
day 84 
(±3 days)
Provide electronic headache diaryh
X
Complete electronic headache diary entriesi
X
X
Review electronic headache diary
X
X
X
X
Return headache diary device
X
Blood samples for plasma drug concentrationj
X
X
X
X
Blood samples for serum ADA assessmentk
X
X
X
Blood sample for pharmacogenomic analysisl
X
Blood collection for serum, plasma, and RNA biomarker analysis
X
X
X
Urine collection for biomarker analysis
X
X
X
MIDAS questionnaire
X
X
PHQ-2/PHQ-9m
X
X
MSQOL questionnaire
X
X
X
X
EQ-5D-5L questionnaire
X
X
PGIC scale
X
X
X
WPAI questionnaire
X
X


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Study period
Pretreatment 
period (incl. 
screening visit
and run-in 
period)
Double-blind treatment period
Visit number
V1
V2
V3
V4
V5
Month number
Month -1
Month 0
Month 1
Month 2
Month 3
Procedures and assessments (completed before dosing, when applicable,
unless otherwise noted)
Screening
days -28 to -1
Baseline 
dose 1
day 0
(+3 days)
Dose 2
day 28 
(±3 days)
Dose 3
day 56 
(±3 days)
EOT or early 
withdrawal
day 84 
(±3 days)
eC-SSRSn
X
X
X
X
Administration of study drug
X
X
X
Injection site assessmentso
X
X
X
Review eligibility for long-term safety study (TV48125-CNS-30051)
X
a Height will only be obtained at screening. 
b Procedure will be performed before other assessments (eg, blood draws and administration of questionnaires).
c Electrocardiograms will be performed in triplicate.
d Inquiries about adverse events will be made before and after study drug administration. Postdose inquiries will be made before the patient leaves the study center.
e Serum chemistry, hematology, coagulation, and urinalysis.
f Women of childbearing potential only.
g Postmenopausal women only.
h Eligible patients will be given an electronic headache diary device and will be trained in its use and compliance requirements on the day of screening.
i Patients will complete electronic headache diary entries about the previous day daily beginning on day -27 through the EOT/early withdrawal visit.
j Blood samples for plasma drug concentration determination will be collected prior to dosing at visits 2, 3, and 4.
k Blood samples for serum ADA assessment will also be collected upon observation of any severe hypersensitivity reaction (eg, anaphylaxis).
l A single blood sample for pharmacogenomic analysis will be collected at visit 2 or any visit thereafter from patients who consent to this procedure. A separate informed consent 
form for pharmacogenomic sampling must be signed by the patient.
m Patients will respond first to the PHQ-2. They will respond to questions 3 through 9 (unique questions) of the PHQ-9 only if PHQ-2 is positive.
n The eC-SSRS Baseline/Screening version will be completed at visit 2, and the eC-SSRS Since Last Visit version will be completed at all other visits.
o Injection sites will be assessed for erythema, induration, ecchymosis, and pain immediately and 1 hour after study drug administration. 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 study drug administration, the patient 
will be reassessed 3 hours after study drug administration and hourly thereafter until the reaction/pain is of moderate or less severity.
ADA=antidrug antibody; β-HCG=beta-human chorionic gonadotropin; ECG=electrocardiogram; eC-SSRS=electronic Columbia-Suicide Severity Rating Scale; EOT=end of 
treatment; EQ-5D-5L=EuroQol-5 Dimension, 5 response level version; FSH=follicle-stimulating hormone; MIDAS=Migraine Disability Assessment; MSQOL=Migraine-Specific 
Quality of Life; PGIC=Patient Global Impression of Change; PHQ-2=2-item Patient Health Questionnaire; PHQ-9=9-item Patient Health Questionnaire; V=visit; WPAI=Work 
Performance and Activity Impairment.


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3.14.1.
Procedures for Screening (Visit 1[Day –28])
A signed and dated informed consent form will be obtained before screening procedures 
commence (see Section 12.1). Evaluations obtained as part of routine medical care and 
performed during the screening period may be used in place of the protocol-specific evaluations. 
In addition, disease-specific assessments performed within a specified time frame before 
informed consent may be used for the study. Patients will acknowledge and agree to the possible 
use of this information for the study by giving informed consent.
After informed consent is obtained, patients who are screened will be assigned an 8-digit 
identification number such that all patients from each country are given consecutive 
identification numbers in successive order of inclusion. The first 2 digits of the screening number 
will be the number assigned to the country where the investigational center is located, the next 
3 digits will be the investigational center number, and the last 3 digits will be the patient number 
assigned at the investigator center (eg, the 3rd patient screened in the US [country 01] at 
center 101 would be assigned the number of 01101003). The screening number is the permanent 
number assigned to the patient for the duration of study.
After confirmation of study eligibility, patients will be screen failed or randomized into 
Study TV48125-CNS-30049 (ie, patients with CM) or the current study (ie, patients with EM).
For randomized patients, an enrollment number will be assigned consisting of the 8-digit 
screening number and the last 2 digits of the assigned protocol (ie, 49 for Study TV48125-CNS-
30049 or 50 for the current study; in the example above, the enrollment number would be 
01101003-50 for this study).
A patient who is screened and does not meet study entry criteria will not be considered for 
screening again.
The screening visit (visit 1) will take place approximately 28 days before the baseline visit. The 
following procedures will be performed at visit 1:

Obtain written informed consent before any other study-related procedures are 
performed.

Record demographic characteristic including race.

Review inclusion/exclusion criteria.

Review medical and psychiatric history.

Review medication history.

Perform vital signs measurements (includes systolic and diastolic blood pressure, 
pulse, body temperature, and respiratory rate).

Perform triplicate 12-lead ECGs.

Perform a physical examination, including height and weight. Body mass index will 
be calculated from the screening height and weight.

Perform clinical laboratory tests (serum chemistry, hematology, coagulation, and 
urinalysis).


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
Perform serum β-HCG test (women of childbearing potential only).

Perform FSH test (postmenopausal women only).
Patients who meet inclusion/exclusion criteria will be given an electronic headache diary device 
and trained on its use and compliance requirements.
3.14.2.
Procedures Before Study Drug Treatment 
3.14.2.1.
28-Day Run-In Period (Days –28 Through –1)
Patients will complete electronic headache diary entries daily beginning on day –27. Patients will 
enter headache information (ie, occurrence of headache, duration of headache, maximum 
severity of headache, and acute migraine-specific medication use) about the previous day into the 
electronic headache diary device. Refer to Section 6.1 for additional details.
3.14.2.2.
Baseline (Visit 2 [Day 0 (±3 Days)])
Patients who meet the inclusion/exclusion criteria at visit 1 will continue to visit 2, when 
baseline evaluations will be conducted.
The following procedures will be performed at visit 2 before study drug administration:

Review inclusion/exclusion criteria.

Review headache diary.

Review study compliance.

Perform vital signs measurements (includes systolic and diastolic blood pressure, 
pulse, body temperature, and respiratory rate).

Perform triplicate 12-lead ECGs.

Perform a physical examination (including weight).

Inquire about adverse events.

Inquire about/review concomitant medications.

Perform clinical laboratory tests (serum chemistry, hematology, coagulation, and 
urinalysis).

Perform urine β-HCG test (women of childbearing potential only).

Obtain a 4-mL blood sample for plasma TEV-48125 concentration determination.

Obtain a 5-mL blood sample for serum ADA assessment.

Obtain a 5-mL urine sample for biomarker analysis.

Obtain an 18.5-mL blood sample (6 mL each for serum and plasma and 6.5 mL for 
ribonucleic acid [RNA]) for serum, plasma, and RNA biomarker analysis.

Complete the eC-SSRS Baseline/Screening version.


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
Administer the MIDAS questionnaire, MSQOL questionnaire, EQ-5D-5L
questionnaire, WPAI questionnaire, and PHQ-2/PHQ-9 (Note: Patients will respond 
first to the PHQ-2. They will respond to questions 3 through 9 [unique questions] of
the PHQ-9 only if the PHQ-2 is positive.)
In addition, a 6-mL blood sample for pharmacogenomics (deoxyribonucleic acid [DNA]) may be 
obtained from patients who consent to pharmacogenomics analysis.
A patient who does not meet study entry criteria on the basis of results of baseline assessments 
and is not randomized in the study will not be considered for screening again.
Patients who continue to meet the inclusion/exclusion criteria will be assigned a permanent 
unique randomization number generated by the IRT. This assigned number will be entered into 
the CRF.
3.14.3.
Procedures During Study Drug Treatment
3.14.3.1.
Double-Blind Treatment Period (Visits 2 Through 5 [Day 0 Through Day 84 
±3 Days])
Each day during the double-blind treatment period, patients will enter headache information 
(ie, occurrence of headache, duration of headache, maximum severity of headache, and acute 
migraine-specific medication use) about the previous day into the electronic headache diary
device. Refer to Section 6.1 for additional details.
3.14.3.1.1. Visit 2 (Day 0 [± 3 Days]/Dose 1)
Patients will receive a single sc TEV-48125 at 675 or 225 mg or sc placebo after completing 
baseline procedures/assessments. The following procedures/assessments will be performed after 
dosing:

Perform local injection site assessment immediately and 1 hour after study drug 
administration. Additional assessments may be performed based on the severity of 
any observed injection site reaction. See Section 7.9 for additional details.

Inquire about postdose adverse events before the patient leaves the study center.
3.14.3.1.2. Visits 3 and 4 (Day 28 [±3 Days]/Dose 2 and Day 56 [±3 Days]/Dose 3)
The following procedures/assessments will be performed before study drug administration at 
visits 3 and 4:

Review headache diary.

Review study compliance.

Perform vital signs measurements (includes systolic and diastolic blood pressure, 
pulse, body temperature, and respiratory rate).

Inquire about adverse events.

Inquire about/review concomitant medications.


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
Perform clinical laboratory tests (serum chemistry, hematology, coagulation, and 
urinalysis).

Perform urine β-HCG test (women of childbearing potential only).

Obtain a 4-mL blood sample for plasma TEV-48125 concentration determination.

Obtain a 5-mL blood sample for serum ADA assessment (visit 3 only).

Obtain a 5-mL urine sample for biomarker analysis (visit 4 only).

Obtain an 18.5-mL blood sample (6 mL each for serum and plasma and 6.5 mL for 
RNA) for serum, plasma, and RNA biomarker analysis (visit 4 only).

Complete the eC-SSRS Since Last Visit version.

Administer the MSQOL questionnaire and the PGIC scale.
In addition, a single 6-mL blood sample for pharmacogenomics (DNA) may be obtained from 
patients who consent to pharmacogenomics analysis at visit 3 or visit 4 if the sample is not 
obtained at visit 2.
Patients will receive a sc TEV-48125 at 225 mg or sc placebo after completing predose 
procedures/assessments. The following procedures/assessments will be performed after dosing:

Perform local injection site assessment immediately and 1 hour after study drug 
administration. Additional assessments may be performed based on the severity of 
any observed injection site reaction. See Section 7.9 for additional details.

Inquire about postdose adverse events before the patient leaves the study center.
3.14.3.1.3. End-of-Treatment Visit (Visit 5 [Day 84 (±3 Days)])
The following procedures/assessments will be performed at the EOT visit (visit 5):

Review headache diary. (Note: Patients will return the electronic headache diary 
device at the EOT visit.)

Review study compliance.

Perform vital signs measurements (includes systolic and diastolic blood pressure, 
pulse, body temperature, and respiratory rate).

Perform triplicate 12-lead ECGs.

Perform physical examination (including weight).

Inquire about adverse events.

Inquire about/review concomitant medications.

Perform clinical laboratory tests (serum chemistry, hematology, coagulation, and 
urinalysis).

Perform a urine β-HCG test (women of childbearing potential only).

Obtain a 4-mL blood sample for plasma TEV-48125 concentration determination.


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
Obtain a 5-mL blood sample for serum ADA assessment.

Obtain a 5-mL urine sample for biomarker analysis.

Obtain an 18.5-mL blood sample (6 mL each for serum and plasma and 6.5 mL for
RNA) for serum, plasma, and RNA biomarker analysis.

Complete eC-SSRS Since Last Visit version.

Administer the MIDAS questionnaire, MSQOL questionnaire, EQ-5D-5L
questionnaire, PGIC scale, WPAI questionnaire, and PHQ-2/PHQ-9. (Note: Patients 
will respond first to the PHQ-2. They will respond to questions 3 through 9 [unique 
questions] of the PHQ-9 only if the PHQ-2 is positive.)
In addition, a single 6-mL blood sample for pharmacogenomics (DNA) may be obtained from 
patients who consent to pharmacogenomics analysis if the sample is not obtained at an earlier 
visit.
3.14.4.
Procedures After Study Drug Treatment
Patients who participate in the study in compliance with the protocol for the entire double-blind 
treatment period (ie, through visit 5) will be considered to have completed the study. See 
Section 12.4 for the definition of the end of the study. Patients who complete the double-blind 
treatment period may enter the 12-month double-blind, long-term safety and efficacy study 
(Study TV48125-CNS-30051). For these patients, final evaluations for the current study will be 
performed at the EOT visit (visit 5).
Patients who withdraw from the study should have final evaluations (EOT/early withdrawal 
visit) performed on the last day they receive the study drug or as soon as possible thereafter. 
Procedures for patients who withdraw prematurely from the study are described in Section 4.4.
All protocol-specified evaluations should be performed at the early withdrawal visit (see 
Table 1).
Patients who do not enroll in the double-blind, long-term safety and efficacy study for any reason
will be offered to enter the long term safety extension for the purpose of evaluating ADA 
approximately 7.5 months (225 days [the approximate equivalent of 5 half-lives]) after 
administration of the final dose of study drug in this study.
3.14.5.
Unscheduled Visits
An unscheduled visit may be performed at any time during the study, at the patient’s request or 
as deemed necessary by the investigator. The date and reason for the unscheduled visit will be 
recorded on the CRF as well as any other data obtained (eg, adverse events, concomitant 
medications and treatments, and results from procedures or tests).
Procedures performed during unscheduled visits include the following:

Review headache diary.

Review study compliance.

Perform vital signs measurements (including systolic and diastolic blood pressure, 
pulse, body temperature, and respiratory rate).


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
Inquire about adverse events.

Inquire about/review concomitant medications.
Other procedures may be performed at the discretion of the investigator.


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4.
SELECTION AND WITHDRAWAL OF PATIENTS
Prospective waivers (exceptions) from study eligibility criteria to allow patients to enter a study 
are not granted by Teva (see Section 11.1.2).
4.1.
Patient Inclusion Criteria
Patients may be included in this study only if they meet all of the following criteria:
a.
Males or females aged 18 to 70 years, inclusive, with migraine onset at ≤50 years of 
age
b. Patient signs and dates the informed consent document.
c.
Patient has history of migraine (according to ICHD-3 criteria [Classification 
Committee of the IHS, 2013]) or clinical judgement suggests a migraine diagnosis 
(not better accounted for by another ICHD-3 diagnosis) for ≥12 months prior to 
screening.
d. Patient fulfills the following criteria for EM in prospectively collected baseline 
information during the 28-day run-in period:

headache occurring on ≥6 and ≤14 days 

on ≥4 days, fulfilling any of the following:
o
ICHD-3 diagnostic criteria C and D for 1.1 Migraine without aura 
(Appendix D)
o
ICHD-3 criteria B and C for 1.2 Migraine with aura (Appendix D)
o
Probable migraine (a migraine subtype where only 1 migraine criterion is 
missing)
o
The patient used a triptan or ergot derivative to treat an established headache.
e.
Not using preventive medications (presented in Appendix B) (ie, at least 5 half-lives 
have passed since last use) or using no more than 1 preventive medication (presented 
in Appendix A) for migraine or other medical conditions (eg, propranolol used for 
hypertension) if the dose and regimen have been stable for at least 2 months prior to 
beginning the 28-day run-in period.
f.
Body mass index of 17.5 to 37.5 kg/m2 and a total body weight between 45 and 
120 kg, inclusive
g. All patients must be of nonchildbearing potential, defined as:

women surgically sterile by documented complete hysterectomy, bilateral 
oophorectomy, or bitubal ligations or confirmed to be postmenopausal (at least 
1 year since last menses and follicle-stimulating hormone [FSH] above 35 U/L)

men surgically sterile by documented vasectomy


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or
if of childbearing potential, patients must meet any of the following criteria:

Patients must simultaneously use 2 forms of highly effective contraception 
methods (defined in Section 5.2) with their partners during the entire study period 
and for 7.5 months after the last dose of study drug.

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 subject. 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.
h. Female patients of childbearing potential must have a negative serum β-HCG 
pregnancy test at screening (confirmed by urine dipstick β-HCG pregnancy test at 
baseline).
i.
The patient demonstrated compliance with the electronic headache diary during the 
run-in period by entry of headache data on a minimum of 24 out of 28 days 
(~85% diary compliance).
j.
The patient is in good health as determined by a medical and psychiatric history, 
medical examination, 12-lead ECG, serum chemistry, hematology, coagulation, and 
urinalysis.
k. 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 evaluation as specified in this protocol.
4.2.
Patient Exclusion Criteria
Patients will be excluded from participating in this study if they meet any of the following 
criteria: 
a.
Patient has received onabotulinumtoxinA for migraine or for any medical or cosmetic 
reasons requiring injections in the head, face, or neck during the 4 months before 
screening.
b. Patient is using medications containing opioids (including codeine) or barbiturates 
(including butalbital/aspirin/caffeine, butalbital/paracetamol/caffeine, or any other 
combination containing butalbital) on more than 4 days per month for the treatment 
of migraine or for any other reason.
c.
Patients who have previously failed (lack of efficacy) 2 or more of the clusters of the 
following medications for treatment of EM or CM after adequate therapeutic trial
defined as use for at least 3 months at accepted migraine therapeutic doses:

cluster A: divalproex sodium and sodium valproate

cluster B: flunarizine and pizotifen


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
cluster C : amitriptyline, nortriptyline, venlafaxine, and duloxetine

cluster D : atenolol, nadolol, metoprolol, propranolol, and timolol
d. Patient has used an intervention/device (eg, scheduled nerve blocks and transcranial 
magnetic stimulation) for migraine during the last 2 months prior to screening
e.
Clinically significant hematological, cardiac, renal, endocrine, pulmonary, 
gastrointestinal, genitourinary, neurologic, hepatic, or ocular disease, at the discretion 
of the investigator
f.
Evidence or medical history of clinically significant psychiatric issues, including any 
suicide attempt in the past, or suicidal ideation with a specific plan in the past 2 years
g. 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
h. Known infection or history of human immunodeficiency virus, tuberculosis, or 
chronic hepatitis B or C infection
i.
Past or current history of cancer in the past 5 years, except for appropriately treated 
nonmelanoma skin carcinoma
j.
Pregnant or nursing females
k. History of hypersensitivity reactions to injected proteins, including monoclonal 
antibodies
l.
Participation in a clinical study of a new chemical entity or a prescription medicine 
within 2 months before study drug administration or 5 half-lives, whichever is longer
m. Any prior exposure to a monoclonal antibody targeting the CGRP pathway 
(AMG 334, ALD304, LY2951742, or TEV-48125)
n. Any finding in the baseline 12-lead ECG considered clinically significant in the 
judgment of the investigator
o. 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)
p. Hepatic enzymes (ALT, AST, and ALP) more than 1.5× the upper limit of the normal 
range (ULN) after confirmation in a repeat test or suspected hepatocellular damage 
that fulfills criteria for Hy’s law at screening
q. Serum creatinine >1.5 × the ULN, clinically significant proteinuria (urine 
dipstick +4), or evidence of renal disease at screening
r.
History of alcohol or drug abuse during the past 2 years, or alcohol or drug 
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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 guardianship, or 
institutionalized

unable to be contacted in case of emergency

has any other condition, which, in the opinion of the investigator, makes the 
patient inappropriate for inclusion in the study
t.
The patient is a study center or sponsor employee who is directly involved in the 
study or the relative of such an employee
4.3.
Justification for Key Inclusion and Exclusion Criteria
The inclusion and exclusion criteria select for patients who meet ICHD-3 revision criteria for 
EM (Classification Committee of the IHS, 2013). Because headache consortium guidelines 
recommend preventive therapies for patients with EM occurring on 4 or more days per month 
due to the frequency of headaches and the high degree of disability, Inclusion Criterion e allows 
for the use of 1 concomitant preventive medication for migraine.
4.4.
Withdrawal Criteria and Procedures
In accordance with the Declaration of Helsinki (in accordance with the applicable country’s 
acceptance), each patient is free to withdraw from the study at any time. The investigator also 
has the right to withdraw a patient from the study in the event of intercurrent illness, adverse 
events, pregnancy (see Section 7.2), or other reasons concerning the health or well-being of the 
patient, or in the event of lack of cooperation. In addition, a patient may be withdrawn from the 
study as described in Sections 3.8, 3.12, 3.14.4, 5.4, and 7.1.7.
Should a patient decide to withdraw after administration of study drug, 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 study drug treatment and the reason for and date of 
withdrawal from the study must be recorded on the source documentation and transcribed onto 
the CRF. If a patient withdraws consent, every attempt will be made to determine the reason. If
the reason for withdrawal is an adverse event or a potentially clinically significant abnormal 
laboratory test result, monitoring will be continued at the discretion of the investigator (eg, until 
the event has resolved or stabilized, until the patient is referred to the care of a health care 
professional, or until a determination of a cause unrelated to the study drug or study procedure is 
made). The specific event or test result must be recorded on the source documentation and 
transcribed onto the CRF.
All protocol-specified procedures/assessments should be performed at the EOT/early withdrawal 
visit (see Table 1). Patients who withdraw from the study will be offered to enter the long-term 


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safety extension for the purpose of evaluating ADA approximately 7.5 months (225 days [the 
approximate equivalent of 5 half-lives]) after their last dose of study drug in this study. 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).


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5.
TREATMENT OF PATIENTS
5.1.
Drugs Administered During the Study
Following the baseline assessments, eligible patients will be randomly assigned with 
stratification based on gender, country, and baseline use of preventive migraine medication 
(yes, no) to receive monthly TEV-48125 at 225 mg, TEV-48125 at 675 mg followed by monthly 
placebo, or monthly placebo.
Study drug will be administered by qualified study personnel as sc injections approximately 
every 28 days for a total of 3 doses, as follows:

Patients randomized to receive monthly TEV-48125 at 225 mg will receive 225 mg of 
TEV-48125 as 1 active injection (225 mg/1.5 mL) and two 1.5-mL placebo injections 
at visit 2 and 225 mg of TEV-48125 as 1 active injection (225 mg/1.5 mL) at visits 3 
and 4. 

Patients randomized to receive TEV-48125 at 675 mg/placebo/placebo will receive 
675 mg of TEV-48125 as 3 active injections (225 mg/1.5 mL) at visit 2 and placebo 
as a single 1.5-mL injection at visits 3 and 4.

Patients randomized to receive placebo will receive three 1.5-mL placebo injections 
at visit 2 and a single 1.5-mL placebo injection at visits 3 and 4.
The 4-week (28-day) period will be determined relative to the planned dosing day provided the 
patient returns to the study center within the tolerance window (±3 days). If the patient returns to 
the study center more than 3 days late, then the 4-week period will be determined from the actual 
dosing day rather than the planned dosing day.
Individual, uniquely numbered visit kits containing 1 prefilled syringe with a staked 
27 G ½” needle will be provided.
At the time of each study visit, the IRT will be queried, and site personnel will retrieve and 
administer 1.5 mL from each syringe contained in the appropriately numbered kit(s).
Recommended sc injection sites follow the National Institutes of Health Patient Education 
Guidelines of June 2012, which are available in Appendix C of this document and in this 
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. Each of the 
injections at visit 2 should be given in a different location (eg, not in precisely the same place), 
and study staff member(s) responsible for administration of injections should inspect previous 
injection sites to ensure that they are free of bruising and tenderness and that proper rotation of 
sites is performed.
Study drug should be removed from the refrigerator and allowed to equilibrate at room 
temperature for 15 to 30 minutes before study drug administration.
A 1.5-mL volume from each syringe in each visit’s kit(s) must be injected sc for dosing to be 
considered complete. The total number of sc injections and their locations will be recorded for 
each dosing visit (visits 2, 3, and 4).


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5.2.
Restrictions
Medications prohibited before and/or during the study are described in Section 5.3 and the 
exclusion criteria (Section 4.2). Restrictions in regard to pregnancy and required laboratory 
values are provided in the inclusion and exclusion criteria (Section 4.1 and Section 4.2, 
respectively). Restrictions in regard to sexual activity are also detailed in the inclusion and 
exclusion criteria (Section 4.1 and Section 4.2, respectively), and highly effective contraception 
methods are reviewed below.
Highly effective contraception methods include the following hormonal and other methods of 
birth control:

combined (estrogen and gestagen) oral contraceptives, hormone implants, hormone 
rings, contraceptive patch, and hormone injectables initiated at least 7 days before 
study drug administration

intrauterine device in place for a period of at least 2 months before study drug 
administration

barrier methods of contraception: condoms with spermicide for males, diaphragm 
with spermicide for females, and portio cap with spermicide for females

vasectomy for male partners of female patients
There were no additional restrictions in this study.
In addition, male patients may not donate sperm for the duration of the study and for 7.5 months 
after discontinuation of study drug.
5.3.
Prior and Concomitant Therapy or Medication
Any prior or concomitant therapy, medication, or procedure that a patient has had within 6 
months before study drug administration and up to the end of the study period will be recorded 
on the CRF. Generic or trade name, indication, and dosage will be recorded. In addition, 
migraine preventive medication that a patient took within 2 years before study drug 
administration will be recorded on the CRF. The sponsor will encode all therapy and medication 
according to the World Health Organization drug dictionary.
5.3.1.
Prior Medications and Therapeutic Failures of Migraine Preventives:
Details regarding excluded prior medications, including migraine preventive treatments, and 
therapeutic failures of migraine preventives are described in the exclusion criteria (Section 4.2).
5.3.2.
Concomitant Therapies and Medications
Up to 30% of patients will be allowed to remain on stable doses of no more than 1 preventive 
migraine medication for the duration of the study provided the medication has at least moderate 
evidence of efficacy as defined by guidelines (Silberstein et al 2012) and presented in 
Appendix A. Patients on preventive medication must be on a stable dose for at least 2 months of 
consecutive use prior to study entry. Alternatively, patients must have discontinued the 
preventive medication at least 5 half-lives prior to screening. Preventive migraine medications 
disallowed for at least 70% of patients for the duration of the study are presented in Appendix B.


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Patients will be allowed to use acute medication to treat acute migraine attacks, as needed.
All concomitant medications taken during the study, including over-the-counter medications, 
vitamins, or herbal or nutritional supplements, must be recorded with indication, daily dose, and 
start and stop dates of administration. All patients will be questioned about concomitant 
medication use at each visit.
5.4.
Procedures for Monitoring Patient Compliance
The investigator will be responsible for monitoring patient compliance. 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. The IEC/IRB should 
be notified.
5.5.
Total Blood Volume
The total volume of blood to be collected for each patient in this study is approximately
140.5 mL, as detailed in Table 2.
Table 2:
Blood Volumes
Type of samples
Volume per sample (mL)
Total number of samples
Total volume
Serum chemistry and 
pregnancya
6
5
30
Hematology
3
5
15
FSHb
3
1
3
Pharmacokinetics
4
4
16
ADA
5
3
15
Biomarker
18.5c
3
55.5
Pharmacogenomicd
6
1
6
Total
--
22
140.5
a A serum pregnancy test will be performed for women of childbearing potential at screening only.
b Postmenopausal women only.
c For each 18.5-mL sample, individual volumes will be 6 mL each for serum and plasma and 6.5 mL for RNA.
d For patients who consent to pharmacogenomic testing.
ADA=antidrug antibody; FSH=follicle-stimulating hormone; RNA=ribonucleic acid.


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6.
ASSESSMENT OF EFFICACY
6.1.
Primary Efficacy Measure and Justification
The primary efficacy endpoint (and secondary and exploratory efficacy endpoints as well) will 
be derived from headache variables collected daily using an electronic headache diary device. 
Eligible patients will receive comprehensive training from site personnel on the use of the 
electronic headache diary device. Site personnel will also instruct patients on the requirement for 
timely and daily completion of the electronic diary.
On each day, the patient will be asked to record diary data for the previous 24-hour period. 
Patients may be asked about their performance at work, at school, and when doing household 
chores (ie, functional assessments). Patients who report headache on the previous day will 
answer questions about the headache (ie, the number of hours with headache, presence of 
associated symptoms, and use of acute migraine medications). Additional details regarding the 
questions patients will answer can be found in the electronic headache diary 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 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.
Rating of headache severity and duration of headache for each day will be completed in the 
electronic diary. Overall headache duration will be recorded numerically, in hours, as well as 
number of hours with headache of at least moderate severity.
If headache is reported, then headache severity will be subjectively rated by the patient as 
follows:

mild headache

moderate headache

severe headache
Patients will also record whether photophobia, phonophobia, nausea, and vomiting are present, 
and they will record any migraine medications (name of drug, number of tablets/capsules, and 
the dose in milligrams per tablet/capsule) taken on each day.
6.2.
Migraine Disability Assessment
The MIDAS questionnaire is a 5-item instrument developed to assess headache-related disability
based on lost days of activity in 3 domains (work, household work, and nonwork) over the 
previous 3 months. The total of the scores of the first 5 questions is used for grading of disability, 
with scores of 0 to 5, 6 to 10, 11 to 20, and ≥21 interpreted as disability grades 1 (little or no 
disability), 2 (mild disability), 3 (moderate disability), and 4 (severe disability), respectively. It 
has been shown to be reliable and valid for migraine, with substantially higher scores in migraine 
cases than non-migraine cases (Stewart et al 1999a, Stewart et al 1999b).


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Patients will complete the MIDAS questionnaire at baseline (visit 2) and the EOT visit (visit 5).
6.3.
Two-Item Patient Health Questionnaire/9-Item Patient Health 
Questionnaire
The PHQ is a 9-item questionnaire with each item corresponding to 1 criterion of the Diagnostic 
and Statistical Manual for Mental Disorders 4th edition diagnostic criteria for major depressive 
disorder. Each of the items is scored on a scale of 0 (“not at all”), 1 (“several days”), 2 (“more 
than half the days”), and 3 (“nearly every day”) based on the frequency of symptoms during the 
past 2 weeks (Spitzer et al 1999). The PHQ-2 was developed from the PHQ-9 to rapidly screen 
for depression and consists of the first 2 questions from the PHQ-9. The PHQ-2 and the PHQ-9 
are validated measures for detecting and monitoring depression, anxiety, and somatization 
(Kroenke et al 2010).
Patients will complete the PHQ-2 at baseline (visit 2) and the EOT visit (visit 5). If the PHQ-2 is 
positive (ie, a score of ≥3), patients will complete questions 3 through 9 (unique questions) of the 
PHQ-9.
6.4.
Migraine-Specific Quality of Life Questionnaire
The MSQOL, version 2.1 is a 14-item questionnaire that assesses the impact of migraine and 
migraine treatment on a patient’s quality of life during the previous 4 weeks, which has been 
shown to be a reliable and valid tool for use in CM and EM (Bagley et al 2012). The MSQOL 
measures the degree to which performance of normal activities is limited by migraine (Role 
Function-Restrictive domain comprising 7 items), the degree to which performance of normal 
activities is prevented by migraine (Role Function-Preventive domain comprising 4 items), and 
the emotional effects of migraine (Emotional Function domain comprising 3 items). Scores range 
from 0 to 100, with higher scores indicating better health-related quality of life.
Patients will complete the MSQOL at baseline (visit 2), visits 3 and 4, and the EOT visit 
(visit 5).
6.5.
EuroQol-5 Dimension Questionnaire
The EQ-5D-5L is a standardized questionnaire that assesses overall state of health. The 
EQ-5D-5L consists of 2 parts. In Part 1, patients rate their health state in 5 domains: mobility, 
self-care, usual activities, pain/discomfort, and mood, using a scale of 1 to 5 where 1=no 
problems, 2=slight problems, 3=moderate problems, 4=severe problems, and 5=extreme 
problems. In Part 2, patients rate their health state on a 100 mm visual analog scale; a rating of 0 
represents the worst imaginable health state, and a rating of 100 represents the best imaginable 
health state.
Patients will complete the EQ-5D-5L at baseline (visit 2) and the EOT visit (visit 5).
6.6.
Patient Global Impression of Change Scale
The PGIC scale is a validated generic tool for assessment of overall change in the severity of 
illness following treatment. Patients will rate how they describe the change (if any) that their 
migraine/headaches have had in their general quality of life and health status since beginning the 
treatment in this study on a 7-point scale where 1=no change (or condition has got worse);


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2=almost the same, hardly any change at all; 3=a little better, but no noticeable change;
4=somewhat better, but the change has not made any real difference; 5=moderately better, and a 
slight but noticeable change; 6=better, and a definite improvement that has made a real and 
worthwhile difference; and 7=a great deal better, and a considerable improvement that has made 
all the difference.
Patients will complete the PGIC scale before study drug administration at visits 3 and 4 and at 
the EOT visit (visit 5).
6.7.
Work Productivity and Activity Impairment Questionnaire
The generic version of the WPAI questionnaire measures the overall effect of health on 
productivity at work and daily activities. The specific health problems version of the WPAI 
questionnaire allows investigators to attribute productivity and activity impairment issues to 
specific health conditions. After the employment status of a respondent is identified, 
3 open-ended questions are asked concerning (1) hours absent from work due to health problems 
(or specific condition), (2) hours absent from work due to other reasons, and (3) hours actually 
worked. Two additional questions are included that ask about the impact of health on 
productivity, 1 concerning productivity at work and the other concerning daily activities outside 
of work. The response format of each item of the WPAI questionnaire consists of an 11-point 
scale ranging from 0 (no impairment) to 10 (complete impairment) (Reilly et al 1993). 
Patients will complete the WPAI questionnaire at baseline (visit 2) and at the EOT visit (visit 5).


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7.
ASSESSMENT OF SAFETY
In this study, safety will be assessed by qualified study personnel by evaluating the following: 
reported adverse events, clinical laboratory test results, vital signs measurements, 12-lead ECG 
findings, physical examination findings (including body weight measurements), eC-SSRS scores,
local injection site assessments, and concomitant medication usage.
7.1.
Adverse Events
7.1.1.
Definition of an Adverse Event
An adverse event is any untoward medical occurrence in a patient administered a pharmaceutical 
product, regardless of whether it has a causal relationship with this treatment.
In this study, any adverse event occurring after the clinical study patient has signed the informed 
consent form should be recorded and reported as an adverse event.
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 a
significant worsening of the disease under study or of any concurrent disease, whether or not 
considered related to the study drug. 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 (Note: A condition recorded as pre-existing that 
is intermittently symptomatic [eg, headache] and that occurs during this study should 
be recorded as an adverse event.)

drug interactions

events occurring during diagnostic procedures of this study or during any follow-up 
period 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 
drug are not considered adverse events.)

all events of possible drug-induced liver injury with hyperbilirubinemia (defined as 
AST or ALT ≥3 times the ULN, plus either total bilirubin ≥2 times the ULN or INR


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>1.5) or Hy’s Law events require immediate study treatment cessation and reporting 
as a serious adverse event. Refer to Appendix E for guidance regarding monitoring 
patients with elevated liver function tests.
Migraine exacerbations, including acute headache, requiring headache medications will be 
collected as part of the efficacy assessment in this study. Migraine exacerbations (including acute 
headache) should be recorded as an adverse event only if the presentation and/or outcome is 
more severe than would typically be expected from the normal course of the disease in a 
particular patient or if they are severe enough to require hospitalization of the patient, in which 
case they are recorded as serious adverse events.
7.1.2.
Recording and Reporting Adverse Events
For adverse event recording, the study period is defined for each patient as the time period from 
signature of the informed consent form through completion of visit 5 or the early withdrawal 
visit for patients who withdraw from the study for any reason. Adverse events will be collected 
at each visit via adverse event inquiry.
All adverse events that occur during the defined study period must be recorded on the source 
documentation and transcribed onto the CRF, regardless of the severity of the event or judged 
relationship to the study drug. For serious adverse events, the serious adverse event form must be 
completed, and the serious adverse event 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 occurring after the defined study period should be reported to the 
sponsor if the investigator becomes aware of them, following the procedures described in 
Section 7.1.5.3.1.
At each contact with the patient, the investigator or designee must question the patient about 
adverse events by asking an open-ended question such as, “Have you had any unusual symptoms 
or medical problems since the last visit? If yes, please describe.” All reported or observed signs 
and symptoms will be recorded individually, except when considered manifestations of a 
medical condition or disease state. A precise diagnosis will be recorded whenever possible. 
When such a diagnosis is made, all related signs, symptoms, and any test findings will be 
recorded collectively as a single diagnosis on the CRF and, if it is a serious adverse event, also 
on the serious adverse event form.
The clinical course of each adverse event will be monitored at suitable intervals until it resolves, 
stabilizes, or returns to baseline; until the patient is referred for continued care to a another health 
care professional; or until a determination of a cause unrelated to the study drug 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 study drug, treatment administered, and outcome for each adverse event must be 
recorded on the source documentation and transcribed onto the CRF.
The relationship of each adverse event to study drug and study procedures, and the severity and 
seriousness of each adverse event, as judged by the investigator, must be recorded, as described 
below.


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7.1.3.
Severity of an Adverse Event
The severity of each adverse event must be recorded as 1 of the choices on the following scale:
Mild: 
No limitation of usual activities
Moderate: Some limitation of usual activities
Severe: 
Inability to carry out usual activities
7.1.4.
Relationship of an Adverse Event to the Study Drug
The relationship of an adverse event to the study drug is characterized as follows:
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 study drug.
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 study drug.

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 
study drug. 

It does not reappear or worsen when the study drug 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 study drug administration 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 study drug.

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 upon 
discontinuation of the study drug, yet a drug 
relationship clearly exists.

It follows a known pattern of response to the study 
drug.


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7.1.5.
Serious Adverse Events
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:

death

a life-threatening adverse event (ie, the patient was at immediate risk of death from 
the event as it occurs); does not include an event that, had it occurred in a more severe 
form, might have caused death

inpatient hospitalization or prolongation of existing hospitalization, which means that 
hospital inpatient admission and/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 prior to study entry will not be considered serious adverse 
events, unless there was worsening of the pre-existing condition during the patient’s 
participation in this study

persistent or significant disability or incapacity (refers to a substantial disruption of
one’s ability to conduct normal life functions)

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.
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 by its specificity, severity, outcome, or frequency is considered an 
unexpected adverse event. The reference safety information for this study is the Investigator’s 
Brochure.
The sponsor’s Pharmacovigilance Department will determine the expectedness for all serious 
adverse events.
For the purpose of SUSAR reporting, the version of the reference safety information document at 
the moment of the 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 (as described in Section 7.1.5.1) 
that occur during the defined study period, regardless of judged relationship to treatment with the 
study drug, 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 in a patient after the defined study period 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 other 
designated personnel (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 & Pharmacovigilance 
Department.
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 study drug 
(no reasonable possibility, reasonable possibility)
Additional information may include the following:

age and sex of patient

date of 1st dose of study drug

date and amount of last administered dose of study drug

action taken

outcome, if known

severity

explanation of assessment of relatedness

concomitant therapy (including doses, routes, and regimens) and treatment of the 
event

pertinent laboratory or other diagnostic test data

medical history

results of dechallenge/rechallenge, if known


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
for an adverse event resulting in death:

cause of death (whether or not the death is related to study drug)

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 study drug, study 
procedures, and underlying disease.
Additional information (follow-up) about any serious adverse event unavailable at the initial 
reporting should be forwarded by the investigational center 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 & Pharmacovigilance Department will 
distribute the Council for International Organizations of Medical Sciences form/extensible 
markup language file to the LSO and/or CRO for local submission to the regulatory authorities, 
IEC/IRBs, and investigators, according to regulations. The investigator is responsible for 
ensuring that the IRB/IEC is also informed of the event, in accordance with local regulations.
Blinding will be maintained for the people who are involved directly in the study. Therefore, in 
case of a SUSAR, only the LSO or CRO personnel involved with safety regulatory submissions 
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 study drug or study 
procedures, the sponsor will take appropriate steps to notify all investigators participating in 
sponsored clinical studies of TEV-48125 and the appropriate regulatory authorities (and 
IEC/IRB, if appropriate).
In addition to notifying the investigators and regulatory authorities (and IEC/IRB, if appropriate), 
other measures may be required, including the following:

altering existing research by modifying the protocol

discontinuing or suspending the study

altering the process of informed consent by modifying the existing consent form and 
informing current study participants of new findings

modifying listings of expected toxicities to include adverse events newly identified as 
related to TEV-48125
7.1.6.
Protocol-Defined Adverse Events of Special Interest
The following are considered protocol-defined adverse events to be sent to the sponsor’s Global 
Patient Safety and Pharmacovigilance Department for evaluation: ophthalmic adverse events of 
at least moderate severity, events of possible drug-induced liver injury (AST or ALT ≥3 × the 


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ULN, total bilirubin ≥2 × the ULN or INR >1.5), Hy’s Law events, or events of suspected 
anaphylaxis and severe hypersensitivity reactions. Severe hypersensitivity reactions will be 
monitored using the diagnostic criteria for anaphylaxis as outlined by the 2006 Joint National 
Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network Second 
Symposium on Anaphylaxis (Sampson et al, 2006 [also see Appendix F]). 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.
The process for reporting a protocol-defined adverse event is the same as that for reporting a 
serious adverse event (see Section 7.1.5.3). Protocol-defined adverse events for reporting to 
Pharmacovigilance Department can be either serious or nonserious according to the criteria 
outlined in Section 7.1.5.
7.1.7.
Withdrawal Due to an Adverse Event
Any patient who experiences an adverse event may be withdrawn from the study or from study 
drug at any time, at the discretion of the investigator. If a patient is withdrawn because of an 
adverse event, both the adverse events page and termination page of the CRF will be completed 
at that time.
The patient will be monitored at the discretion of the investigator (eg, until the event has 
resolved or stabilized, until the patient is referred to the care of a health care professional, or 
until a determination of a cause unrelated to the study drug or study procedure is made). The 
investigator must inform the clinical project physician/clinical leader as soon as possible of all 
patients who are being considered for withdrawal due to adverse events. Additional reports must 
be provided when requested.
If a patient is withdrawn from the study or study drug for multiple reasons that include adverse 
events, the termination page of the CRF should indicate that the withdrawal is 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 requires the 
use of a prohibited medication, thereby requiring discontinuation of the patient. In such a case, 
the reason for discontinuation would be the need to take a prohibited medication, not the adverse 
event.
7.1.8.
Overdose of Study Drug
Any dose of study drug (whether the investigational product or placebo), whether taken 
intentionally or unintentionally, in excess of that prescribed must be immediately reported to the 
sponsor. When the identification of the study drug must be known, the investigator must follow 
the procedures outlined in Section 3.8.
7.1.9.
Protocol Deviations Because of an Adverse Event
If a patient experiences an adverse event or medical emergency, departures from the protocol 
may be allowed on a case-by-case basis. After stabilization and/or treatment has been 
administered to ensure patient safety, the investigator or other physician in attendance must 
contact the individual 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.


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7.2.
Pregnancy
All pregnancies of women participating in the study that occur during the study, or within
7.5 months after the last administration of TEV-48125, 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 LSO and/or CRO with the pregnancy form. The process for 
reporting a pregnancy is the same as that for reporting a serious adverse event (see 
Section 7.1.5.3).
Any female patient becoming pregnant during the study will discontinue the study drug. All 
patients who become pregnant will be monitored for the outcome of the pregnancy (including 
spontaneous or voluntary termination). 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 termination from the study will be reported as an 
adverse event or serious adverse event, as appropriate.
If the pregnancy 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.
For pregnancies of partners of men participating in the study, the Teva Pharmacovigilance 
Department will determine the procedure to appropriately follow up after notification as 
described above. All partners who become pregnant and provide appropriate consent to the Teva 
Pharmacovigilance Department will be monitored to the completion or termination of the 
pregnancy.
7.3.
Clinical Laboratory Tests
All clinical laboratory test results outside of the reference range will be interpreted by the 
investigator as belonging to 1 of the following categories:

abnormal but not a clinically significant worsening from baseline

abnormal and a clinically significant worsening from baseline
A laboratory test result that has significantly worsened (according to medical judgment) from the 
baseline result will be recorded on the source documentation, transcribed onto the CRF as an 
adverse event, and monitored as described in Section 7.1.2. An adverse event includes a 
laboratory or diagnostic test abnormality (once confirmed by repeat testing) that results in the 
withdrawal of the patient from the study, the temporary or permanent cessation of treatment with 
study drug, or medical treatment or further diagnostic work-up.
In addition, potentially clinically significant values will be predefined by the sponsor for selected 
laboratory parameters and will be detailed in the statistical analysis plan.


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Clinical laboratory tests (serum chemistry, hematology, coagulation, and urinalysis) will be 
performed at the time points detailed in Table 1. Clinical laboratory tests will be performed using 
the central laboratory. Specific laboratory tests to be performed are listed below.
7.3.1.
Serum Chemistry
The following serum chemistry tests will be performed:

calcium

phosphorus

sodium

potassium

chloride

carbon dioxide

magnesium

glucose

blood urea nitrogen

creatinine

ALT

AST

total bilirubin

direct bilirubin

indirect bilirubin (calculated)

lactate dehydrogenase 

GGT

ALP

albumin

creatine phosphokinase

total protein
7.3.2.
Hematology
The following hematology tests will be performed:

hemoglobin

hematocrit

red blood cell (RBC) count 


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
RBC indices

mean corpuscular volume

mean corpuscular hemoglobin concentration

RBC distribution width

platelet count

white blood cell (WBC) count and differential count (absolute values and 
percentages)

neutrophils

lymphocytes

eosinophils

monocytes

basophils
7.3.3.
Coagulation
The following coagulation tests will be performed: 

prothrombin time

partial thromboplastin time

INR
7.3.4.
Urinalysis
Urinalysis will include testing for the following:

color and appearance

specific gravity

pH

blood (hemoglobin)

glucose

albumin

protein

ketones

leukocyte esterase

nitrite

direct bilirubin


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
microscopic

bacteria

RBCs

WBCs

casts

crystals
7.3.5.
Other Clinical Laboratory Tests
7.3.5.1.
Human Chorionic Gonadotropin Tests
Serum β-HCG tests will be performed for women of childbearing potential at screening (visit 1), 
and urine β-HCG tests will be performed for women of childbearing potential at visits 2 
through 5. Any patient who becomes pregnant during the study will be withdrawn. Procedures 
for reporting the pregnancy are provided in Section 7.2. 
7.3.5.2.
Follicle-Stimulating Hormone Tests
Postmenopausal women will have an FSH test at screening (visit 1).
7.4.
Vital Signs
Vital signs (pulse, systolic and diastolic blood pressure, body temperature, and respiratory rate) 
will be measured before other assessments (eg, blood draws and administration of 
questionnaires) at the time points detailed in Table 1.
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 9.7.2) and, if so, will be documented in the statistical analysis 
plan or other relevant documents (eg, medical monitoring plan).
7.5.
Electrocardiography
Twelve-lead ECGs will be conducted before other assessments (eg, blood draws and 
administration of questionnaires) at the time points detailed in Table 1. The ECGs should be 
performed after the patient has been supine for at least 5 minutes. The ECGs will be performed 
in triplicate.
A qualified physician at a central diagnostic center will be responsible for interpreting the ECG. 
ECGs should be performed and transmitted according to the central ECG reading instructions 
provided in the ECG user manual. ECG equipment will be provided to all clinical sites.


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Although the ECG interpretation will be performed centrally, the clinical evaluation remains 
under the Investigator’s responsibility.
The ECG will be evaluated by the Investigator at the time of recording (signed and dated), and 
the printout should be kept in the source documentation file. When potentially clinically 
significant findings are detected by the Investigator, a cardiologist should be consulted for a 
definitive interpretation. All communications and diagnoses should be filed in the source 
documentation file. The Investigator’s interpretation will be recorded in the CRF regardless of 
the central reading interpretation. Any abnormal findings assessed by the Investigator as 
clinically significant should be recorded in the relevant CRF modules (eg, adverse event, medical 
history).
Objective alerts are predefined as described in the central ECG reading manual. In these cases, 
the site and the sponsor will be informed immediately.
Any unscheduled ECGs must also be submitted for central ECG reading.
Any ECG finding that is judged by the investigator as a potentially clinically significant change 
(worsening) compared with a baseline value will be considered an adverse event, recorded on the 
source documentation and transcribed onto the CRF, and monitored as described in 
Section 7.1.2.
7.6.
Physical Examinations
Physical examinations, including height (to be obtained at the screening visit only) and weight 
will be performed at the time points detailed in Table 1.
A complete physical examination will include the following organ systems: general appearance; 
head, eyes, ears, nose, and throat; chest and lungs; heart; abdomen; musculoskeletal; skin; lymph 
nodes; and neurological. Any physical examination finding that is judged by the investigator as a 
potentially clinically significant change (worsening) compared with a baseline value will be 
considered an adverse event, recorded on the CRF, and monitored as described in Section 7.1.2.
7.7.
Electronic Columbia-Suicide Severity Rating Scale
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 2, and the eC-SSRS Since Last Visit version will be completed by the patient at 
all other time points, as described in Table 1. Any positive findings on the eC-SSRS Since Last 
Visit version requires evaluation by a physician or doctoral-level psychologist.
7.8.
Concomitant Therapy or Medication
Concomitant therapy or medication usage will be monitored throughout the study. Details of 
prohibited medications are found in Section 5.3. 
7.9.
Immunogenicity
Blood samples for serum ADA assessment will be collected at visits 2, 3, and the EOT/early 
withdrawal visit. Only the samples from TEV-48125-treated patients will be analyzed for ADA. 
Blood samples for ADA assessment will also be collected upon observation of any severe 


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hypersensitivity reaction (eg, anaphylaxis). See Appendix F for the clinical criteria for 
diagnosing anaphylaxis. Bioanalytical personnel should be made aware of any anaphylaxis 
occurrence as soon as possible in case an anti-TEV-48125 immunoglobulin E assay is required.
7.10.
Injection Site Assessments
Injection site assessments will be performed immediately and 1 hour after administration of each 
dose of study drug (Table 1). The injection site(s) will be assessed for erythema, induration, 
ecchymosis, and pain, and severity 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.

Injection-site pain will be measured as summarized in Table 3.
Table 3:
Severity of Pain Scale for Injection Site Assessments
Grade
Assessments
0
No pain
1
Mild
2
Moderate
3
Severe
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 study drug 
administration, the patient will be reassessed at 3 hours after study drug 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 will also be recorded as adverse events as described in Section 7.1.
7.11.
Methods and Timing of Assessing, Recording, and Analyzing Safety 
Data
All adverse events will be reviewed on a periodic basis by the clinical project physician/medical 
monitor according to the safety monitoring plan (eg, scheduled safety reviews for TEV-48125)
as interim/preliminary safety databases become available. Safety data will additionally be 
evaluated periodically and ad hoc (if necessary) in the Product Safety Group.
Methods and timing of assessing safety data are discussed in Section 3.14. Procedures for 
recording safety data are discussed in Section 13.1 and methods of analyses are discussed in 
Section 9.7.2.


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8.
ASSESSMENT OF PHARMACOKINETICS/ BIOMARKERS/ 
IMMUNOGENICITY
8.1.
Pharmacokinetic Variables
Sampling for pharmacokinetics will be sparse. Thus, the TEV-48125 pharmacokinetic samples 
will be analyzed using a population pharmacokinetic approach and will be reported separately to 
the clinical study report.
Samples from patients who receive active study drug will be analyzed for TEV-48125 using a 
validated method. Samples from patients who receive placebo will not be analyzed.
8.1.1.
Specimen Sampling and Handling
Blood samples (4 mL) will be collected via venipuncture or indwelling catheter at the time points 
detailed in Table 1 for plasma concentration measurements of TEV-48125.
The dates and times of study drug administration and the date and time of each pharmacokinetic 
sample will be recorded on the source documentation and transcribed onto the CRF.
For plasma collection, samples will be collected into dipotassium EDTA collection tubes, 
inverted slowly 6 to 8 times to mix the contents, and placed on water/ice (~4°C). Blood samples 
will be centrifuged (1500g, ~10 minutes, 2°C to 6°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 into 2 labeled, 2-mL polypropylene tubes (sets A and B).
Labels for samples should include study number, patient number, period, nominal collection 
time, set (A or B), and indication that they are pharmacokinetic samples. Samples will be stored 
at a temperature within the range of -70°C ±20°C in an upright position until they are shipped to 
the central laboratory.
8.1.2.
Shipment and Analysis of Samples
Plasma samples for all patients will be shipped frozen on dry ice from the investigational center 
to the central laboratory, where they will be stored until shipment to the sponsor or its designee
for analysis.

Set A samples will be transported (frozen) with a temperature data logger, by 
next-day courier, to the central laboratory.

Set B samples will either be sent to the same laboratory as that for set A on a 
subsequent day, by next-day courier, or be retained at the investigational center until 
the study is completed and the clinical study report has been issued (unless shipment 
to another facility is requested by the sponsor).
Samples will be analyzed using a validated method. Timing of the initiation of sample analysis 
will be determined by the Teva Pharmaceuticals bioanalytical representative responsible for the 
bioanalysis. Refer to the laboratory manual for additional details.


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8.2.
Immunogenicity Testing
8.2.1.
Blood Sampling and Handling
Samples from patients who receive active study drug will be analyzed for ADA using a validated 
method. Samples from patients who receive placebo will not be analyzed.
Blood samples (5 mL) will be collected via venipuncture or indwelling catheter at the time points 
detailed in Table 1 for immunogenicity testing.
For serum collection, samples will be collected into Vacutainer tubes containing no 
anticoagulant, and allowed to set at room temperature less than 30 minutes to allow for serum 
separation to occur. Samples will then be centrifuged (1500g, approximately 10 minutes, 2°C to 
6°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 into 
2 labeled, 2-mL polypropylene tubes (sets A and B).
Sample labels should include study number, patient number, period, nominal collection time, set 
(A or B), and indication that they are ADA samples. Serum samples will be stored at a 
temperature within the range of -70°C ± 20°C in an upright position until they are shipped to the 
central laboratory.
8.2.2.
Shipment and Analysis of Samples
Serum samples for all patients will be shipped frozen on dry ice from the investigational center 
to the central laboratory, where they will be stored until shipment to the sponsor or its designee
for analysis.

Set A samples will be transported (frozen) with a temperature data logger, by 
next-day courier, to the central laboratory.

Set B samples will either be sent to the same laboratory as that for set A on a 
subsequent day, by next-day courier, or be retained at the investigational center until 
the study is completed and the clinical study report has been issued (unless shipment 
to another facility is requested by the sponsor).
Samples will be analyzed using an appropriate validated method. Timing of the initiation of 
sample analysis will be determined by the Teva Pharmaceuticals department representative 
responsible for the bioanalysis. Refer to the laboratory manual for additional details.
8.3.
Assessment of Exploratory Biofluid Biomarkers
Biomarkers are defined as biological substances that monitor physiological effects, assess drug 
activity, and predict clinical outcome, safety, and response to therapy.
Calcitonin gene-related peptide-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 


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analysis may be conducted on blood (serum, plasma, and RNA) and urine biomarkers, 
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 TEV-48125 alters angiogenic markers.
Calcitonin gene-related peptide 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 TEV-48125 
in patients with migraine.
Based on the known biology of CGRP’s mechanism of action, biomarker assessment will 
potentially include markers of bone remodeling, inflammation, and angiogenesis. 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.
8.3.1.
Pharmacogenomic Assessment
A blood sample (6 mL) will be collected from each patient who signs the separate informed 
consent form for pharmacogenomic assessment during this study. Pharmacogenomic assessment 
potentially includes the association analysis of both known and unknown DNA and RNA genetic 
variations. In the current study, known CGRP and migraine-associated genes will be examined to 
determine their association with clinical treatment responses to study drug and their potential to 
be markers predictive of migraine severity and progression (eg, efficacy, pharmacokinetics, 
tolerability, and safety features or disease susceptibility and severity features). The current list of 
genes with polymorphisms associated with either CGRP target engagement or migraine 
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 may be investigated may be edited at a later time before the analysis to allow updating 
with new scientific information. Genetic analysis could also include sequencing of the whole 
genome and/or RNA transcripts, if required.
Pharmacogenomic assessment will be performed based on study results. Samples will be used for 
investigations related to headache, indications where CGRP pathways are implicated, and 
indications that may be associated with the risk of headache or those that are common 
comorbidities associated with headache and/or response to study drug or related investigational 
drugs.
8.3.2.
Specimen Sampling and Handling
Blood samples (a total of 18.5 mL; 6 mL each for plasma and serum and 6.5 mL for RNA 
[PAXgene]) will be collected via venipuncture or indwelling catheter at the time points detailed 
in Table 1 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 for 


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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 coded number. Following DNA 
extraction from pharmacogenomic sample, the sample will be labeled with a new code 
(ie, double coding), so that genetic data will not be recorded having a patient number.
Samples will be stored for a period of up to 15 years from the last patient last visit in the main 
study and then destroyed.
8.3.3.
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 laboratory 
manual. An electronic file containing sample demographics will be e-mailed 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.
8.4.
Methods and Timing of Assessing, Recording, and Analyzing Clinical 
Pharmacology Data
Methods and timing of assessing clinical pharmacology data are discussed in Section 3.14. 
Procedures for recording clinical pharmacology data are discussed in Section 13.1, and methods 
of analyses are discussed in Section 9.5.4.


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9.
STATISTICS
This study is a Phase 3, multicenter, randomized, double-blind, placebo-controlled parallel-group 
study to assess the efficacy and safety of 2 dose regimens of sc administration of TEV-48125 
compared with placebo for preventive treatment of EM. Eligible patients will be randomized in a 
1:1:1 ratio to receive monthly TEV-48125 at 225 mg, TEV-48125 at 675 mg followed by 
monthly placebo, or monthly placebo. Randomization will be stratified by gender, country, and
baseline preventive medication use (yes, no).
9.1.
Sample Size and Power Considerations
A total of 768 patients are planned to be randomized in this study to have 675 completers 
(225 completers per treatment group); a 12% drop-out rate is anticipated. A sample size of 
675 patients (ie, 225 evaluable patients completing the study per treatment group) will provide 
90% power to detect a 1.6 difference in migraine days between an active arm and placebo arm at 
an alpha level of 0.05, assuming a common standard deviation (SD) of 5.2 days.
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 this population, 
treatment will be assigned based on the treatment to which patients are randomized, regardless of 
which treatment they actually received.
9.2.2.
Safety Analysis Set
The safety analysis set will include all patients who receive at least 1 dose of study drug. In this 
population, treatment will be assigned based upon the treatment patients actually receive, 
regardless of the treatment to which they are randomized.
9.2.3.
Full Analysis Set
The full analysis set (FAS) will include all patients in the ITT population who receive at least 
1 dose of study drug and have at least 1 postbaseline efficacy assessment on the primary 
endpoint.
9.2.4.
Additional Analysis Sets
The per-protocol population 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.
9.3.
Data Handling Conventions
Efficacy variables from patients who do not have diary completed for the entire study period will 
be imputed. The detailed data imputation rules will be described in the statistical analysis plan.


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9.4.
Study Population
The ITT analysis set (see Section 9.2) will be used for all study population summaries unless 
otherwise noted. 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 not randomized,
patients who are randomized (ie, in the ITT set), patients randomized but not treated, patients in 
the 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 12-lead ECG findings, will be summarized by treatment group 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 
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 migraine day is endorsed when at least 1 of the following 
situations occur:

A calendar day (0:00 to 23:59) demonstrating at least 2 consecutive hours of a 
headache endorsing criteria for migraine with or without aura

A calendar day (0:00 to 23:59) demonstrating at least 2 consecutive hours of a 
headache endorsing criteria for probable migraine, a migraine subtype where only 
1 migraine criterion is missing

A calendar day (0:00 to 23:59) demonstrating a headache of any duration that was 
treated with migraine specific medications (triptans and ergot compounds)
9.5.1.
Primary Endpoint
The primary efficacy endpoint is the mean change from baseline (28-day run-in period) in the 
monthly average number of migraine days during the 12-week period after the 1st dose of study 
drug.


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9.5.2.
Secondary Endpoints
The secondary efficacy endpoints are as follows:

proportion of patients reaching at least 50% reduction in the monthly average number 
of migraine days during the 12-week period after the 1st dose of study drug

mean change from baseline (28-day run-in period) in the monthly average number of 
days of use of any acute headache medications during the 12-week period after the 
1st dose of study drug

mean change from baseline (28-day run-in period) in the number of migraine days 
during the 4-week period after the 1st dose of the study drug

mean change from baseline (28-day run-in period) in the monthly average number of 
migraine days during the 12-week period after the 1st dose of study drug in patients 
not receiving concomitant migraine preventive medications 

mean change from baseline (day 0) in disability score, as measured by the MIDAS 
questionnaire, at 4 weeks after administration of the last (3rd) dose of study drug
9.5.3.
Exploratory Endpoints
The exploratory efficacy endpoints are as follows:

mean change from baseline (28-day run-in period) in the number of headache days of 
at least moderate severity during the 12-week period after the 1st dose of study drug

proportion of patients reaching at least 75% reduction and total (100%) reduction in 
the monthly average number of migraine days during the 12-week period after the 
1st dose of study drug

proportion of patients reaching at least 50% reduction and at least 75% reduction in 
the number of migraine days during the 4-week period after the 1st dose of study drug 
for whom this level of effect is sustained throughout the 12-week period after the 1st
dose of study drug

mean change from baseline (28-day run-in period) in the monthly average number of 
migraine days during the 12-week period after the 1st dose of study drug in patients 
who used topiramate for migraine in the past

mean change from baseline (28-day run-in period) in the number of migraine days 
during the 12-week period after the 1st dose of study drug for patients who used 
onabotulinumtoxinA for migraine in the past

mean change from baseline (28-day run-in period) in the number of migraine days 
during the 4-week period after the 2nd dose of study drug

mean change from baseline (28-day run-in period) in the number of migraine days 
during the 4-week period after the last (3rd) dose of study drug

mean change from baseline (28-day run-in period) in the monthly average number of 
headache days of any severity during the 12-week period after the 1st dose of study 
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
mean change from baseline (28-day run-in period) in the number of headache days of 
at least moderate severity during the 4-week period after each dose of study drug

proportion of patients reaching at least 50% reduction, at least 75% reduction, and 
total (100%) reduction in the monthly average number of headache days of at least 
moderate severity during the 12-week period after the 1st dose of study drug

proportion of patients reaching at least 50% reduction and at least 75% reduction in 
the number of headache days of at least moderate severity during the 4-week period 
after the 1st dose of study drug for whom this level of effect is sustained throughout 
the 12-week period after the 1st dose of study drug

mean change from baseline (28-day run-in period) in the number of headache days of 
at least moderate severity during the 12-week period after the 1st dose of study drug 
for patients not receiving concomitant preventive migraine medications

mean change from baseline (28-day run-in period) in the number of headache days of 
at least moderate severity during the 12-week period after the 1st dose of study drug 
for patients who used topiramate for migraine in the past

mean change from baseline (28-day run-in period) in the number of headache days of 
at least moderate severity during the 12-week period after the 1st dose of study drug 
for patients who used onabotulinumtoxinA for migraine in the past

mean change from baseline (28-day run-in period) in the monthly average number of 
headache hours of any severity during the 12-week period after the 1st dose of study 
drug

mean change from baseline (28-day run-in period) in the monthly average number of 
headache hours of at least moderate severity during the 12-week period after the 1st
dose of study drug

mean change from baseline (28-day run-in period) in the monthly average number of 
days of use of migraine-specific acute headache medications (triptans and ergot 
compounds) during the 12-week period after the 1st dose of study drug

mean change from baseline (28-day run-in period) in the monthly average number of 
days with nausea or vomiting during the 12-week period after the 1st dose of study 
drug

mean change from baseline (28-day run-in period) in the monthly average number of 
days with photophobia and phonophobia during the 12-week period after the 1st dose 
of study drug

mean change from baseline (day 0) in quality of life, as measured by the MSQOL
questionnaire, at 4 weeks after administration of the last (3rd) dose of study drug

mean change from baseline (day 0) in the health status, as measured by the 
EQ-5D-5L questionnaire at 4 weeks after administration of the last (3rd) dose of study 
drug

mean change from baseline (day 0) in patient depression status, as measured by the 
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
mean change from baseline (day 0) in patient work productivity and activity 
impairment, as measured by the WPAI questionnaire, at 4 weeks after administration 
of the last (3rd) dose of study drug

assessment of patient satisfaction, as measured by the PGIC scale, at 4 weeks after 
administration of the 1st dose of study drug, at 4 weeks after the 2nd dose of study 
drug, and at 4 weeks after the last (3rd) dose of study drug
9.5.4.
Planned Method of Analysis
The FAS (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 (28-day run-in period) in the 
monthly average number of migraine days during the 12-week period after the 1st dose of study 
drug, will be analyzed using an analysis of covariance method. The model will include treatment, 
gender, country, and baseline preventive medication use as fixed effects, and baseline number of 
migraine days and years since onset of migraines as covariates. Ninety-five percent confidence 
intervals will be constructed for the least squares mean differences between each TEV-48125 
group and the placebo group. A hierarchical procedure will be used to control type 1 error rate. 
9.5.4.2.
Sensitivity Analysis
Sensitivity analysis may be conducted to explore the impact of missing data in the primary 
efficacy analysis.
9.5.4.3.
Secondary Efficacy Analysis
The same analysis used for the primary efficacy endpoint will be performed for the secondary 
efficacy endpoints. For the proportion of responders defined as 50% or more reduction from 
baseline in the monthly average number of migraine days, Cochran-Mantel-Haenszel test will be 
used.
9.5.4.4.
Exploratory Efficacy Analysis
The same analyses used for the primary and secondary efficacy endpoints will be performed for 
the exploratory efficacy endpoints, as appropriate.
9.6.
Multiple Comparisons and Multiplicity
A fixed-sequence (hierarchical) testing procedure will be implemented to control the type 1 error 
rate at 0.05. The sequence of comparisons will be described in detail in the statistical analysis 
plan. 
9.7.
Safety and Tolerability Endpoints and Analysis
Safety and tolerability analyses will be performed on the safety analysis set.


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9.7.1.
Safety and Tolerability Endpoints
The safety and tolerability endpoints for this study are as follows:

occurrence of adverse events throughout the study

abnormal standard 12-lead ECG findings

changes from baseline in vital signs (systolic and diastolic blood pressure, pulse, body 
temperature, and respiratory rate) measurements 

changes from baseline in clinical laboratory (serum chemistry, hematology, 
coagulation, and urinalysis) test results

abnormal physical examination findings

abnormal local injection site tolerability findings (ie, erythema, induration, 
ecchymosis) and occurrence of injection site pain

suicidal ideation and behavior as suggested by the eC-SSRS
Safety and tolerability measures and time points are provided in Table 1.
9.7.2.
Safety Analysis
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 study treatment (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.
Injection site erythema, induration, ecchymosis, and pain will be assessed as described in 
Section 7.9, and findings will be listed and summarized.
Changes in laboratory 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.
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 study drug.
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.


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9.8.
Pharmacokinetic Analysis
Pharmacokinetic plasma concentration results (TEV-48125) will be tabulated descriptively at 
each planned sampling time point by treatment group.
9.9.
Biomarker Analysis
Biomarker analysis will include logistic regression, receiver operating characteristic curves, and 
summary statistics. Results will be reported separately. 
9.10.
Pharmacokinetic/Pharmacodynamic Analysis
The pharmacokinetic/pharmacodynamic relationship will be estimated by compartmental 
techniques. The pharmacokinetic parameters will be based on TEV-48125 measurements. The 
pharmacodynamic measures will be the efficacy responses.
The pharmacokinetic/pharmacodynamic relationship will be estimated using the most 
appropriate model after comparing different candidate models for their quality of fit. Covariates 
that may affect the pharmacokinetic/pharmacodynamic relationship will be tested for inclusion in 
the model. This analysis will be reported separately.
9.11.
Immunogenicity Analysis
Summary of immunogenicity results will be provided, and the incidence of immunogenicity will 
be calculated. The impact of immunogenicity on the pharmacokinetic profile, drug efficacy, and 
clinical safety will be evaluated. This impact analysis will be reported separately.
9.12.
Planned Interim Analysis
No interim analysis is planned for this study.
9.13.
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 local and regional 
requirements and regulations.


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10.
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS
The medical experts, study monitors, auditors, IEC/IRB, and health authority inspectors (or their 
agents) will be given direct access to source data and documentation (eg, medical charts/records, 
laboratory test results, printouts, and videotapes) for source data verification, provided that 
patient confidentiality is maintained in accordance with local requirements.
The investigator must maintain the original records (ie, source documents) of each patient’s data 
at all times. Examples of source documents are hospital records, office visit records, examining 
physician’s finding or notes, consultant’s written opinion or notes, laboratory reports, drug 
inventory, study drug label records, diary data, protocol-required worksheets, and CRFs that are 
used as the source (see Section 3.13).
The investigator will maintain a confidential patient identification list that allows the 
unambiguous identification of each patient. All study-related documents must be kept until 
notification by the sponsor.


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11.
QUALITY CONTROL AND QUALITY ASSURANCE
11.1.
Protocol Amendments and Protocol Deviations and Violations
11.1.1.
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.
11.1.2.
Protocol Violations
Any deviation from the protocol that affects, to a significant degree, (a) the safety, physical, or 
mental integrity of the subjects of the study and/or (b) the scientific value of the study will be 
considered a protocol violation. Protocol violations may include nonadherence 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 study drug 
administration; and use of prohibited medications. Protocol violations will be identified and 
recorded by investigational center personnel in the CRF. All protocol violations will be reported 
to the responsible IEC/IRB, as required.
When a protocol violation 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.
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 violation. If such patient has already completed the study or has 
withdrawn early, no action will be taken but the violation will be recorded.
11.2.
Information to Study Personnel
The investigator is responsible for giving information about the study to all staff 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 staff members become involved). The investigator 
must assure that all study staff members are qualified by education, experience, and training to 
perform their specific responsibilities. These study staff members must be listed on the 
investigational center authorization form, which includes a clear description of each staff 
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 staff, including the 
investigator, and for ensuring that they comply with the protocol. Additional information will be 


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made available during the study when new staff members become involved in the study and as 
otherwise agreed upon with either the investigator or the study monitor.
11.3.
Study Monitoring
To ensure compliance with GCP guidelines, the study monitor or representative is responsible 
for ensuring that patients have signed the informed consent form and the study is conducted 
according to applicable standard operating procedures (SOPs), the protocol, and other written 
instructions and regulatory guidelines.
The study monitor is the primary association between the sponsor and the investigator. The main 
responsibilities of the study monitor(s) are to visit the investigator before, during, and after the 
study to ensure adherence to the protocol, that all data are correctly and completely recorded and 
reported, and that informed consent is obtained and recorded for all patients before they 
participate in the study and when changes to the consent form are warranted, in accordance with 
IEC/IRB approvals.
The study monitor(s) will contact the investigator and visit the investigational center at regular 
intervals throughout the study. The study monitor will be permitted to check and verify the 
various records (CRFs and other pertinent source data records, including specific electronic 
source documentation [see Section 3.13]) relating to the study to verify adherence to the protocol 
and to ensure the completeness, consistency, and accuracy of the data being recorded. If 
electronic CRFs are used for the study, the study monitor will indicate verification by 
electronically applying source document verification flags to the CRF and will ensure that all 
required electronic signatures are being implemented accordingly.
As part of the supervision of study progress, other sponsor personnel may, on request, 
accompany the study monitor on visits to the investigational center. The investigator and 
assisting staff must agree to cooperate with the study monitor to resolve any problems, errors, or 
possible misunderstandings concerning the findings detected in the course of these monitoring 
visits and/or provided in follow-up written communication.
11.4.
Clinical Product Complaints
A clinical product complaint is defined as a problem or potential problem with the physical 
quality or characteristics of clinical drug supplies and/or clinical device supplies used in a 
clinical research study sponsored by Teva. Examples of a product complaint include, but are not 
limited to, the following:

suspected contamination

questionable stability (eg, color change, flaking, crumbling, etc)

defective components

missing or extra units (eg, primary container is received at the site 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)


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
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 a drug product, all relevant samples (eg, the remainder of the patient’s drug supply) 
should be sent back to the sponsor for investigative testing whenever possible.
11.4.1.
Product Complaint Information Needed from the Investigational Center
In the event that the Product Complaint Form cannot be completed, the investigator will obtain 
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

patient number, bottle, and kit numbers (if applicable)

product available for return (yes, no)

product was taken or used according to protocol (yes, no)

description or nature of complaint

associated serious adverse event (yes, no)

clinical supplies unblinded (yes, no)

date and name of person receiving the complaint
Note: Reporting a complaint must not be delayed because not all the required information can be 
immediately obtained. Known information must be immediately reported. The sponsor will 
collaborate with the investigator to obtain any outstanding information.
11.4.2.
Handling the Study Drug at the Investigational Center
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 study drug.
If it is determined that the investigational center must return all of the study drug, 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 


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problem existing beyond the scope of the complaint may be a reason to unblind the clinical 
supplies for an affected patient.
11.4.3.
Adverse Events or Serious Adverse Events Associated with a Product Complaint
If there is an adverse event or serious adverse event, the protocol should be followed.
11.4.4.
Documenting a Product Complaint
The investigator will record a description of the product complaint in the source documentation 
as well as 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.
11.5.
Audit and Inspection
The sponsor may audit the investigational center to evaluate study conduct and compliance with 
protocols, SOPs, GCPs, and applicable regulatory requirements. The sponsor’s Global Clinical 
Quality Assurance department, independent of the Global Clinical Development department, is 
responsible for determining the need for (and timing of) an investigational center audit.
The investigator must accept that regulatory authorities, and sponsor representatives may 
conduct inspections to verify compliance with GCP guidelines.


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12.
ETHICS
Details of compliance with regulatory guidances and applicable laws are provided in Section 1.6.
12.1.
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/or oral information about the study will be provided in a language as 
nontechnical as practical and 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 documentation.
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, according to the IEC/IRB requirements. The patient’s 
willingness to participate in the study will be documented in a 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 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 entry 
into the study and free to withdraw from the study at any time without prejudice to future 
treatment.
Patients will be asked to sign a separate informed consent form if they agree to provide blood 
samples for pharmacogenomic assessment.
12.2.
Health Authorities and Independent Ethics Committees/Institutional 
Review Boards
Before this study starts, the protocol will be submitted to the national/local health authorities and 
to each IEC/IRB for review. As required, the study will not start at a given investigational center 
before the IEC/IRB and health authority (where applicable) for the center to give written 
approval or a favorable opinion.
12.3.
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 code (ie, identification number).
Personal medical information may be reviewed for the purpose of patient safety and/or verifying 
data in the source and transcribed onto the CRF. This review may be conducted by the study 
monitor, properly authorized persons on behalf of the sponsor, the quality assurance unit, and/or 
regulatory authorities. Personal medical information will always be treated as confidential.


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12.4.
Declaration of the End of the Clinical Study
The end of the study is defined as the date the last patient attends the EOT/early withdrawal visit. 
For clinical investigational centers located in the EU, a declaration of the end of the clinical 
study will be made according to the procedures outlined in Directive 2001/20/ED, Article 10(c); 
for other countries, local regulations will be followed.
12.5.
Registration of the Clinical Study
In compliance with local regulations and in accordance with Teva standard procedures, this 
clinical study may be registered on clinical studies registry websites.


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13.
DATA HANDLING, DATA QUALITY CONTROL, AND RECORD 
KEEPING
13.1.
Data Collection
Data will be collected using CRFs that are specifically designed for this study. The data collected 
on the CRFs will be captured in a clinical data management system (CDMS) that meets the 
technical requirements described in 21CFR Part 11. The CDMS will be fully validated to ensure 
that it meets the scientific, regulatory, and logistical requirements of the study before it is used to 
capture data from this study. Before using the CDMS, 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. Data will be verified using 
the data source by the study monitor, and reviewed for consistency by Data Management using 
both automated logical checks and manual review. 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.
If data are processed from other sources (eg, central laboratory, bioanalytical laboratory, central 
image center, electronic diary data, or ePRO Tablet), the results will be sent to the investigational 
center, where they will be retained but not entered into the CRF, unless otherwise specified in the 
protocol. These data may also be sent electronically to the sponsor (or organization performing 
data management) for direct entry into the clinical database. Laboratory test results will not be 
entered into the CRF, unless otherwise noted in the protocol. All data from other sources will be 
available to the investigators.
For patients who enter a study but do not meet entry criteria, at a minimum, data for screen 
failure reason, demography, and adverse events from the time of informed consent will be 
entered into the CRF. 
13.2.
Data Quality Control 
Data Management is responsible for the accuracy, quality, completeness, and internal 
consistency of the data from this study. Data handling, including data quality control (QC), will 
comply with international regulatory guidelines, including ICH GCP guidelines. Data 
management and control processes specific to this study, along with all steps and actions taken 
regarding data management and data QC, will be described in a data management plan.
Case report forms received will be processed and reviewed for completeness, consistency, and 
the presence of mandatory values. Applicable terms will be coded according to the coding 
conventions for this study. Logical checks will be implemented to ensure data quality and 
accuracy. Any necessary changes will be made in the clinical database, and data review and 
validation procedures will be repeated as needed. Data from external sources will be compared 
with the information available in the CDMS. Discrepancies found will be queried.


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Data corrections in the CDMS will be made using the CDMS update function. The system 
requires a reason for each change and keeps a complete audit trail of the data values, dates and 
times of modifications, and authorized electronic approvals of the changes.
At the conclusion of the 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.
13.3.
Archiving of Case Report Forms and Source Documents
13.3.1.
Sponsor Responsibilities
The sponsor will have final responsibility for the processing and QC of the data. Data 
management 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 CRO, 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. The original 
CRFs will be archived by the sponsor. Center-specific CRFs will be provided to the respective 
investigational centers for archiving.
13.3.2.
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 other local laws, including, but not limited to, the following:

full case histories

signed informed consent forms

patient identification lists

CRFs for each patient on a per-visit basis

data results from other sources (eg, central laboratory, bioanalytical laboratory, 
central image center, and electronic diary data)

safety reports

financial disclosure reports/forms

reports of receipt, use, and disposition of the study drug

copies of all correspondence with sponsor, the IRB/IEC, and any regulatory authority


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The investigator will retain all records related to the study until the CRO or sponsor sends 
written notification that records may be destroyed. If, after 10 years from study completion, or 
earlier (in the case of the investigative 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 sixty 60 days before any planned disposition of study records. Upon 
receipt of such request, the sponsor may make arrangements for appropriate archival or 
disposition, including requiring that the investigator deliver such records to the sponsor. The 
investigator shall notify the sponsor of any accidental loss or destruction of study records.


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14.
FINANCING AND INSURANCE
A separate clinical study agreement, including a study budget, will be entered into between each 
principal investigator and the sponsor (or the CRO designated by the sponsor) before the study 
drug is delivered.
This clinical study is insured in accordance with the corresponding local legal provisions. The 
policy coverage is subject to the full policy terms, conditions, extensions, and exclusions. 
Excluded from the insurance cover 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 Form FDA 3454. 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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15.
REPORTING AND PUBLICATION OF RESULTS
The sponsor is responsible for ensuring that the public has access to the appropriate information 
about the study by conforming to local and regional requirements and regulations for registration 
and posting of results.
The sponsor is responsible for the preparation of a clinical study report, in cooperation with the 
coordinating investigator. The final report is signed by the sponsor and, if applicable, by the 
coordinating investigator.
When the sponsor generates reports from the data collected in this study for presentation to 
regulatory authorities, drafts may be circulated to the coordinating investigator for comments and 
suggestions. An endorsement of the final report will be sought from the coordinating 
investigator.
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 primary 
publication from this study will report the results of the study in accordance with the current 
“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. Authorship will be restricted to parties who have editorial or 
conceptual input to protocol design, collection of data and/or analysis, interpretation of data, and 
manuscript preparation.
Authorship will be based on meeting all of the following 4 criteria:

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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16.
REFERENCES
Anttila V, Winsvold BS, Gormley P, Kurth T, Bettella F, McMahon G, et al. Genome-wide 
meta-analysis identifies new susceptibility loci for migraine. Nat Genet 2013;45(8):912-7.
Armour KL, Clark MR, Hadley AG, Williamson LM. Recombinant human IgG molecules 
lacking Fcgamma receptor I binding and monocyte triggering activities. Eur J Immunol 
1999;29(8):2613–24.
Ashina M, Bendtsen L, Jensen R, Schifter S, Jansen-Olesen I, Olesen J. Plasma levels of 
calcitonin gene-related peptide in chronic tension-type headache. Neurology 2000;55(9):1335–
40.
Bagley CL, Rendas-Baum R, Maglinte GA, Yan M, Varon SF, Lee J, et al. Validating Migraine-
specific Quality of Life questionnaire v 2.1 in episodic and chronic migraine. Headache 
2012;52(3):409-21.
Benschop RJ, Collins EC, Darling RJ, Allan BW, Leung D, Conner EM, et al. Development of a 
novel antibody to cGRP for the treatment of osteoarthritis-related pain. Osteoarthritis Cartilage 
2014;22(4):578-85.
Bigal ME, Lipton RB. Clinical course in migraine: conceptualizing migraine transformation. 
Neurology 2008;71(11):848-55.
Bigal ME, Serrano D, Buse D, Scher A, Stewart WF, Lipton RB. Acute migraine medications 
and evolution from episodic to chronic migraine: a longitudinal population-based study. 
Headache 2008;48:1157-68.
Brandes JL, Saper JR, Diamong M, Couch JR, Lewise DW, Schmitt J, et al. Topiramate for 
migraine prevention: a randomized controlled trial. JAMA 2004;291(8):965-73.
Edvinsson L, Goadsby PJ. Extracerebral manifestations in migraine. A peptidergic involvement? 
J Intern Med 1990;228(4):299–304.
Eftekhari S, Edvinsson L. Possible sites of action of the new calcitonin gene-related peptide 
receptor antagonists. Ther Adv Neurol Disord 2010;3(6):369–78.
Goadsby PJ, Edvinsson L, Ekman R. Vasoactive peptide release in the extracerebral circulation 
of humans during migraine headache. Ann Neurol 1990:28(2):183–7.
Goadsby PJ, Hargreaves R. Refractory migraine and chronic migraine: pathophysiological 
mechanisms. Headache 2008;48(6):799–804.
Goadsby PJ, Lipton RB, Ferrari MD. Migraine--current understanding and treatment. N Engl J 
Med 2002;346(4):257–70.
Hansen JM, Hauge AW, Olesen J, Ashina M. Calcitonin gene-related peptide triggers 
migraine-like attacks in patients with migraine with aura. Cephalalgia 2010;30(10):1179–86.
Hewitt DJ, Aurora SK, Dodick DW, Goadsby PJ, Ge YJ, Bachman R, et al. Randomized 
controlled trial of the CGRP receptor antagonist MK-3207 in the acute treatment of migraine. 
Cephalalgia 2011;31(6):712–22.


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Ho TW, Edvinsson L, Goadsby PJ. CGRP and its receptors provide new insights into migraine 
pathophysiology. Nat Rev Neurol 2010;6(10):573–82.
Ho TW, Ferrari MD, Dodick DW, Galet V, Kost J, Fan X, et al. Efficacy and tolerability of 
MK-0974 (telcagepant), a new oral antagonist of calcitonin gene-related peptide receptor, 
compared with zolmitriptan for acute migraine: a randomised, placebo-controlled, parallel-
treatment trial. Lancet 2008;372(9656):2115–23.
International Committee of Medical Journal Editors (ICMJE). Recommendations for the 
Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical Journals. Available 
at http://www.icmje.org/recommendations/. Accessed 02 July 2014.
Classification Committee of the International Headache Society. The International Classification 
of Headache Disorders, 3rd edition (beta version). Cephalalgia 2013;33(9):629-808.
Klapper J. Divalproex sodium in migraine prophylaxis: a dose-controlled study. Cephalalgia 
1997;17(2):103-8.
Kroenke K, Spitzer RL, Williams JB, Löwe B. The Patient Health Questionnaire somatic, 
anxiety, and depressive symptom scales: a systematic review. Gen Hosp Psychiatry 
2010;32(4):345-59.
Lipton RB, Bigal ME, Diamond M, Freitag F, Reed ML, Stewart WF. Migraine prevalence, 
disease burden, and the need for preventive therapy. Neurology 2007;68(5):343–9.
Lipton RB, Silberstein SD. Episodic and chronic migraine headache: breaking down barriers to 
optimal treatment and prevention. Headache 2015;55(S2):103-22.
Mathew NT, Saper JR, Silberstein SD, Rankin L, Markley HG, Solomon S, et al. Migraine 
prophylaxis with divalproex. Arch Neurol 1995;52(3):281-6.
Nadelmann JW, Phil M, Stevens J, Saper JR. Propranolol in the prophylaxis of migraine. 
Headache 1986;26(4):175-82.
Olesen J, Diener HC, Husstedt IW, Goadsby PJ, Hall D, Meier U, et al. Calcitonin gene-related 
peptide receptor antagonist BIBN 4096 BS for the acute treatment of migraine. N Engl J Med 
2004;350(11):1104–10.
Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, et al. The 
Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings from 
three multisite studies with adolescents and adults. Am J Psychiatry 2011;168(12):1266-77.
Reilly MC, Zbrozek AS, Dukes EM. The validity and reproducibility of a work productivity and 
activity impairment instrument. PharmacoEconomics 1993;4(5):353-65.
Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF, Jr., Bock SA, Branum A, et al. 
Second symposium on the definition and management of anaphylaxis: summary report-Second 
National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network 
symposium.[reprint in Ann Emerg Med 2006 Apr;47(4):373-80; PMID:16546624]. J Allergy 
Clin Immunol 2006 Feb;117(2):391-7.
Scher AI, Stewart WF, Ricci JA, Lipton RB. Factors associated with the onset and remission of 
chronic daily headache in a population-based study. Pain 2003;106(1-2):81–9.


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Silberstein SD, Neto W, Schmitt J, Jacobs D; for the MIGR-001 Study Group. Topiramate in 
migraine prevention; results of a large controlled trial. Arch Neurol 2004;61:490-5.
Silberstein S, Holland S, Freitag F, Dodick DW, Argoff C, Ashma E. Evidence-based guideline 
update: pharmacologic treatment of episodic migraine prevention in adults. Neurology 
2012;78:1337-45.
Spitzer RL, Kroenke K, Williams JB. Validation and utility of self-report version of 
PRIME-MD: the PHQ primary care study. Primary care evaluation of metal disorders. Patient 
health questionnaire. JAMA 1999;282(18):1737-44.
Stewart WF, Lipton RB, Kolodner K, Liberman J, Sawyer J. Reliability of the migraine 
disability assessment score in a population-based sample of headache sufferers. Cephalalgia 
1999a Mar;19(2):74,107-14.
Stewart WF, Lipton RB, Whyte J, Dowson A, Kolodner K, Liberman JN, et al. An international 
study to assess reliability of the Migraine Disability Assessment (MIDAS) score. Neurology 
1999b;53(5):988-94.
Tfelt-Hansen P, Pascual J, Ramadan N, Dahlöf C, D’Amico D, Diener H, et al. Guidelines for 
controlled trials of drugs in migraine: third edition. A guide for investigators. Cephalalgia 
2012;32(1):6-38.
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.


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17.
SUMMARY OF CHANGES TO PROTOCOL TV48125-CNS-30049
17.1.
Amendment 01 Dated 30 March 2016
The primary reasons for this amendment are as follows:

To incorporate required revisions based on health authority input from the European 
Medicines Agency, FDA, and Pharmaceuticals and Medical Devices Agency.

To provide clarifying language for the inclusion and exclusion criteria.

To clarify allowed and disallowed preventive medications

To revise protocol-defined adverse events of special interest, and to add clinical 
criteria for diagnosing anaphylaxis

To update and/or clarify versions of certain exploratory endpoints, including the 
EQ-5D (now -5L) and PGIC, respectively.
This revision is considered to be substantial by the sponsor’s Authorized Representative. Other 
nonsubstantial revisions have been made to the protocol (and protocol synopsis, as appropriate). 
These changes are unlikely to affect to a significant degree the safety or rights (physical or 
mental integrity) of the patients in the clinical study or the scientific value of the clinical study.
Where indicated, Table 1 (Study Procedures and Assessments) has been revised to reflect 
changes described below.


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Table 4:
Changes to the Protocol
Original text with changes shown
New wording
Reason/Justification for change
TITLE PAGE (Other section affected by this change: Clinical Study Personnel Contact Information)
Monitors
NCGS, Inc.
65 Society288 Meeting Street
Suite 400
Charleston, South Carolina 29401
United States
Monitors
NCGS, Inc.
288 Meeting Street
Suite 400
Charleston, South Carolina 29401
United States
Update was made to the address of 
the monitors.
Authorized Representative
Teva Branded Pharmaceutical Products R&D, Inc.
Teva Branded Pharmaceutical Products R&D, 
Inc.
Authorized Representative
Teva Branded Pharmaceutical Products R&D, Inc.
This reflects a change in 
responsibilities at Teva, Inc.
Sponsor’s Medical Expert
Teva Pharmaceuticals
Sponsor’s Medical Expert
Teva Pharmaceuticals
This reflects a change in 
responsibilities at Teva, Inc. and a 
minor correction to the department 
name. 
Minor change was made in the 
representative’s title and 
department name.


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© 20152016 Teva Branded Pharmaceutical Products 
R&D, Inc. All rights reserved.
© 2016 Teva Branded Pharmaceutical Products 
R&D, Inc. All rights reserved.
Administrative change.
Amendment history was added.
Administrative change.
Signature pages were updated according to most the recent template.
Administrative change.


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CLINICAL LABORATORY AND OTHER DEPARTMENTS AND INSTITUTIONS
Bioanalytical Pharmacokinetics Evaluation
(bioanalytical analysis)
 
Teva Branded Pharmaceuticals R&D, Inc.
Bioanalytical Immunogenicity Evaluation
 
 
Teva Branded Pharmaceuticals R&D, Inc.
Biomarker Evaluation
 
Teva Branded Pharmaceuticals R&D, Inc.
Bioanalytical Pharmacokinetics Evaluation
 
Teva Branded Pharmaceuticals R&D, Inc.
Bioanalytical Immunogenicity Evaluation
 
Teva Branded 
Pharmaceuticals R&D, Inc.
Biomarker Evaluation
 
Teva Branded Pharmaceuticals R&D, Inc.
This change was made to update 
the personnel responsible for the 
applicable evaluations and their 
titles, as applicable.
Pharmacogenomic and Biomarker Sample 
Storage
BioStorage Technologies, Inc. 
2910 Fortune Circle West, Suite E 
Indianapolis, IN 46241 USA
BioStorage Technologies, GmbH 
Im Leuschnerpark 1b 
64347 Griesheim, Germany
Pharmacogenomic and Biomarker Storage
BioStorage Technologies, Inc. 
2910 Fortune Circle West, Suite E 
Indianapolis, IN 46241 USA
BioStorage Technologies, GmbH 
Im Leuschnerpark 1b 
64347 Griesheim, Germany
Available vendor information was 
added.


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CLINICAL STUDY PROTOCOL SYNOPSIS 
Study Drug Dose, Mode of Administration, and Administration Rate
Prefilled syringes (active or placebo) will be 
contained in uniquely numbered kits and stored 
(refrigerated at 2°C to 8°C) on site. Active syringes 
will contain 150 mg/mL of TEV-48125, and placebo 
syringes will contain the same vehicle and excipients 
as those for active injections. Each kit will contain 1 
prefilled syringe. All study drugs will be 
administered by a qualified clinic staff member 
separate from the staff member(s) responsible for 
collecting safety and efficacy information from the 
patients.
Prefilled syringes (active or placebo) will be 
contained in uniquely numbered kits and stored 
(refrigerated at 2°C to 8°C) on site. Active syringes 
will contain 150 mg/mL of TEV-48125, and placebo 
syringes will contain the same vehicle and excipients 
as those for active injections. Each kit will contain 1 
prefilled syringe.
The requirement for 
administration of study drugs by a 
qualified clinic staff member 
separate from the staff member(s) 
responsible for collecting safety 
and efficacy information from the 
patients was removed. 
1
BACKGROUND INFORMATION
1.1 Introduction (Other sections affected by this change: Section 16)
However, approximately 3% to 6% of individuals 
with EM evolve, in any given year, to a significantly 
more disabling condition called chronic migraine 
(CM) (Bigal et al 2008, Lipton et al 2007, Scher et 
al 2003). Individuals with CM present with 
headaches of any severity on 15 or more days per 
month and have full-blown migraine on at least 8 
days per month (Classification Committee of the 
IHS, 2013). A sizable proportion of individuals with 
CM experiences daily headaches and, therefore, faces
considerable disability (Bigal and Lipton 2008).
[…]
Calcitonin gene-related peptide (CGRP) is a well-
studied neuropeptide found at the centers of the 
migraine processes, both centrally and peripherally 
(Eftekhari and Edvinsson 2010, Olesen 2011).
However, approximately 3% of individuals with EM 
evolve, in any given year, to a significantly more 
disabling condition called chronic migraine (CM) 
(Bigal et al 2008, Lipton et al 2007, Scher et al 
2003). Individuals with CM present with headaches 
of any severity on 15 or more days per month and 
have full-blown migraine on at least 8 days per 
month (Classification Committee of the IHS, 2013). 
A sizable proportion of individuals with CM 
experiences daily headaches and, therefore, faces 
considerable disability (Bigal and Lipton 2008).
[…]
Calcitonin gene-related peptide (CGRP) is a well-
studied neuropeptide found at the centers of the 
migraine processes, both centrally and peripherally 
(Eftekhari and Edvinsson 2010).
Update/correction of information 
and associated literature on 
evolution of EM to CM was made.
Revision of other select literature 
cited was made here and 
throughout the document.
Although there are more than 40 medications within 
Although there are more than 40 medications within 
Update/correction was made 


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these classes of drugs that are used with varying 
response rates to prevent migraine, only 5 marketed 
drugs are approved by the Food and Drug 
Administration (FDA) in the United States (US) 
for the preventive treatment of migraine; 4 of 
them are approved for the prophylaxis of 
migraine: propranolol, timolol maleate, 
divalproex sodium, and topiramate. The clinical 
trials (Brandes et al 2004, Klapper 1997, Mathew 
et al 1995, Nadelmann et al 1986, Silberstein et al 
2004) that supported registration of these drugs 
for this indication were conducted before the 
establishment of CM as a single entity and 
generally included patients with headaches on less 
than 15 days per month. 4 (propranolol [Inderal®, 
Akrimax Pharmaceuticals], timolol [Blocadren®, 
Merck & Co, Inc.], divalproex sodium [Depakote®, 
AbbVie, Inc.], and topiramate [Topamax®, Jannsen]) 
are approved by the United States Food and Drug 
Administration (FDA) for the prevention or 
prophylaxis of EM and only 1 (onabotulinumtoxinA 
[Botox®, Allergan, Inc.]) is approved for the 
prevention of CM Only 1 medication, 
onabotulinumtoxinA, is approved for prophylaxis 
of CM (Lipton and Silberstein 2015). Notably, 
despite evidence suggesting that inhibition of CGRP 
is effective as a preventive migraine treatment, no 
available treatment directly targets CGRP.
these classes of drugs that are used with varying 
response rates to prevent migraine, only 5 marketed 
drugs are approved by the Food and Drug 
Administration (FDA) in the United States (US) for 
the preventive treatment of migraine; 4 of them are 
approved for the prophylaxis of migraine: 
propranolol, timolol maleate, divalproex sodium, and 
topiramate. The clinical studies (Brandes et al 2004, 
Klapper 1997, Mathew et al 1995, Nadelmann et al 
1986, Silberstein et al 2004) that supported 
registration of these drugs for this indication were 
conducted before the establishment of CM as a 
single entity and generally included patients with 
headaches on less than 15 days per month. Only 
1 medication, onabotulinumtoxinA, is approved for 
prophylaxis of CM (Lipton and Silberstein 2015).
regarding approved drugs for 
preventive treatment of migraine 
and associated literature.
1.3.1
Nonclinical Studies
In vivo pharmacology studies of TEV-48125 in 
animal models indicate that TEV-48125 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 
In vivo pharmacology studies of TEV-48125 in 
animal models indicate that TEV-48125 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 
Text was updated with the latest 
relevant information available 
from the nonclinical studies.


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response in cynomolgus monkey.
[…]
The inflammation was consideredsuspected to be the 
result of immune complex formation/deposition from 
the monkeys’ immunogenic response to the drug 
(TEV-48125) and was not considered to be clinically 
relevant. In the pivotal 6-month chronic toxicity 
study in monkeys following once-weekly sc dosing at 
dosage levels of up to 300 mg/kg/week, achieving 
high exposure throughout the study, no 
microscopic findings were noted in any of the organs, 
including the ciliary vessels of the eyes, and the 
NOAEL of the chronic toxicity study was 
determined to be the highest dose tested, 300 
mg/kg/week. Thus, it is believed that in view of the 
low frequency (ie, observed in very few animals) 
and minimal severity, the finding (perivascular 
inflammation) that was only recorded in the 3-
month toxicity study, and had been resolved 
during the recovery period, is an incidental 
finding.
The pharmacokinetics of TEV-48125 in animals 
(rats and monkeys) is typical of a humanized IgG2 
molecule, with low mean plasma clearance, low 
volume of distribution at steady state, and a long 
t½. Exposure as defined by the maximum observed 
plasma drug concentration (Cmax) and the area 
under the plasma concentration-time curve 
increased linearly across doses following single 
and repeated once-weekly dosing. No gender 
differences in exposure were observed in rats or 
monkeys.
Additionally, pivotal reproductive and developmental 
toxicity studies in animalsrabbits and rats with 
TEV-48125 were conducted. The in life portion was
monkey.
[…]
The inflammation was suspected to be the result of 
immune complex formation/deposition from the 
monkeys’ immunogenic response to the drug 
(TEV-48125). In the pivotal 6-month chronic 
toxicity study in monkeys following once-weekly sc 
dosing at dosage levels of up to 300 mg/kg/week, 
achieving high exposure throughout the study, no 
microscopic findings were noted in any of the 
organs, including the ciliary vessels of the eyes, and 
the NOAEL of the chronic toxicity study was 
determined to be the highest dose tested, 300 
mg/kg/week. Thus, it is believed that in view of the 
low frequency (ie, observed in very few animals) and 
minimal severity, the finding (perivascular 
inflammation) that was only recorded in the 3-month 
toxicity study, and had been resolved during the 
recovery period, is an incidental finding. 
The pharmacokinetics of TEV-48125 in animals (rats 
and monkeys) is typical of a humanized IgG2 
molecule, with low mean plasma clearance, low 
volume of distribution at steady state, and a long t½. 
Exposure as defined by the maximum observed 
plasma drug concentration (Cmax) and the area under 
the plasma concentration-time curve increased 
linearly across doses following single and repeated 
once-weekly dosing. No gender differences in 
exposure were observed in rats or monkeys.
Additionally, pivotal reproductive and 
developmental toxicity studies in rabbits and rats 
with TEV-48125 were conducted and completed.


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and completed, and evaluation is ongoing.
1.8 Location and Timing of Study (Other sections affected by this change: Synopsis)
This study is planned to be conducted …at 
approximately 130140 centers.
This study is planned to be conducted …at 
approximately 140 centers.
The number of study centers was 
expanded.
2
PURPOSE OF THE STUDY AND STUDY OBJECTIVES
2.2.2
Secondary Objectives (Other sections affected by this change: Synopsis and Sections 2.3.2 and 9.5.2)
The secondary objectives of this study are as follows:

to evaluate the proportion of patients 
reaching at least 50% reduction in the 
monthly average number of migraine days 
with TEV-48125 during the 12-week period 
after the 1st dose of study drug relative to 
the baseline period
[…]

to demonstrate the efficacy of TEV-48125, 
as assessed by the reduction in the 
monthly average number of migraine days 
during the 12-week period after the 1st 
dose of study drug relative to the baseline 
period in patients not receiving 
concomitant migraine preventive 
medications at baseline
[…]

to evaluate the incidenceimmunogenicity of 
TEV-48125 and the impact of antidrug 
antibodies (ADAs) on efficacy and 
tolerabilitysafety during 12 weeks of 
treatment with TEV-48125 relative to 
placebo
The secondary objectives of this study are as 
follows:

to evaluate the proportion of patients 
reaching at least 50% reduction in the 
monthly average number of migraine days 
with TEV-48125 during the 12-week period 
after the 1st dose of study drug relative to the 
baseline period
[…]

to demonstrate the efficacy of TEV-48125, 
as assessed by the reduction in the monthly 
average number of headache days of at least 
moderate severity during the 12-week period 
after the 1st dose of study drug relative to the 
baseline period in patients not receiving 
concomitant migraine preventive 
medications 

to evaluate the immunogenicity of TEV-
48125 and the impact of antidrug antibodies 
(ADAs) on efficacy and safety during 
12 weeks of treatment with TEV-48125
Two secondary objectives were 
revised for clarity and correctness.
A secondary objective was added 
for patients not receiving 
concomitant medications at 
baseline.
For all secondary objectives, 
corresponding changes were made 
to the associated endpoints.
2.2.3
Exploratory Objectives (Other sections affected by this change: Synopsis and Sections 2.3.3 and 9.5.3)
The exploratory objectives of the study are as 
The exploratory objectives of the study are as 
Two related objectives (responder 


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follows: 

to demonstrate the efficacy of TEV-48125, 
as assessed by the decrease in the monthly 
average number of headache days of at 
least moderate severity during the 12-week 
period after the 1st dose of study drug 
relative to the baseline period

to evaluate the proportion of patients 
reaching at least 75% reduction and total 
(100%) reduction in the monthly average 
number of migraine days during the 12-week 
period after the 1st dose of study drug

to evaluate the proportion of patients 
reaching total (100%) reduction in the 
number of migraine days during the 12 week 
period after the 1st dose of study drug 

to evaluate the proportion of patients 
reaching at least 50% reduction and at least 
75%, or100% reduction in the number of 
migraine days during the 4-week period after 
the 1st dose of study drug relative to the 
baseline period who sustain this level of 
response over the 12-week period after the 1st
dose of study drug

to demonstrate the efficacy of TEV-48125 in 
patients who previously used topiramate 
for migraine, but discontinued, as assessed 
by the reduction inof the monthly average 
number of headachemigraine days of at least 
moderate severity during the 12-week period 
after the 1st dose of study drug relative to the 
baseline period

to demonstrate the efficacy of TEV-48125 in 
patients who previously used topiramate
onabotulinumtoxinA for migraine, but 
follows: 

to demonstrate the efficacy of TEV-48125, 
as assessed by the decrease in the monthly 
average number of headache days of at least 
moderate severity during the 12-week period 
after the 1st dose of study drug relative to the 
baseline period

to evaluate the proportion of patients 
reaching at least 75% reduction and total 
(100%) reduction in the monthly average 
number of migraine days during the 12-week 
period after the 1st dose of study drug

to evaluate the proportion of patients 
reaching at least 50% reduction and at least 
75% reduction in the number of migraine 
days during the 4-week period after the 1st
dose of study drug relative to the baseline 
period who sustain this level of response 
over the 12-week period after the 1st dose of 
study drug

to demonstrate the efficacy of TEV-48125 in 
patients who previously used topiramate for 
migraine, but discontinued, as assessed by 
the reduction of the monthly average number 
of migraine days during the 12-week period 
after the 1st dose of study drug relative to the 
baseline period

to demonstrate the efficacy of TEV-48125 in 
patients who previously used 
onabotulinumtoxinA for migraine, but 
discontinued, as assessed by the reduction of 
the monthly average number of migraine 
days during the 12-week period after the 1st
dose of study drug relative to the baseline 
period
analysis) were combined.
Several objectives were added for 
improved alignment across 
migraine studies.
Several minor editorial changes 
were made.
For all exploratory objectives, 
corresponding changes were made 
to the associated endpoints.


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125
discontinued, as assessed by the reduction of 
the monthly average number of migraine
days during the 12-week period after the 1st
dose of study drug relative to the baseline 
period
[…]

to demonstrate the efficacy of TEV-48125, 
as assessed by the reduction in the number 
of headache days of at least moderate 
severity during the 4-week period after 
each dose of study drug

to evaluate the proportion of patients 
reaching at least 50% reduction, at least 
75% reduction, and total (100%) 
reduction in the monthly average number 
of headache days of at least moderate 
severity during the 12-week period after 
the 1st dose of study drug

to evaluate the proportion of patients 
reaching at least 50% reduction and at 
least 75% reduction in the number of 
headache days of at least moderate 
severity during the 4-week period after the 
1st dose of study drug for whom this level 
of effect is sustained throughout the 12-
week period after the 1st dose of study 
drug

to demonstrate the efficacy of TEV-48125, 
as assessed by the reduction in the number 
of headache days of at least moderate 
severity during the 12-week period after 
the 1st dose of study drug for patients not 
receiving concomitant preventive migraine 
medications 

to demonstrate the efficacy of TEV-48125, 
[…]

to demonstrate the efficacy of TEV-48125, 
as assessed by the reduction in the number of 
headache days of at least moderate severity 
during the 4-week period after each dose of 
study drug

to evaluate the proportion of patients 
reaching at least 50% reduction, at least 75% 
reduction, and total (100%) reduction in the 
monthly average number of headache days 
of at least moderate severity during the 12-
week period after the 1st dose of study drug

to evaluate the proportion of patients 
reaching at least 50% reduction and at least 
75% reduction in the number of headache 
days of at least moderate severity during the 
4-week period after the 1st dose of study drug 
for whom this level of effect is sustained 
throughout the 12-week period after the 1st 
dose of study drug

to demonstrate the efficacy of TEV-48125, 
as assessed by the reduction in the number of 
headache days of at least moderate severity 
during the 12-week period after the 1st dose 
of study drug for patients not receiving 
concomitant preventive migraine 
medications 

to demonstrate the efficacy of TEV-48125, 
as assessed by the reduction in the number of 
headache days of at least moderate severity 
during the 12-week period after the 1st dose 
of study drug for patients who used 
topiramate for migraine in the past

to demonstrate the efficacy of TEV-48125, 
as assessed by the reduction in the number of 


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as assessed by the reduction in the number 
of headache days of at least moderate 
severity during the 12-week period after 
the 1st dose of study drug for patients who 
used topiramate for migraine in the past

to demonstrate the efficacy of TEV-48125, 
as assessed by the reduction in the number 
of headache days of at least moderate 
severity during the 12-week period after 
the 1st dose of study drug for patients who 
used onabotulinumtoxinA for migraine in 
the past

to demonstrate the efficacy of TEV-48125, 
as assessed by the reduction in the 
monthly average number of headache 
hours of any severity during the 12-week 
period after the 1st dose of study drug

to demonstrate the efficacy of TEV-48125, 
as assessed by the reduction in the 
monthly average number of headache 
hours of at least moderate severity during 
the 12-week period after the 1st dose of 
study drug
[…]

to explore the relationship between genetic 
polymorphisms within the CGRP receptor-
ligand complex (eg, CALCA, CALCB, 
CALCRL, CRCP, and RAMP) and migraine-
associated genes (eg, PRDM16, AJAP1, 
TSPAN2, MEF2D, TRPM8, TGFBR2, 
PHACTR1, FHL5, C7orf10, MMP16, 
ASTN2, LRP1, APOA1BP, TBC1D7, FUT9, 
STAT6, ATP5B, and MTHFR) and mode-
of-action-related pathways versus 
hypertension, migraine severity, and safety
headache days of at least moderate severity 
during the 12-week period after the 1st dose 
of study drug for patients who used 
onabotulinumtoxinA for migraine in the past

to demonstrate the efficacy of TEV-48125, 
as assessed by the reduction in the monthly 
average number of headache hours of any 
severity during the 12-week period after the 
1st dose of study drug

to demonstrate the efficacy of TEV-48125, 
as assessed by the reduction in the monthly 
average number of headache hours of at least 
moderate severity during the 12-week period 
after the 1st dose of study drug
[…]

to explore the relationship between genetic 
polymorphisms within the CGRP receptor-
ligand complex (eg, CALCA, CALCB, 
CALCRL, CRCP, and RAMP) and 
migraine-associated genes (eg, PRDM16, 
AJAP1, TSPAN2, MEF2D, TRPM8, 
TGFBR2, PHACTR1, FHL5, C7orf10, 
MMP16, ASTN2, LRP1, APOA1BP, 
TBC1D7, FUT9, STAT6, ATP5B, and 
MTHFR) and mode-of-action-related 
pathways versus hypertension, migraine 
severity, and safety and efficacy responses


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and efficacy responses
2.3.3
Exploratory Efficacy Endpoints (Other sections affected by this change: Synopsis, List of Abbreviations, and Sections 3.1, 3.6, 3.14 
[Table 1], 3.14.2.2, 3.14.3.1.3, 6.5, and 9.5.3)

mean change from baseline (day 0) in the 
health status, as measured by the EuroQol-5 
Dimension, 5 response level version
(EQ-5D-5L) questionnaire at 4 weeks after 
administration of the last (3rd) dose of study 
drug

mean change from baseline (day 0) in the 
health status, as measured by the EuroQol-5 
Dimension, 5 response level version (EQ-
5D-5L) questionnaire at 4 weeks after 
administration of the last (3rd) dose of study 
drug
This change reflects the update to 
the 5-level version instead of the 
3-level version of the EQ-5D 
(5 responses).
2.3.4
Safety and Tolerability Endpoints (Other sections affected by this change: Synopsis and Section 3.4)
changes from baseline in vital signs (systolic and 
diastolic blood pressure, pulse, oral temperature, and 
respiratory rate) measurements
changes from baseline in vital signs (systolic and 
diastolic blood pressure, pulse, temperature, and 
respiratory rate) measurements
“Oral” was removed to allow 
temperature to be measured using 
other methods (eg, under arm).
3.1 General Design and Study Schema (Other sections affected by this change: Synopsis and Sections 3.14.1, 3.14.2.2, and 5.3.2)
If pPatients are should not be using concomitant 
preventive migraine medications (presented in 
Appendix B) before enrolling in the study (ie, 
signing of the informed consent form) at the time of 
the screening visit, they and will not be allowed to 
initiate these medications after study start.
Patients should not be using concomitant preventive 
migraine medications (presented in Appendix B) at 
the time of the screening visit and will not be 
allowed to initiate these medications after study start.
An error was corrected. In this 
study, enrollment is considered to 
occur at the time of randomization 
rather than at the time of consent 
form signature.
3.7 Randomization and Blinding (Other sections affected by this change: Synopsis and Sections 3.1, 5.1, and 9)
This study is a randomized study with stratification 
based on gender, country, and baseline preventive 
medication use (yes, no).
This is a randomized study with stratification based 
on gender, country, and baseline preventive 
medication use (yes, no).
Clarification was made regarding 
a stratification factor.


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3.8.2
Blinding/Unblinding
Pharmacokinetic data may be assessed during the 
study. For patients who have pharmacokinetic sample 
bioanalysis and/or data analysis conducted, the 
individuals responsible for sample bioanalysis and 
other responsible personnel will know who received 
each TEV 48125 dose regimen and who received 
placebo during the study (of those patients only).
Personnel responsible for bioanalysis will be 
provided with the randomization code in order to 
facilitate the analysis. However, the personnel 
responsible for bioanalysis and pharmacokinetic data 
analysis will not have access to clinical safety and 
efficacy data and will provide concentration data to 
other personnel in a manner that will not identify 
individual patients (ie, a dummy patient identifier 
will be linked to an individual patient’s concentration 
data). 
Pharmacokinetic data may be assessed during the 
study. Personnel responsible for bioanalysis will be 
provided with the randomization code in order to 
facilitate the analysis. However, the personnel 
responsible for bioanalysis 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 an individual 
patient’s concentration data).
The blinding criteria and 
procedures with respect to 
pharmacokinetic data were 
updated. 
3.11
Duration of Patient Participation and Justification
This is consistent with the 2009 FDA Guidance for 
Industry on Assay Development for Immunogenicity 
Testing of Therapeutic Proteins; a complete washout 
of the antibody drug from the circulating blood is 
expected after approximately 7.5 months (≥5 half-
lives), allowing a more precise evaluation of ADA.
This is consistent with the 2009 FDA Guidance for 
Industry on Assay Development for Immunogenicity 
Testing of Therapeutic Proteins; a complete washout 
of the drug from the circulating blood is expected 
after approximately 7.5 months (≥5 half-lives), 
allowing a more precise evaluation of ADA
An error was corrected.
3.14
Study Procedures, Table 1 (Other sections affected by this change: Sections 3.14.3.1.2, 3.14.3.1.3, and 7.3.5.1)
Serum/urine β-HCG testf
Urine β-HCG testf
f
Women of childbearing potential only; a serum 
β HCG test will be performed at screening, and urine 
β HCG tests will be performed at subsequent visits.
Serum β-HCG testf
Urine β-HCG testf
f
Women of childbearing potential only.
The footnote describing serum and 
urine β-HCG tests was simplified, 
and the rows for these tests were 
placed on 2 separate rows in Table 
1 for ease of reference to time 
points.


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3.14
Study Procedures, Table 1 (Related to the change in Section 7.1.6 described below; Other sections affected by this change: 
Sections 3.14.2.2, 3.14.3.1.2, and 3.14.3.1.3)
Blood samples for serum ADA 
concentrationassessmentk
k
Blood samples for serum ADA assessment will 
also be collected upon observation of any severe 
hypersensitivity reaction (eg, anaphylaxis).
Blood samples for serum ADA assessmentk
k
Blood samples for serum ADA assessment will 
also be collected upon observation of any severe 
hypersensitivity reaction (eg, anaphylaxis).
These additional blood sample 
collections are related to the 
designation of anaphylaxis and 
severe hypersensitivity reactions 
as adverse events of special 
interest in this amendment.
“Concentration” and “assay” were 
changed to “assessment” 
throughout the document for 
consistency of verbiage.” Please 
check if this should also be added 
here.
3.14
Study Procedures, Table 1
Blood sample for pharmacogenomic analysisl
l
A single blood sample for pharmacogenomic 
analysis will be collected at visit 2 or any visit 
thereafter from patients who consent to this 
procedure. A separate informed consent form for 
pharmacogenomic sampling must be signed by the 
patient.
Blood sample for pharmacogenomic analysisl
l
A single blood sample for pharmacogenomic 
analysis will be collected at visit 2 or any visit 
thereafter from patients who consent to this 
procedure. A separate informed consent form for 
pharmacogenomic sampling must be signed by the 
patient.
Details of this sampling were 
moved to a footnote and revised to 
emphasize that a separate ICF is 
required.
3.14
Study Procedures, Table 1 (Other sections affected by this change: Section 7.5)
c
Electrocardiograms will be performed in 
triplicate, with approximately 1 minute between 
recordings.
c
Electrocardiograms will be performed in 
triplicate.
Specification for approximately 
1 minute interval between 
recordings was removed, as it was 
deemed unnecessary. 


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3.14.1 Procedures for Screening (Visit 1 [Day –28])
The first 2 digits of the screening number will be the 
number assigned to the country where the 
investigational center is located, the next 3 digits will 
be the investigational center number, and the last 
3 digits will be the patient number assigned at the 
investigator center (eg, the 3rd patient screened in 
Italythe US [country 01] at center 101 would be 
assigned the number of 01101003).
The first 2 digits of the screening number will be the 
number assigned to the country where the 
investigational center is located, the next 3 digits will 
be the investigational center number, and the last 
3 digits will be the patient number assigned at the 
investigator center (eg, the 3rd patient screened in the 
US [country 01] at center 101 would be assigned the 
number of 01101003).
Country 01 is the US.
4
SELECTION AND WITHDRAWAL OF PATIENTS
4.1 Patient Inclusion Criteria (Other sections affected by this change: Synopsis)
d.
[…]

on ≥4 days, fulfilling any of the following:
o
ICHD-3 diagnostic criteria C and D for 
1.1 Migraine without aura (Appendix 
CD)
o
ICHD-3 criteria B and C for 1.2 
Migraine with aura (Appendix CD)
o
Probable migraine (a migraine 
subtype where only 1 migraine 
criterion is missing)
o
[…]
e. Not using preventive medications (presented in 
Appendix B) (ie, at least 5 half-lives have 
passed since last use) or using no more than 1 
preventive medication (presented in 
Appendix Amedications) for migraine or other 
medical conditions (eg, topiramate) for migraine 
or other medical conditions (eg, propranolol used 
for hypertension) if the dose and regimen have 
been stable for at least 2 months prior to 
d. […]

on ≥4 days, fulfilling any of the following:
o
ICHD-3 diagnostic criteria C and D for 
1.1 Migraine without aura (Appendix D)
o
ICHD-3 criteria B and C for 1.2 
Migraine with aura (Appendix D)
o
Probable migraine (a migraine subtype 
where only 1 migraine criterion is 
missing)
o
[…]
e. Not using preventive medications (presented in 
Appendix B) (ie, at least 5 half-lives have passed 
since last use) or using no more than 1 preventive 
medication (presented in Appendix A) for 
migraine or other medical conditions (eg, 
propranolol used for hypertension) if the dose and 
regimen have been stable for at least 2 months 
prior to beginning the 28 day run-in period.
f. Body mass index of 17.5 to 37.5 kg/m2 and a total 
body weight between 45 and 120 kg, inclusive
A criterion of a probable migraine 
was added to further define the 
patient population.
Allowed/disallowed preventive 
medication was clarified.
Upper boundary of the total body 
weight was expanded up to 
120 kg. This limit was used in 
Phase 2 studies; no associated 
safety signals were detected.
Contraception criteria were 
updated and clarified to comply 
with the current Teva standards.
Language regarding the timing of 
the serum β-HCG pregnancy 
testing was clarified.


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beginning the 28 day run-in period. A list of 
preventive medications is presented in Appendix 
A.
f. Body mass index of 17.5 to 37.5 kg/m2 and a total 
body weight between 45 and 115120 kg, inclusive
g. […]
if of childbearing potential, patients must meet 
any of the following criteria:
[…]

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 subject. 
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.

Patients will remain abstinent throughout the 
study in the context of the preferred and usual 
lifestyle. Declaration of abstinence for the 
duration of the study and withdrawal are not 
acceptable methods of contraception.

Patients have sexual preference that precludes 
the possibility of pregnancy.
h. Female patients of childbearing potential must 
have sa negative serum β-HCG pregnancy test 
prior to randomization at screening (confirmed by 
urine dipstick β-HCG pregnancy test at 
baseline).
g. […]
if of childbearing potential, patients must meet 
any of the following criteria:
[…]

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 subject. 
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.
h.Female patients of childbearing potential must
have a negative serum β-HCG pregnancy test at 
screening (confirmed by urine dipstick β-HCG 
pregnancy test at baseline).


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4.2 Patient Exclusion Criteria (Other sections affected by this change: Synopsis)
b.
Patient is using medications containing opioids 
(including codeine) or barbiturates (including 
butalbital/aspirin/caffeine [Fiorinal®, Actavis plc], 
butalbital/paracetamol/caffeine [Fioricet®, Cardinal 
Health], or any other combination containing 
butalbital) on more than 4 days per month for the 
treatment of migraine or for any other reason.
c.
Patients who are taking migraine preventative 
treatment at the time of screening and who have 
previously failed (lack of efficacy) 2 or more of the 
clusters of the following medications for treatment of 
EM or CM after adequate therapeutic trial defined as 
use for at least 3 months at accepted migraine 
therapeutic doses:

cluster A: divalproex sodium and sodium 
valproate

cluster B: topiramate flunarizine and
pizotifen

cluster C : amitriptyline, nortriptyline, and 
venlafaxine, and duloxetine

[…]
f. Evidence or medical history of clinically 
significant psychiatric issues, including major 
depression, panic disorder, or generalized anxiety 
disorder any suicide attempt in the past or 
suicidal ideation with a specific plan in the past 
2 years, at the discretion of the investigator
[…]
j. Past or current history of cancer in the past 5 
years, except for appropriately treated 
nonmelanoma skin carcinoma in the last 5 years
[…]
b.
Patient is using medications containing opioids 
(including codeine) or barbiturates (including 
butalbital/aspirin/caffeine, 
butalbital/paracetamol/caffeine, or any other 
combination containing butalbital) on more than 4 
days per month for the treatment of migraine or for 
any other reason.
c.
Patients who have previously failed (lack of 
efficacy) 2 or more of the clusters of the following 
medications for treatment of EM or CM after 
adequate therapeutic trial defined as use for at least 3 
months at accepted migraine therapeutic doses:

cluster A: divalproex sodium and sodium 
valproate

cluster B:flunarizine and pizotifen

cluster C : amitriptyline, nortriptyline,
venlafaxine, and duloxetine

[…]
f. Evidence or medical history of clinically 
significant psychiatric issues, including any 
suicide attempt in the past or suicidal ideation 
with a specific plan in the past 2 years
[…]
j. Past or current history of cancer in the past 5 
years, except for appropriately treated 
nonmelanoma skin carcinoma
[…]
r. History of alcohol or drug abuse during the past 2 
years, or alcohol or drug dependence during the 
past 5 years
s. The patient cannot participate or successfully 
complete the study, in the opinion of their 
References to drug brand names 
have been removed.
Exclusion criterion related to prior 
migraine medication use was 
updated in line with clinical 
practice.
Editorial change was made to the 
prior history of cancer criterion.
Minor editorial changes were also 
made to other exclusion criteria 
(not shown)
Psychiatric history criterion was 
updated to specifically address 
suicidal ideation or behavior 
within the last 6 months.
History of alcohol and drug abuse 
and dependence criterion was 
modified to align with Teva’s 
current practice.
Language was updated to reflect 
commonly used terminology.


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r. Lifetime History of alcohol or drug abuse during 
the past 2 years, or alcohol or drug dependence 
during the past 5 years
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:

[…]

in custody due to an administrative or a legal 
decision, under tutelageguardianship, or 
being admitted to a sanitarium or social 
institution institutionalized
healthcare provider or the investigator, for any of 
the following reasons:

[…]

in custody due to an administrative or a legal 
decision, under guardianship, or or 
institutionalized
5.2 Restrictions
Highly effective contraception methods include the 
following hormonal and other methods of birth 
control:

combined (estrogen and gestagen) oral 
contraceptives, hormone implants, hormone 
rings, contraceptive patch, and hormone 
injectables initiated at least 7 days before 
study drug administration

hormone containing intrauterine device in 
place for a period of at least 2 months before 
study drug administration

[…]
There were no additional restrictions in this study.
In addition, male patients may not donate sperm 
for the duration of the study and for 7.5 months 
after discontinuation of study drug.
Highly effective contraception methods include the 
following hormonal and other methods of birth 
control:

combined (estrogen and gestagen) oral 
contraceptives, hormone implants, hormone 
rings, contraceptive patch, and hormone 
injectables initiated at least 7 days before study 
drug administration

intrauterine device in place for a period of at 
least 2 months before study drug administration

[…]
There were no additional restrictions in this study.
In addition, male patients may not donate sperm for 
the duration of the study and for 7.5 months after 
discontinuation of study drug.
Contraception criteria were 
updated.


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5.3 Prior and Concomitant Therapy or Medication
Any prior or concomitant therapy, medication, or 
procedure (ie, procedures for the treatment of 
migraine [eg, nerve blocks])that a patient has had 
within 6 months before study drug administration and 
up to the end of the study period will be recorded on 
the CRF. Generic or trade name, indication, and 
dosage will be recorded. In addition, migraine 
preventive medication that a patient took within 
2 years before study drug administration will be 
recorded on the CRF. Generic or trade name, 
indication, and dosage will be recorded.
Any prior or concomitant therapy, medication, or 
procedure that a patient has had within 6 months 
before study drug administration and up to the end of 
the study period will be recorded on the CRF. 
Generic or trade name, indication, and dosage will be 
recorded. In addition, migraine preventive 
medication that a patient took within 2 years before 
study drug administration will be recorded on the 
CRF.
Parenthetical clarification was 
considered to be limiting and was 
therefore removed.
Process clarification was added.


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5.3.2
Concomitant Therapy: Therapies and Medications (Other sections affected by this change: Synopsis, Sections 3.1 and 4.1, and 
Appendix A)
Up to 30% of patients will be allowed to remain on 
stable doses of no more than 1 preventive migraine 
medication for the duration of the study provided the 
medication has at least moderate evidence of efficacy 
as defined by guidelines (Silberstein et al 2012) and 
presented in Appendix A. Patients on preventive 
medication must be on a stable dose for at least 2 
months of consecutive use prior to study entry. 
Alternatively, patients must have discontinued the 
preventive medication at least 5 half-lives prior to 
screening. Preventive migraine medications 
disallowed for at least 70% of patients for the 
duration of the study are presented in Appendix 
B.
Patients will be allowed to use acute medications to 
treat acute migraine attacks, as needed, with the 
exception of medications containing opioids and 
barbiturates, which cannot be used more than 4 times 
per month prior to study entry.
Use of concomitant therapies for indications other 
than migraine prevention is allowed throughout the 
course of the study, provided they are not effective 
for migraine or they meet the criteria for permitted 
concomitant preventive medication.
All concomitant medications taken during the 
study…
Up to 30% of patients will be allowed to remain on 
stable doses of no more than 1 preventive migraine
medication for the duration of the study provided the 
medication has at least moderate evidence of efficacy 
as defined by guidelines (Silberstein et al 2012) and 
presented in Appendix A. Patients on preventive 
medication must be on a stable dose for at least 2 
months of consecutive use prior to study entry. 
Alternatively, patients must have discontinued the 
preventive medication at least 5 half-lives prior to 
screening. Preventive migraine medications 
disallowed for at least 70% of patients for the 
duration of the study are presented in Appendix B.
Patients will be allowed to use acute medications to 
treat acute migraines attacks, as needed.
All concomitant medications taken during the 
study…
The title of this section was 
updated.
It was specified that up to 30% of 
patients could remain on stable 
doses of 1 preventive migraine 
medication.
An alternative option was 
provided for patients to 
discontinue preventive medication 
at least 5 half-lives prior to 
screening.
Provision regarding the use of 
medications containing opioids 
and barbiturates was removed, as 
it was redundant with exclusion 
criterion b.
Provision regarding the use of 
other concomitant medications 
was removed to further align with 
current approach.
A clarification was made. In this 
study, acute medications can be 
used to treat acute migraine 
attacks.
5.5 Total Blood Volume, Table 2


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c
For each 18.5-mL sample, individual volumes 
will be 6 mL each for serum and plasma and 6.5 
mL for RNA.
d
For patients who consent to pharmacogenomic 
testing.
c
For each 18.5-mL sample, individual volumes 
will be 6 mL each for serum and plasma and 6.5 mL 
for RNA.
d
For patients who consent to pharmacogenomic 
testing.
A footnote was added for 
consistency with the blood 
volumes described throughout the 
protocol.
6
ASSESSMENT OF EFFICACY
6.3 Two-Item Patient Health Questionnaire/9-Item Patient Health Questionnaire (Other sections affected by this change: Synopsis and 
Sections 3.6, 3.14 [Table 1], 3.14.2.2, and 3.14.3.1.3)
Each of the items is scored on a scale of 0 (“not at 
all”) to, 1 (“several days”), 2 (“more than half the 
days”), and 3 (“nearly every day”) based on the 
frequency of symptoms during the past 2 weeks 
(Spitzer et al 1999). The PHQ-2 was developed from 
the PHQ-9 to rapidly screen for depression and 
consists of the first 2 questions from the PHQ-9. 
[…]
If the PHQ-2 is positive (ie, a score of ≥3), patients 
will complete questions 3 through 9 (unique 
questions) of the PHQ-9.
Each of the items is scored on a scale of 0 (“not at 
all”), 1 (“several days”), 2 (“more than half the 
days”), and 3 (“nearly every day”) based on the 
frequency of symptoms during the past 2 weeks
(Spitzer et al 1999). The PHQ-2 was developed from 
the PHQ-9 to rapidly screen for depression and 
consists of the first 2 questions from the PHQ-9. […]
If the PHQ-2 is positive (ie, a score of ≥3), patients 
will complete questions 3 through 9 ([unique 
questions) of the PHQ-9.
Time period for symptom 
frequency in the PHQ was 
specified.
Update/correction was made 
indicating that patients will only 
complete the unique portions of 
the PHQ-9 after a positive PHQ-2 
score.
6.6 Patient Global Impression of Change Scale
The PGIC scale is a validated generic tool for 
assessment of overall change in the severity of illness 
following treatment. Patients will rate how they feel 
now compared with how they felt before receiving 
study drug on a 7 point scale where 3 is “very much 
worse,” 0 is “no change,” and 3 is “very much 
improved”. Patients will rate how they describe the 
change (if any) that their migraine/headaches 
have had in their general quality of life and health 
status since beginning the treatment in this study 
on a 7-point scale where 1=no change (or 
condition has got worse); 2=almost the same, 
hardly any change at all; 3=a little better, but no 
The PGIC scale is a validated generic tool for 
assessment of overall change in the severity of 
illness following treatment. Patients will rate how 
they describe the change (if any) that their 
migraine/headaches have had in their general quality 
of life and health status since beginning the treatment 
in this study on a 7-point scale where 1=no change 
(or condition has got worse); 2=almost the same, 
hardly any change at all; 3=a little better, but no 
noticeable change; 4=somewhat better, but the
change has not made any real difference;
5=moderately better, and a slight but noticeable 
change; 6=better, and a definite improvement that 
Correction was made regarding 
PGIC scale numbering and 
descriptors.


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noticeable change; 4=somewhat better, but the 
change has not made any real difference;
5=moderately better, and a slight but noticeable 
change; 6=better, and a definite improvement that 
has made a real and worthwhile difference; and 
7=a great deal better, and a considerable 
improvement that has made all the difference.
has made a real and worthwhile difference; and 7=a 
great deal better, and a considerable improvement 
that has made all the difference.
7
ASSESSMENT OF SAFETY
7.1.6
Protocol Defined Adverse Events of Special Interest (Other sections affected by this change: Appendices [Appendix F added], 
Section 3.14 [Table 1], and Section 16)
7.1.6
Protocol-Defined Adverse Events of Special
Interest
The following are considered protocol-defined 
adverse events 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), or Hy’s 
Law events, or events of suspected anaphylaxis 
and severe hypersensitivity reactions. Severe 
hypersensitivity reactions will be monitored using 
the diagnostic criteria for anaphylaxis as outlined 
by the 2006 Joint National Institute of Allergy and 
Infectious Disease/Food Allergy and Anaphylaxis 
Network Second Symposium on Anaphylaxis 
(Sampson et al, 2006 [also see Appendix F]). 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.
The process for reporting a protocol-defined 
adverse event is the same as that for reporting a 
7.1.6
Protocol-Defined Adverse Events of 
Special Interest
The following are considered protocol-defined 
adverse events to be sent to the sponsor’s Global 
Patient Safety and Pharmacovigilance Department 
for evaluation: ophthalmic adverse events of at least 
moderate severity, events of possible 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 suspected anaphylaxis and
severe hypersensitivity reactions. Severe 
hypersensitivity reactions will be monitored using 
the diagnostic criteria for anaphylaxis as outlined by 
the 2006 Joint National Institute of Allergy and 
Infectious Disease/Food Allergy and Anaphylaxis 
Network Second Symposium on Anaphylaxis 
(Sampson et al, 2006 [also see Appendix F]). 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.
The process for reporting a protocol-defined adverse 
event is the same as that for reporting a serious 
The title of this section was 
updated, adding the word 
“Special”.
Adverse events of special interest 
were updated to include 
anaphylaxis and severe 
hypersensitivity reactions.
Relatedly, Appendix F (clinical 
criteria for diagnosing 
anaphylaxis) was added.


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serious adverse event (see Section 7.1.5.3).
adverse event (see Section 7.1.5.3).
7.3.1
Serum Chemistry (Other sections affected by this change: Sections 7.1.1, 7.1.6, 7.3.4. and Appendix E)
The following serum chemistry tests will be 
performed:

[…]

total bilirubin

direct bilirubin

indirect bilirubin (calculated)

lactate dehydrogenase

[…]
The following serum chemistry tests will be 
performed:

[…]

total bilirubin

direct bilirubin

indirect bilirubin (calculated)

lactate dehydrogenase

[…]
Total and direct bilirubin tests will 
be conducted at all visits that have 
chemistry laboratory assessments. 
Previously, direct bilirubin 
collection was triggered only 
under certain conditions.
Relatedly, editorial changes were 
made throughout the protocol to 
clarify when total or direct (or 
both) bilirubin was being referred 
to.
7.3.2
Hematology
The following hematology tests will be performed:

[…]

white blood cell (WBC) count and 
differential count (absolute values and 
percentages)

neutrophils

lymphocytes

eosinophils

monocytes

basophils

atypical lymphocytes
The following hematology tests will be performed:

[…]

white blood cell (WBC) count and 
differential count (absolute values and 
percentages)

neutrophils

lymphocytes

eosinophils

monocytes

basophils
A hematology test that was 
determined not to be needed was 
removed.


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7.4 Vital Signs
In addition, potentially clinically significant values 
may be predefined by the sponsor for selected 
vital signs (see Section 9.7.2) and, if so, will be 
documented in the statistical analysis plan or 
other relevant documents (eg, medical monitoring 
plan).
In addition, potentially clinically significant values 
may be predefined by the sponsor for selected vital 
signs (see Section 9.7.2) and, if so, will be 
documented in the statistical analysis plan or other 
relevant documents (eg, medical monitoring plan).
This language was added to align 
with Teva’s standard practices.
7.9 Immunogenicity
7.9. Injection Site Assessments Immunogenicity 
Blood samples for serum ADA assessment will be 
collected at visits 2, 3, and the EOT/early 
withdrawal visit. Only the samples from TEV-
48125-treated patients will be analyzed for ADA. 
Blood samples for ADA assessment will also be 
collected upon observation of any severe 
hypersensitivity reaction (eg, anaphylaxis). See 
Appendix F for the clinical criteria for diagnosing 
anaphylaxis. Bioanalytical personnel should be 
made aware of any anaphylaxis occurrence as 
soon as possible in case an anti-TEV-48125 
immunoglobulin E assay is required.
7.10. Injection Site Assessments
7.9. Immunogenicity
Blood samples for serum ADA assessment will be 
collected at visits 2, 3, and the EOT/early withdrawal 
visit. Only the samples from TEV-48125-treated 
patients will be analyzed for ADA. Blood samples 
for ADA assessment will also be collected upon 
observation of any severe hypersensitivity reaction 
(eg, anaphylaxis). See Appendix F for the clinical 
criteria for diagnosing anaphylaxis. Bioanalytical 
personnel should be made aware of any anaphylaxis 
occurrence as soon as possible in case an anti-TEV-
48125 immunoglobulin E assay is required.
7.10. Injection Site Assessments
A dedicated immunogenicity 
subsection was added for clarity 
and completeness; it includes 
anaphylaxis-related text according 
to the change to Section 7.1.6 
(above).
8
ASSESSMENT OF PHARMACOKINETICS/ BIOMARKERS/ IMMUNOGENICITY
8.1.1
Specimen Sampling and Handling (Other sections affected by this change: Section 8.2.1)
Blood samples will be centrifuged (1500g, ~10 
minutes, 02°C to 56°C) between 5 minutes and 1 
hour after sampling…Separated plasma will be 
transferred in approximately equal portions into 2 
opaque, labeled, 2-mL polypropylene tubes (sets A 
and B).
Blood samples will be centrifuged (1500g, ~10 
minutes, 2°C to 6°C) between 5 minutes and 1 hour 
after sampling…Separated plasma will be transferred 
in approximately equal portions into 2 labeled, 2-mL 
polypropylene tubes (sets A and B).
Procedures for plasma and serum 
collection were updated.


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8.2.2
Shipment and Analysis of Samples
Serum samples for all patients will be shipped frozen 
on dry ice from the investigational center to the 
central laboratory
Serum samples for all patients will be shipped 
frozen on dry ice from the investigational center to 
the central laboratory
Shipping requirements for serum 
were clarified and aligned with 
those for plasma (Section 8.1.2).
8.3 Assessment of Exploratory Biofluid Biomarkers (Other sections affected by this change: Synopsis and Sections 3.14 [Table 1], 3.14.2.2, 
3.14.3.1.2, 3.14.3.1.3, 5.5 [Table 2], 8.3.2, and 9.9)
In the current study, exploratory analysis may be 
conducted on blood (serum, plasma, and RNA) and 
urine biomarkers for extracellular matrix turnover, 
bone formation, and bone resorption.
[…]
Validated mMultiplex immunoassay panels will be 
applied to measure changes in urine, serum, and 
plasma markers, and RNA biomarkers.
In the current study, exploratory analysis may be 
conducted on blood (serum, plasma, and RNA) and 
urine biomarkers for extracellular matrix turnover, 
bone formation, and bone resorption.
[…]
Multiplex immunoassay panels will be applied to 
measure changes in urine, serum, plasma, and RNA 
biomarkers.
Clarification was made for 
internal consistency throughout 
the protocol specifying that serum, 
plasma, and RNA would be 
collected from blood. The blood 
volume required for each separate 
biomarker assessment is now 
reiterated in Table 2.
Statement regarding the assays 
being validated was removed to 
allow for operational flexibility.
9
STATISTICS
9.2.4
Additional Analysis Sets
The per-protocol population 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 per-protocol population 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.
An error was corrected.
9.4.1
Patient Disposition
Data from patients screened; patients screened but not 
randomized and reason not randomized; patients who 
are randomized (ie, in the ITT set); 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 screened, patients screened but 
not randomized and reason not randomized, patients 
who are randomized (ie, in the ITT set), patients 
randomized but not treated, patients in the safety 
and other analysis sets; patients who complete the 
study; and patients who withdraw from the study 
will be summarized using descriptive statistics.
Editorial changes were made.


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9.6 Multiple Comparisons and Multiplicity (Other sections affected by this change: Synopsis, Section 9.5.4.1)
A fixed-sequence (hierarchical) testing procedure 
will be implemented to control the type 1 error rate at 
0.05. The sequence of comparisons will be as 
follows: described in detail in the statistical 
analysis plan.
1.
mean change from baseline (28 day run in 
period) in the monthly average number of 
migraine days during the 12 week period 
after the 1st dose of study drug for the TEV 
48125 225/225/225 mg treatment group 
versus the placebo treatment group
2.
proportion of patients reaching at least 50% 
reduction in monthly average number of 
migraine days during 12 week period after 
the 1st dose of study drug for the TEV 48125 
225/225/225 mg treatment group versus the 
placebo treatment group
3.
mean change from baseline (28 day run in 
period) in the monthly average number of 
migraine days during the 12 week period 
after the 1st dose of study drug for the TEV 
48125 675 mg/placebo/placebo treatment 
group versus the placebo treatment group
4.
mean change from baseline (28 day run in 
period) in the monthly average number of 
days of use of any acute headache 
medications during the 12 week period after 
the 1st dose of the study drug for the TEV 
48125 225/225/225 mg treatment group 
versus the placebo treatment group
5.
mean change from baseline (28 day run in 
period) in the number of migraine days 
during the 4 week period after the 1st dose of 
A fixed-sequence (hierarchical) testing procedure 
will be implemented to control the type 1 error rate 
at 0.05. The sequence of comparisons will be 
described in detail in the statistical analysis plan.
The text was updated to reflect 
that the hierarchical testing 
procedure will not be 
finalized/available until the 
statistical analysis plan has been 
completed.


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the study drug for the TEV 48125 675 
mg/placebo/placebo treatment group versus 
the placebo treatment group
6.
mean change from baseline (28 day run in 
period) in the number of migraine days 
during the 4 week period after the 1st dose of 
the study drug for the TEV 48125 
225/225/225 mg treatment group versus the 
placebo treatment group
7.
proportion of patients reaching at least 50% 
reduction in the monthly number of migraine 
days during 12 week period after the 1st dose 
of study drug for the TEV 48125 675 
mg/placebo/placebo treatment group versus 
the placebo treatment group
8.
mean change from baseline (28 day run in 
period) in the monthly average number of 
days of use of any acute headache 
medications during the 12 week period after 
the 1st dose of study drug for the TEV 48125 
675 mg/placebo/placebo treatment group 
versus the placebo treatment group
9.
mean change from baseline (day 0) in 
disability score, as measured by the MIDAS 
questionnaire, at 4 weeks after administration 
of the last (3rd) dose of study drug for the 
TEV 48125 675 mg/placebo/placebo 
treatment group versus the placebo treatment 
group
10. mean change from baseline (day 0) in 
disability score, as measured by the MIDAS 
questionnaire, at 4 weeks after administration 
of the last (3rd) dose of study drug for the 
TEV 48125 225/225/225 mg treatment group 
versus the placebo treatment group


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If the resulting 2 sided p value from the first 
comparison is ≤0.05, then the next comparison of 
interest will be interpreted inferentially at the alpha 
level of 0.05. This process will continue either until 
all comparisons of interest 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 p>0.05, no further comparisons 
will be interpreted inferentially. 
9.11
Immunogenicity Analysis (Other sections affected by this change: Synopsis)
This impact analysis will be reported separately.
This impact analysis will be reported separately.
Clarification was added.
11 QUALITY CONTROL AND QUALITY ASSURANCE
11.1.1 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. Each investigator The 
principal investigator at each investigational 
center, the coordinating investigator (if applicable), 
and the sponsor will sign the protocol amendment.
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.
Updates were made to align with 
the latest Teva practices.
11.1.2 Protocol Violations
A protocol deviation is any change, divergence, or 
departure from the study design or procedures defined 
in the protocol.
Important protocol deviations, referred to as protocol 
violations, are a subset of protocol deviations that may 
significantly impact the completeness, accuracy, 
and/or reliability of the study data or that may 
Any deviation from the protocol that affects, to a 
significant degree, (a) the safety, physical, or mental 
integrity of the subjects of the study and/or (b) the 
scientific value of the study will be considered a 
protocol violation. Protocol violations may include 
nonadherence on the part of the patient, the 
investigator, or the sponsor to protocol-specific 
inclusion and exclusion criteria, primary objective 
Updates were made to align with 
the latest Teva practices.


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significantly affect a patient’s rights, safety, or 
well being. Any deviation from the protocol that 
affects, to a significant degree, (a) the safety, 
physical, or mental integrity of the subjects of the 
study and/or (b) the scientific value of the study 
will be considered a protocol violation. Protocol 
violations include enrolling patients in violation of key 
eligibility criteria designed to ensure a specific subject 
population, failing to collect data necessary to 
interpret primary endpoints, Protocol violations may 
include nonadherence 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 study drug administration,; use of prohibited 
medications, GCP noncompliance, or any other 
deviations that may have an impact on the processes 
put in place for the care and safety of the patients or 
compromise the scientific value of the trial. 
Protocol violations will be identified and recorded by 
investigational center personnel onin the CRF. All 
protocol violations will be reported to the responsible 
IEC/IRB, as required.
When a protocol violation 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 
representativeexpert. The decision will be based on 
ensuring the safety of the patient and preserving the 
integrity of the study. 
Deviations from 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 eligibilityinclusion and exclusion criteria 
was entered into a study, they must immediately 
variable criteria, or GCP guidelines; noncompliance 
to study drug administration; use of prohibited 
medications. Protocol violations will be identified 
and recorded by investigational center personnel in 
the CRF. All protocol violations will be reported to 
the responsible IEC/IRB, as required.
When a protocol violation 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. 
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 into a study, they 
must immediately inform the sponsor of the 
protocol violation. If such patient has already 
completed the study or has withdrawn early, no 
action will be taken, but the violation will be 
recorded.


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inform the sponsor of the protocol violation. If such 
patient has already completed the study or has 
withdrawn early, no action will be taken, but the 
violation will be recorded. If such patient is still 
participating in the study, a determination will be 
made by the sponsor and the investigator as to whether 
it is in the best interest of the patient to continue in the 
study.
APPENDIX A PREVENTIVE MEDICATIONS ALLOWED FOR THE DURATION OF THE STUDY
Preventive migraine medications allowed for up to 
30% of patients for the duration of the study 
specifically include the following (only if they were 
previously prescribed for migraine or for another 
indication if used at an approved dose for migraine 
prophylaxis):

beta-blockers: atenolol, propranolol, 
metoprolol, nadolol, and timolol

calcium channel blocker/benzocycloheptene: 
verapamilflunarizine and pizotifen

tricyclic antidepressants: amitriptyline, 
venlafaxine, nortriptyline, and duloxetine

serotonin norepinephrine reuptake inhibitor: 
venlafaxine 

triptans: frovatriptan, naratriptan, and 
zolmitriptan if they were used as preventive 
medications for the treatment of menstrual 
migraine. (Note: They cannot be used daily 
for the preventive treatment of migraine.)

anti-epileptic medications: topiramate, 
valproate, and divalproate
Preventive migraine medications allowed for up to 
30% of patients for the duration of the study 
specifically include the following (if they were 
previously prescribed for migraine or for another 
indication):

beta-blockers: atenolol, propranolol, 
metoprolol, nadolol, and timolol

calcium channel 
blocker/benzocycloheptene: flunarizine and 
pizotifen

antidepressants: amitriptyline, venlafaxine, 
nortriptyline, and duloxetine

anti-epileptic medications: topiramate, 
valproate, and divalproate
Appendix A was updated to 
reflect the most recent list of 
preventive medications allowed 
for the duration of the study.
APPENDIX B. DISALLOWED MEDICATIONS FOR THE DURATION OF THE STUDY
Preventive migraine medications/treatments 
Preventive migraine medications disallowed for at 
A new Appendix B was added to 


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disallowed for at least 70% of patients for the 
duration of the study specifically include the 
following:

beta-blockers: atenolol, propranolol, 
metoprolol, nadolol, and timolol

calcium channel 
blocker/benzocycloheptene: flunarizine and
pizotifen

antidepressants: amitriptyline, venlafaxine, 
nortriptyline, and duloxetine

anti-epileptic medications: topiramate, 
valproate, carbamazepine, and divalproate

angiotensin receptor blocker: candesartan 
and lisinopril

onabotulinimtoxinA: botox

triptans/ergots: used as preventive therapy 
for migraine

NSAIDs: used as preventive therapy for 
migraine or on a daily basis for other 
indications

devices for migraine prophylaxis

nerve blocks in the head and neck
Any of the listed medications are allowed if given 
as topical or eye drops.
Other medications in the same classes but not 
included in this list are allowed.
least 70% of patients for the duration of the study 
specifically include the following:

beta-blockers: atenolol, propranolol, 
metoprolol, nadolol, and timolol

calcium channel 
blocker/benzocycloheptene: flunarizine and
pizotifen

antidepressants: amitriptyline, venlafaxine,
nortriptyline, and duloxetine

anti-epileptic medications: topiramate, 
valproate, carbamazepine, and divalproate

angiotensin receptor blocker: candesartan 
and lisinopril

onabotulinimtoxinA: botox

triptans/ergots: used as preventive therapies 
for migraine

NSAIDs: used as preventive therapy for 
migraine or on a daily basis for other 
indications

devices for migraine prophylaxis

nerve blocks in the head and neck
Any of the listed medications are allowed if given as 
topical or eye drops.
Other medications in the same classes but not 
included in this list are allowed.
show the most recent list of 
preventive medications 
disallowed for the duration of the 
study. The numbering of all 
subsequent appendices shifted.
APPENDIX F. CLINICAL CRITERIA FOR DIAGNOSING ANAPHYLAXIS
Anaphylaxis is highly likely when any one of the 
following 3 criteria are fulfilled:
a. Acute onset of an illness (minutes to several 
hours) with involvement of the skin, mucosal 
Anaphylaxis is highly likely when any one of the 
following 3 criteria are fulfilled:
a. Acute onset of an illness (minutes to several 
hours) with involvement of the skin, mucosal 
Appendix F was added to provide 
the criteria for diagnosis of 
anaphylaxis.


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tissue, or both (eg, generalized hives, pruritus or 
flushing, swollen lips-tongue-uvula) AND AT 
LEAST ONE OF THE FOLLOWING

Respiratory compromise (eg, dyspnea, 
wheeze-bronchospasm, stridor, reduced 
peak expiratory flow [PEF], hypoxemia)

Reduced blood pressure (BP) or associated 
symptoms of end-organ dysfunction (eg, 
hypotonia [collapse], syncope, incontinence)
b. Two or more of the following that occur 
rapidly after exposure to a likely allergen for 
that subject (minutes to several hours):

Involvement of the skin-mucosal tissue (eg, 
generalized hives, itch-flush, swollen lips-
tongue-uvula)

Respiratory compromise (eg, dyspnea, 
wheeze-bronchospasm, stridor, reduced 
PEF, hypoxemia)

Reduced BP or associated symptoms (eg, 
hypotonia [collapse], syncope, incontinence)

Persistent gastrointestinal symptoms (eg, 
crampy abdominal pain, vomiting)
c. Reduced BP after exposure to known allergen 
for that subject (minutes to several hours):

Infants and children: low systolic BP (age 
specific) or greater than 30% decrease in 
systolic BP

Adults: systolic BP of less than 90 mm Hg 
or greater than 30% decrease from that 
person’s baseline
Source: Modified from Sampson HA, Munoz-
Furlong A, Campbell RL, Adkinson NF, Jr., Bock 
SA, Branum A, et al. Second symposium on the 
tissue, or both (eg, generalized hives, pruritus or 
flushing, swollen lips-tongue-uvula) AND AT 
LEAST ONE OF THE FOLLOWING

Respiratory compromise (eg, dyspnea, 
wheeze-bronchospasm, stridor, reduced 
peak expiratory flow [PEF], hypoxemia)

Reduced blood pressure (BP) or associated 
symptoms of end-organ dysfunction (eg, 
hypotonia [collapse], syncope, 
incontinence)
b. Two or more of the following that occur rapidly 
after exposure to a likely allergen for that subject 
(minutes to several hours):

Involvement of the skin-mucosal tissue (eg, 
generalized hives, itch-flush, swollen lips-
tongue-uvula)

Respiratory compromise (eg, dyspnea, 
wheeze-bronchospasm, stridor, reduced 
PEF, hypoxemia)

Reduced BP or associated symptoms (eg, 
hypotonia [collapse], syncope, 
incontinence)

Persistent gastrointestinal symptoms (eg, 
crampy abdominal pain, vomiting)
c. Reduced BP after exposure to known allergen 
for that subject (minutes to several hours):

Infants and children: low systolic BP (age 
specific) or greater than 30% decrease in 
systolic BP

Adults: systolic BP of less than 90 mm Hg 
or greater than 30% decrease from that 
person’s baseline
Source: Modified from Sampson HA, Munoz-


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definition and management of anaphylaxis: 
summary report-Second National Institute of 
Allergy and Infectious Disease/Food Allergy and 
Anaphylaxis Network symposium.[reprint in Ann 
Emerg Med 2006 Apr;47(4):373-80; 
PMID:16546624]. J Allergy Clin Immunol 2006 
Feb;117(2):391-7.
Furlong A, Campbell RL, Adkinson NF, Jr., Bock 
SA, Branum A, et al. Second symposium on the 
definition and management of anaphylaxis: 
summary report-Second National Institute of 
Allergy and Infectious Disease/Food Allergy and 
Anaphylaxis Network symposium.[reprint in Ann 
Emerg Med 2006 Apr;47(4):373-80; 
PMID:16546624]. J Allergy Clin Immunol 2006 
Feb;117(2):391-7.


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17.2.
Administrative Letter Dated 01 March 2016


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17.3.
Administrative Letter Dated 22 January 2016


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APPENDIX A. PREVENTIVE MEDICATIONS ALLOWED FOR THE 
DURATION OF THE STUDY
Preventive migraine medications allowed for up to 30% of patients for the duration of the study 
specifically include the following (if they were previously prescribed for migraine or for another 
indication):

beta-blockers: atenolol, propranolol, metoprolol, nadolol, and timolol

calcium channel blocker/benzocycloheptene: flunarizine and pizotifen

antidepressants: amitriptyline, venlafaxine, nortriptyline, and duloxetine

anti-epileptic medications: topiramate, valproate, and divalproate


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APPENDIX B. DISALLOWED MEDICATIONS FOR THE DURATION 
OF THE STUDY
Preventive migraine medications/treatments disallowed for at least 70% of patients for the 
duration of the study specifically include the following:

beta-blockers: atenolol, propranolol, metoprolol, nadolol, and timolol

calcium channel blocker/benzocycloheptene: flunarizine and pizotifen

antidepressants: amitriptyline, venlafaxine, nortriptyline, and duloxetine

anti-epileptic medications: topiramate, valproate, carbamazepine, and divalproate

angiotensin receptor blocker: candesartan and lisinopril

onabotulinimtoxinA: botox

triptans/ergots: used as preventive therapies for migraine

NSAIDs: used as preventive therapy for migraine or on a daily basis for other 
indications

devices for migraine prophylaxis

nerve blocks in the head and neck
Any of the listed medications are allowed if given as topical or eye drops.
Other medications in the same classes but not included in this list are allowed.


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APPENDIX C. NATIONAL INSTITUTES OF HEALTH PATIENT 
EDUCATION GUIDELINES OF JUNE 2012


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APPENDIX D. ICHD-3 DIAGNOSTIC CRITERIA
For further details, refer to Classification Committee of the IHS, 2013.
1.1 Migraine without Aura
a.
at least 5 attacks fulfilling criteria B through D
b. headache attacks lasting 4 to 72 hours (untreated or unsuccessfully treated)
c.
headache has at least 2 of the following 4 characteristics:

unilateral location

pulsating quality

moderate or severe pain intensity

aggravation by, or causing avoidance of, routine physical activity (eg, walking or 
climbing stairs)
d. during headache, at least 1 of the following:

nausea and/or vomiting

photophobia and phonophobia
e.
not better accounted for by another ICHD-3 diagnosis
1.2 Migraine with Aura
a.
at least 2 attacks fulfilling criteria B and C
b. 1 or more of the following fully reversible aura symptoms:

visual

sensory

speech and/or language

motor

brainstem

retinal
c.
at least 2 of the following 4 characteristics:

at least 1 aura symptom spreads gradually over ≥5 minutes, and/or 2 or more 
symptoms occur in succession

each individual aura symptom lasts 5 to 60 minutes

at least 1 aura symptom is unilateral

the aura is accompanied, or followed within 60 minutes, by headache
d. not better accounted for by another ICHD-3 diagnosis, and transient ischemic attack 
has been excluded


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APPENDIX E. GUIDANCE ON SAFETY MONITORING
Guidance on Monitoring Patients with Elevated Liver Function Tests
Liver enzymes (ALT, AST, GGT, and ALP) as well as total and direct bilirubin will be measured 
(and indirect bilirubin will be calculated) 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.1 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 or direct bilirubin, not 
accompanied by elevations of ALT or AST should be managed according to the discretion of the 
treating physician.
Elevation of Either ALT or AST to ≥3× ULN
Confirmation is required prior to study drug discontinuation in cases of elevation of either ALT 
or AST ≥3× ULN (Note: In cases of elevation of ALT or AST ≥8× the ULN, no confirmation is 
required prior to study drug discontinuation, but the assessments below should be performed). 
The following procedures should be followed:

The day in which the abnormal value is received from the laboratory will be 
considered as day 0.

The investigator should repeat the test for confirmation purposes (this may be 
performed in a local laboratory along with complete blood count [CBC] and 
differential to assess for eosinophilia. In general, in case a blood sample is sent to a 
local laboratory, the following assessments [and reference ranges] are mandatory: 
ALT [serum glutamic pyruvic transaminase], AST [serum glutamic oxaloacetic 
transaminase], ALP, total and direct bilirubin, CBC [with differential for eosinophil 
count, separate tube], and INR [separate tube; not to be sent in a confirmatory test]). 
The investigator should also question the 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
                                                
1 Thorough medical history with a focus on liver disease: personal or family history of liver disease; personal history 
of a systemic disease with potential liver involvement; exposure to alcohol, medications (prescription or 
over-the-counter), herbal preparations, dietary supplements, recreational drugs, special diets, or environmental 
chemical agents; potential exposure to infectious agents (eg, travel to developing countries, history of potential 
exposure to blood or blood products, high-risk sexual relations); and any additional information deemed relevant 
by the investigator. Physical examination, including signs of chronic liver disease.


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


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ALT or AST ≥8× the ULN
In addition to the above procedures required for any elevation to levels >3× the ULN:

The study drug should be discontinued immediately, and the early withdrawal visit 
should be performed.

For follow-up guidance, please see below section “Follow-Up of Liver Enzymes 
After Stopping Rules Are Met.”
Stopping Rules
In the following circumstances, the study drug will be discontinued immediately:

any increase in ALT or AST to ≥3× the ULN, combined with INR >1.5× the ULN or 
total bilirubin >2× the ULN

any increase in ALT or AST to ≥3× the ULN, which is accompanied by symptoms 
clearly associated with impaired liver function (eg, vomiting, nausea, fever, rash, 
eosinophilia) and not deemed related to other diseases (eg, vomiting or nausea 
triggered by migraine)

any increase in ALT or AST to levels ≥5 but <8× the ULN, which is persistent for 
≥2 weeks of repeated measurements

any increase in ALT or AST to levels ≥8× the ULN

in any case where monitoring of liver enzymes cannot be performed according to the 
protocol guidance
Follow-Up of Liver Enzymes After Stopping Rules Are Met

A patient who meets the above criteria for discontinuation of the study drug should be 
invited to the site to return the study drug. 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 F.
CLINICAL CRITERIA FOR DIAGNOSING 
ANAPHYLAXIS
Anaphylaxis is highly likely when any one of the following 3 criteria are fulfilled:
a.
Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (eg, generalized hives, pruritus or flushing, swollen lips-
tongue-uvula) AND AT LEAST ONE OF THE FOLLOWING

Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced 
peak expiratory flow [PEF], hypoxemia)

Reduced blood pressure (BP) or associated symptoms of end-organ dysfunction 
(eg, hypotonia [collapse], syncope, incontinence)
b. Two or more of the following that occur rapidly after exposure to a likely allergen for 
that subject (minutes to several hours):

Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, swollen 
lips-tongue-uvula)

Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced 
PEF, hypoxemia)

Reduced BP or associated symptoms (eg, hypotonia [collapse], syncope, 
incontinence)

Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting)
c.
Reduced BP after exposure to known allergen for that subject (minutes to several 
hours):

Infants and children: low systolic BP (age specific) or greater than 30% decrease 
in systolic BP

Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from that 
person’s baseline
Source: Modified from Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF, Jr., Bock 
SA, Branum A, et al. Second symposium on the definition and management of anaphylaxis: 
summary report-Second National Institute of Allergy and Infectious Disease/Food Allergy and 
Anaphylaxis Network symposium.[reprint in Ann Emerg Med 2006 Apr;47(4):373-80; 
PMID:16546624]. J Allergy Clin Immunol 2006 Feb;117(2):391-7.

SAP_001.pdf: 
Statistical Analysis Plan with Amendment 02
A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study
Comparing the Efficacy and Safety of 2 Dose Regimens of Subcutaneous Administration 
of TEV-48125 Versus Placebo for the Preventive Treatment of Episodic Migraine
Study TV48125-CNS-30050
NCT02629861
Statistical Analysis Plan with Amendment 02 Approval Date: 26 May 2017


Statistical Analysis Plan with Amendment 02
TV48125-CNS-30050
1
 
Statistical Analysis Plan
TV48125-CNS-30050
A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study 
Comparing the Efficacy and Safety of 2 Dose Regimens of Subcutaneous Administration of 
TEV-48125 Versus Placebo for the Preventive Treatment of Episodic Migraine
Phase 3
IND number: 106,533     EudraCT number: 2015-004549-23
Statistical Analysis Plan Approval Date: 31-May-16
Statistical Analysis Plan with Amendment 01 Approval Date: 27-March-17
Statistical Analysis Plan with Amendment 02 Approval Date: 26-May-17
Sponsor
Teva Branded Pharmaceutical 
Products R&D, Inc.
41 Moores Road
Frazer, Pennsylvania 19355
United States
Prepared by:


Statistical Analysis Plan with Amendment 02
TV48125-CNS-30050
2
STATISTICAL ANALYSIS PLAN APPROVAL


Statistical Analysis Plan with Amendment 02
TV48125-CNS-30050
3
TABLE OF CONTENTS
TITLE PAGE...................................................................................................................................1
STATISTICAL ANALYSIS PLAN APPROVAL..........................................................................2
AMENDMENT HISTORY .............................................................................................................8
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS................................................10
PREFACE  ....................................................................................................................................12
1.
STUDY OBJECTIVES ..............................................................................................13
1.1.
Primary Objectives .....................................................................................................13
1.2.
Secondary Objectives .................................................................................................13
1.3.
Exploratory Objectives ...............................................................................................13
2.
STUDY DESIGN .......................................................................................................16
2.1.
General Design and Study Schema.............................................................................16
2.2.
Primary and Secondary Measures and Endpoints ......................................................22
2.2.1.
Primary Efficacy Endpoint .........................................................................................22
2.2.2.
Secondary Efficacy Endpoints....................................................................................22
2.2.3.
Exploratory Efficacy Endpoints .................................................................................22
2.2.4.
Safety and Tolerability Endpoints ..............................................................................24
2.2.5.
Pharmacokinetic/Immunogenicity/Biomarker Endpoints ..........................................24
2.2.5.1.
Pharmacokinetic Endpoints ........................................................................................24
2.2.5.2.
Immunogenicity Endpoint ..........................................................................................24
2.2.5.3.
Biomarker Endpoints..................................................................................................25
2.3.
Sample Size and Power Considerations .....................................................................25
2.4.
Randomization and Blinding......................................................................................25
2.4.1.
Randomization............................................................................................................25
2.4.2.
Blinding/Unblinding...................................................................................................25
2.5.
Sequence of Planned Analyses ...................................................................................26
2.5.1.
Interim Analyses.........................................................................................................26
2.5.2.
Final Analyses and Reporting.....................................................................................26
3.
POPULATIONS / ANALYSIS SETS........................................................................27
3.1.
Intent-to-Treat Population ..........................................................................................27
3.2.
Safety Population........................................................................................................27
3.3.
Full Analysis Set.........................................................................................................27


Statistical Analysis Plan with Amendment 02
TV48125-CNS-30050
4
3.4.
Per-Protocol Analysis Set...........................................................................................27
4.
GENERAL ISSUES FOR DATA ANALYSIS..........................................................28
4.1.
General........................................................................................................................28
4.2.
Specification of Baseline Values................................................................................28
4.3.
Region of Pooled Countries........................................................................................29
4.4.
Multiple Comparisons and Multiplicity......................................................................29
4.5.
Handling Withdrawals and Missing Data...................................................................30
4.6.
Study Days and Visit Windows..................................................................................31
5.
STUDY POPULATION SUMMARY .......................................................................32
5.1.
General........................................................................................................................32
5.2.
Patient Disposition......................................................................................................32
5.3.
Demographics and Baseline Characteristics...............................................................32
5.4.
Medical History ..........................................................................................................32
5.5.
Prior Medications or Therapy.....................................................................................33
5.6.
Electrocardiography....................................................................................................33
5.7.
Physical Examinations................................................................................................33
5.8.
Protocol Violations.....................................................................................................33
5.9.
Childbearing Potential ................................................................................................33
6.
EFFICACY ANALYSIS ............................................................................................34
6.1.
General........................................................................................................................34
6.2.
Primary Efficacy Variable(s) and Analysis ................................................................35
6.2.1.
Variable Definition.....................................................................................................35
6.2.2.
Primary Analysis ........................................................................................................36
6.2.3.
Sensitivity Analysis ....................................................................................................36
6.2.3.1.
MMRM Analysis........................................................................................................36
6.2.3.2.
Analysis with Multiple Imputation Method ...............................................................37
6.3.
Secondary Efficacy Variables and Analysis...............................................................38
6.3.1.
Variable Definition.....................................................................................................38
6.3.1.1.
Electronic Headache Diary Data ................................................................................38
6.3.1.2.
Migraine Disability Assessment (MIDAS) ................................................................38
6.3.2.
Analysis of Secondary Efficacy Variables .................................................................39
6.4.
Exploratory Efficacy Variables and Analysis.............................................................40
6.4.1.
Variable Definition.....................................................................................................40


Statistical Analysis Plan with Amendment 02
TV48125-CNS-30050
5
6.4.1.1.
Electronic Headache Diary Data ................................................................................40
6.4.1.2.
Migraine-Specific Quality of Life ..............................................................................41
6.4.1.3.
EuroQol-5 Dimension Questionnaire .........................................................................41
6.4.1.4.
Patient Health Questionnaire ......................................................................................41
6.4.1.5.
Work Productivity and Activity Impairment Questionnaire: General Health 
V2.0 ............................................................................................................................42
6.4.1.6.
Patient’s Global Impression of Change......................................................................42
6.4.2.
Exploratory Efficacy Analysis....................................................................................42
6.4.2.1.
Electronic Headache Diary Data ................................................................................42
6.4.2.2.
Migraine-Specific Quality of Life ..............................................................................43
6.4.2.3.
EuroQol-5 Dimension Questionnaire .........................................................................43
6.4.2.4.
Patient Health Questionnaire ......................................................................................43
6.4.2.5.
Work Productivity and Activity Impairment Questionnaire : General Health 
V2.0 ............................................................................................................................43
6.4.2.6.
Patient’s Global Impression of Change Scale ............................................................44
6.5.
Subgroup Analysis......................................................................................................44
7.
SAFETY ANALYSIS ................................................................................................45
7.1.
General........................................................................................................................45
7.2.
Study Drug Administration.........................................................................................45
7.3.
Adverse Events ...........................................................................................................45
7.4.
Injection Site Assessments .........................................................................................46
7.5.
Deaths .........................................................................................................................47
7.6.
Clinical Laboratory Tests ...........................................................................................48
7.7.
Vital Signs ..................................................................................................................50
7.8.
Electrocardiography....................................................................................................50
7.9.
Physical Examinations................................................................................................51
7.10.
Electronic Columbia-Suicide Severity Rating Scale..................................................51
7.11.
Concomitant Therapy or Medication..........................................................................51
8.
PHARMACOKINETIC ANALYSIS.........................................................................52
9.
BIOMARKER ANALYSIS........................................................................................52
10.
STATISTICAL SOFTWARE ....................................................................................53
11.
CHANGES TO PROTOCOL SPECIFIED ANALYSES ..........................................54
12.
REFERENCES ...........................................................................................................55


Statistical Analysis Plan with Amendment 02
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6
APPENDIX A.
E-DIARY QUESTIONNAIRE..........................................................................56
APPENDIX B.
LOGICS FOR ENDPOINTS DERIVATION ...................................................58
APPENDIX C.
THE MIGRAINE DISABILITY ASSESSMENT.............................................59
APPENDIX D.
MIGRAINE-SPECIFIC QUALITY OF LIFE QUESTIONNAIRE (MSQ) 
(VERSION 2.1) ..........................................................................................................60
APPENDIX E.
SCORING INSTRUCTIONS FOR MSQ (VERSION 2.1)...............................65
APPENDIX F.
EQ-5D-5L AND EQ VAS .................................................................................67
APPENDIX G.
PATIENT HEALTH QUESTIONNAIRE (PHQ-2) AND (PHQ-9).................69
APPENDIX H.
WORK PRODUCTIVITY AND ACTIVITY IMPAIRMENT 
QUESTIONNAIRE: GENERAL HEALTH V2.0 (WPAI:GH).................................71
APPENDIX I.
PATIENT’S GLOBAL IMPRESSION OF CHANGE (PGIC) SCALE ............73


Statistical Analysis Plan with Amendment 02
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LIST OF TABLES
Table 1:
Study Procedures and Assessments............................................................................19
Table 2:
Pooled Countries by Region.......................................................................................29
Table 3:
Severity of Pain Scale for Injection Site Assessments ...............................................47
Table 4:
Clinical Laboratory Test.............................................................................................48
Table 5:
Criteria for Potentially Clinically Significant Laboratory Values..............................49
Table 6:
Criteria for Potentially Clinically Significant Vital Signs..........................................50
LIST OF FIGURES
Figure 1:
Overall Study Schema ................................................................................................18


Statistical Analysis Plan with Amendment 02
TV48125-CNS-30050
8
AMENDMENT HISTORY
The Statistical Analysis Plan for study TV48125-CNS-30050 (study protocol with amendment 01 
dated 30 March 2016) has been amended and reissued as follows:
Amendment 
number
Date
Summary of changes
Reason for 
amendment
01
27 March 2017
Section 2.2.3, two exploratory efficacy endpoints to 
analyze the change from baseline of the weekly number 
of migraine days /headache days of at least moderate 
severity are added.
Teva Clinical 
decision
Section  3.3, the definition of FAS is changed from “all 
patients in the ITT population who receive at least 1 
dose of study drug and have at least 1 post baseline 
efficacy assessment on the primary endpoint” to “all 
patients in the ITT population who receive at least 1 
dose of study drug and have at least 10 days of post 
baseline efficacy assessments on the primary endpoint”.
Per review 
comments from the 
FDA
Section 4.2, the baseline for calculating weekly 
endpoints is added. 
Teva Clinical 
decision
Section 4.3, Germany is removed fromTable 2, Israel 
and Finland are added.
Germany did not 
participate in the 
study.  Israel and 
Finland enrolled 
patients.
Section 4.4, the hierarchical testing sequence is 
modified.
Teva Clinical 
decision
Section 4.5, the missing data handling rule is modified. 
The BOCF imputation is removed. The monthly 
efficacy variables will be prorated to 28 days if the 
patient has  ≥10 days of e-diary data for the month. If a 
patient has <10 days of e-diary data for a month, the 
monthly number of days/hours of efficacy variables 
will be considered as missing.
Per review 
comments from the 
FDA
Section 4.5, The missing data handling rule for 
calculating weekly efficacy variables is added.
Section 4.6, the weekly window for the first month (28-
days) post the first dose is defined. 
Teva Clinical 
decision


Statistical Analysis Plan with Amendment 02
TV48125-CNS-30050
9
Amendment 
number
Date
Summary of changes
Reason for 
amendment
01
27 March 2017
Section 5.3, the population for the baseline efficacy 
summary is changed from FAS/PP to ITT population. 
Section 6.1, derivation of the change from baseline of 
the weekly number of days of the efficacy variables is 
added. 
Teva Clinical 
direction
Section 6.2.2, the normality of the residuals from the 
ANCOVA model will be checked using Shapiro Wilk’s 
normality test. If the test has a p value ≤0.001, 
Wilcoxon rank-sum test will be conducted as the 
primary analysis.
Section 6.2.3.1, the BOCF sensitivity analysis is 
removed. The missing value handling for MMRM 
analysis is updated per rules in section 4.5. 
Incorporation of 
review comments 
from the FDA
Section 6.4.1.1, the analysis for weekly efficacy 
endpoints is added. 
Teva Clinical 
decision
Section 6.5, age groups of ‘46-65’ and ‘>65’ are 
consolidated as 1 group, “>45 years old”
Teva Clinical 
decision
02
18 May 2017
Section 6.2.2: changed test level for Shapiro-Wilk’s test 
from 0.001 to 0.01
FDA feedback 
5/18/2017


Statistical Analysis Plan with Amendment 02
TV48125-CNS-30050
10
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
β-HCG
beta-human chorionic gonadotropin
ADA
antidrug antibody
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANC
absolute neutrophil counts
ANCOVA
analysis of covariance
AST
aspartate aminotransferase 
BUN
Blood urea nitrogen
CM
chronic migraine
CRF
case report form (refers to any media used to collect study data [ie, paper 
or electronic])
CSR
Clinical study report
ECG
electrocardiography/electrocardiogram
eC-SSRS
Electronic Columbia-Suicide Severity Rating Scale
EM
episodic migraine
EOT
end of treatment (visit)
EQ-5D-5L
EuroQol-5 Dimension, 5 response level version
EU
European Union
FAS
full analysis set
FDA
Food and Drug Administration (United States)
FSH
follicle-stimulating hormone
GBP
global branded product
GGT
gamma-glutamyl transpeptidase
HCG
Human chorionic gonadotropin
ICH
International Conference on Harmonisation
ICHD-3
International Classification of Headache Disorders, 3rd revision
IHS
International Headache Society
INR
international normalized ratio 
IRT
interactive response technology


Statistical Analysis Plan with Amendment 02
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Abbreviation
Term
ITT
intent-to-treat 
LDH
lactate dehydrogenase
LS
least square
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
Mixed-effects Model Repeated Measures
MIDAS
Migraine Disability Assessment
MSQOL
Migraine-Specific Quality of Life 
NSAID
non-steroidal anti-inflammatory drug
PBO
placebo
PGIC
Patient Global Impression of Change
PHQ-2
2-item Patient Health Questionnaire
PHQ-9
9-item Patient Health Questionnaire
PT
Preferred term
RBC
red blood cell
R&D
Research and Development
SAP
Statistical Analysis Plan
sc
subcutaneous(ly)
SD
standard deviation
SOC
system organ class
SUSAR
suspected unexpected serious adverse reaction
ULN
upper limit of the normal range
WBC
white blood cell
WHO Drug
World Health Organization dictionary of medical codes
WPAI (:GH)
Work Productivity and Activity Impairment (:General Health)


Statistical Analysis Plan with Amendment 02
TV48125-CNS-30050
12
PREFACE  
This Statistical Analysis Plan (SAP) describes the planned analysis and reporting for Teva Branded 
Pharmaceuticals Products R&D, Inc. study TV48125-CNS-30050, (A Multicenter, Randomized, 
Double-Blind, Placebo-Controlled, Parallel Group Study Comparing the Efficacy and Safety of 2 
Dose Regimens of Subcutaneous Administration of TEV-48125 Versus Placebo for the Preventive 
Treatment of Episodic Migraine) and was written in accordance with standard operating procedure  
GBP_RD_702 (Teva Pharmaceuticals Global Branded Product (GBP) Research and Development 
(R&D) Statistical Analysis Plan).
This Phase 3 study is being conducted to evaluate the efficacy, safety, and immunogenicity of 2 
dose regimens of subcutaneous (sc) administration of TEV-48125 versus placebo for the preventive 
treatment of episodic migraine (EM).
The structure and content of this SAP provides sufficient detail to meet the requirements identified 
by the Food and Drug Administration (FDA) and International Conference on Harmonization (ICH)
of Technical Requirements for Trials. All work planned and reported for this SAP will follow 
internationally accepted Registration of Pharmaceuticals for Human Use (ICH): E9 Guidance on 
Statistical Principles in Clinical guidelines, published by the American Statistical Association, and 
the Royal Statistical Society, for statistical practice.
The following documents were reviewed in preparation of this SAP:

Clinical Study Protocol TV48125-CNS-30050 with Amendment 01

Case report forms (CRFs) for Study TV48125-CNS-30050.

ICH E9 Guidance on Statistical Principles for Clinical Trials.

ICH E3 Structure and Content of Clinical Study Reports
The reader of this SAP is encouraged to also read the clinical protocol for details on the conduct of 
this study, and the operational aspects of clinical assessments and timing for completing a patient in 
this study. When differences exist in descriptions or explanations provided in the protocol and this 
SAP, the SAP prevails; the discrepancies will be explained in the Clinical Study Report (CSR). 


Statistical Analysis Plan with Amendment 02
TV48125-CNS-30050
13
1.
STUDY OBJECTIVES
1.1.
Primary Objectives
The primary objectives of this study are as follows:

to demonstrate the efficacy of 2 dose regimens of TEV-48125, as assessed by the 
decrease in the monthly average number of migraine days during the 12-week period 
after the 1st dose of study drug relative to the baseline period

to evaluate the safety and tolerability of 2 dose regimens of TEV-48125 in the 
preventive treatment of EM
1.2.
Secondary Objectives
The secondary objectives of the study are as follows:

to evaluate the proportion of patients reaching at least 50% reduction in the monthly 
average number of migraine days with TEV-48125 during the 12-week period after the 
1st dose of study drug relative to the baseline period

to demonstrate the efficacy of TEV-48125, as assessed by the reduction in the monthly 
average number of days of use of any acute headache medications during the 12-week 
period after the 1st dose of study drug relative to the baseline period

to demonstrate the efficacy of TEV-48125, as assessed by the reduction of the number 
of migraine days during the 4-week period after the 1st dose of study drug relative to the 
baseline period

to demonstrate the efficacy of TEV-48125, as assessed by the reduction in the monthly 
average number of migraine days during the 12-week period after the 1st dose of study 
drug relative to the baseline period in patients not receiving concomitant migraine 
preventive medications at baseline

to demonstrate the efficacy of TEV-48125, as assessed by the reduction of 
migraine-related disability as measured by the Migraine Disability Assessment 
(MIDAS) questionnaire, at 4 weeks after the last (3rd) dose of study drug relative to 
baseline

to evaluate the immunogenicity of TEV-48125 and the impact of antidrug antibodies 
(ADA)s on efficacy and safety during 12 weeks of treatment with TEV-48125 
1.3.
Exploratory Objectives
The exploratory objectives of the study are as follows: 

to demonstrate the efficacy of TEV-48125, as assessed by the decrease in the monthly 
average number of headache days of at least moderate severity during the 12-week 
period after the 1st dose of study drug relative to the baseline period


Statistical Analysis Plan with Amendment 02
TV48125-CNS-30050
14

to evaluate the proportion of patients reaching at least 75% reduction and total (100%) 
reduction in the monthly average number of migraine days during the 12-week period 
after the 1st dose of study drug

to evaluate the proportion of patients reaching at least 50% reduction and at least 75% 
reduction in the number of migraine days during the 4-week period after the 1st dose of 
study drug relative to the baseline period who sustain this level of response over the 
12-week period after the 1st dose of study drug

to demonstrate the efficacy of TEV-48125 in patients who previously used topiramate 
for migraine, but discontinued, as assessed by the reduction of the monthly average 
number of migraine days during the 12-week period after the 1st dose of study drug 
relative to the baseline period

to demonstrate the efficacy of TEV-48125 in patients who previously used 
onabotulinumtoxinA for migraine, but discontinued, as assessed by the reduction of the 
monthly average number of migraine days during the 12-week period after the 1st dose 
of study drug relative to the baseline period

to demonstrate the efficacy of TEV-48125, as assessed by the reduction of the number 
of migraine days during the 4-week period after the 2nd dose of study drug and the 
4-week period after the last (3rd) dose of study drug relative to the baseline period

to demonstrate the efficacy of TEV-48125, as assessed by the reduction of the monthly 
average number of headache days of any severity during the 12-week period after the 1st
dose of study drug relative to the baseline period

to demonstrate the efficacy of TEV-48125, as assessed by the reduction in the number of 
headache days of at least moderate severity during the 4-week period after each dose of 
study drug relative to the baseline period

to evaluate the proportion of patients reaching at least 50% reduction, at least 75% 
reduction, and total (100%) reduction in the monthly average number of headache days 
of at least moderate severity during the 12-week period after the 1st dose of study drug 

to evaluate the proportion of patients reaching at least 50% reduction and at least 75% 
reduction in the number of headache days of at least moderate severity during the 
4-week period after the 1st dose of study drug for whom this level of effect is sustained 
throughout the 12-week period after the 1st dose of study drug 

to demonstrate the efficacy of TEV-48125, as assessed by the reduction in the number of 
headache days of at least moderate severity during the 12-week period after the 1st dose 
of study drug for patients not receiving concomitant preventive migraine medications 
relative to the baseline period

to demonstrate the efficacy of TEV-48125, as assessed by the reduction in the number of 
headache days of at least moderate severity during the 12-week period after the 1st dose 
of study drug for patients who used topiramate for migraine in the past relative to the 
baseline period


Statistical Analysis Plan with Amendment 02
TV48125-CNS-30050
15

to demonstrate the efficacy of TEV-48125, as assessed by the reduction in the number of 
headache days of at least moderate severity during the 12-week period after the 1st dose 
of study drug for patients who used onabotulinumtoxinA for migraine in the past relative 
to the baseline period

to demonstrate the efficacy of TEV-48125, as assessed by the reduction in the monthly 
average number of headache hours of any severity during the 12-week period after the 
1st dose of study drug relative to the baseline period

to demonstrate the efficacy of TEV-48125, as assessed by the reduction in the monthly 
average number of headache hours of at least moderate severity during the 12-week 
period after the 1st dose of study drug relative to the baseline period

to demonstrate the efficacy of TEV-48125, as assessed by the reduction of the monthly 
average number of days of the use of migraine-specific acute headache medications 
(triptans and ergot compounds) during the 12-week period after the 1st dose of study 
drug relative to the baseline period

to demonstrate the efficacy of TEV-48125, as assessed by the reduction of the monthly 
average number of days with nausea or vomiting during the 12-week period after the 1st
dose of study drug relative to the baseline period

to demonstrate the efficacy of TEV-48125, as assessed by the reduction of the monthly 
average number of days with photophobia and phonophobia during the 12-week period 
after the 1st dose of study drug relative to the baseline period

to demonstrate the efficacy of TEV-48125, as assessed by a change in quality of life at 
4 weeks after the last (3rd) dose of study drug relative to baseline

to explore the correlation between pharmacokinetic parameters and drug efficacy

to explore the relationship between genetic polymorphisms within the CGRP receptor-
ligand complex (eg, CALCA, CALCB, CALCRL, CRCP, and RAMP) and migraine-
associated genes (eg, PRDM16, AJAP1, TSPAN2, MEF2D, TRPM8, TGFBR2, 
PHACTR1, FHL5, C7orf10, MMP16, ASTN2, LRP1, APOA1BP, TBC1D7, FUT9, 
STAT6, ATP5B, and MTHFR) and mode-of-action-related pathways versus 
hypertension, migraine severity, and safety and efficacy responses

to explore the relationship between biofluid bone, angiogenic, and inflammatory 
biomarkers with TEV-48125 concentrations and efficacy responses


Statistical Analysis Plan with Amendment 02
TV48125-CNS-30050
16
2.
STUDY DESIGN  
2.1.
General Design and Study Schema
This is a 16-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study 
to compare the safety, tolerability, and efficacy of 2 dose regimens of sc TEV-48125 and placebo in 
adults with EM. The study consists of a screening visit, a 28-day run-in period, and a 12-week (84-
day) treatment period, including a final evaluation at week 12 (end-of-treatment [EOT] visit, 
approximately 4 weeks [28 days] after the final dose of study drug).
This study will include female and male patients, aged 18 to 70 years, inclusive, with a history of 
migraine for at least 12 months and EM (as defined by International Classification of Headache 
Disorders, 3rd edition [ICHD-3] criteria [Classification Committee of the IHS, 2013IHS]). The 
diagnosis will be prospectively confirmed via a review of headache data recorded daily during a 28-
day run-in period in an electronic headache diary device.
Patients using no more than 1 preventive medication at the time of study enrollment will be allowed 
to remain on the medication if the medication has at least moderate evidence of efficacy for 
migraine (Silberstein et al 2012). Patients should not be initiating any preventive migraine 
medications (presented in protocol Appendix B) at the time of the screening visit, and will not be 
allowed to initiate these medications after randomization. A small subgroup of patients 
(approximately 30%) will be allowed to use concomitant migraine preventive medications 
(presented in protocol Appendix A), and no changes in these medications will be allowed until the 
last study assessments are complete. Patients will be allowed to use acute medications to treat acute 
migraine attacks, as needed.
After completing the informed consent process (screening visit [visit 1]), patients will be screened 
for eligibility. Eligible patients will enter a 28-day run-in period. Headache information will be 
captured daily throughout study participation using the electronic headache diary device. After 
completing the run-in period, patients will be asked to return to the study center on day 0 (visit 2). 
Patients who have confirmed EM and meet all other eligibility criteria (including electronic 
headache diary compliance criteria during the 28-day run-in period) will be randomly assigned in a 
1:1:1 ratio to 1 of 3 treatment groups:

monthly sc administration of TEV-48125 at 225 mg

sc administration of 675 mg of TEV-48125 at visit 2 followed by monthly sc placebo 

monthly sc administration of placebo 
(Note: For this study, monthly dosing refers to dosing approximately every 4 weeks [28 days].)
Randomization will be performed using electronic interactive response technology (IRT). Patients 
will be stratified based on sex, country, and baseline preventive migraine medication use (yes, no) 
to ensure balance for the covariates (treatment group, preventive migraine medication use, country, 
and sex). The total number of patients receiving concomitant preventive medication during the 
study will not exceed 30% of the total sample size of the study.
Blinded treatment will be administered sc once monthly (ie, approximately every 4 weeks) for a 
total of 3 doses. First treatment administration will occur at visit 2 (day 0), and additional doses will 


Statistical Analysis Plan with Amendment 02
TV48125-CNS-30050
17
be administered at visits 3 and 4. Final study assessments will be performed at visit 5 (EOT visit), 
approximately 4 weeks after administration of the 3rd and final dose of study drug. 
Headache information will be captured daily during the entire study using an electronic headache 
diary device. Assessments of migraine-related disability and change in quality of life (using the 
MIDAS questionnaire, 2-item Patient Health Questionnaire (PHQ-2)/9-item Patient Health 
Questionnaire (PHQ-9), Migraine-Specific Quality of Life (MSQOL) questionnaire, EuroQol-5 
Dimension, 5 response level version (EQ-5D-5L) questionnaire, Patient Global Impression of 
Change (PGIC) scale, and Work Productivity and Activity Impairment (WPAI) questionnaire); 
safety evaluations; blood draws for pharmacokinetic, immunogenicity, and biomarker analysis; and 
urine sampling for biomarker analysis will be performed throughout the study according to the 
schedule of assessments (Table 1 ). In addition, patients who consent to pharmacogenomic 
assessment will provide a blood sample for testing.
Upon completion of the final study assessments patients who complete all scheduled visits may be 
eligible to enter a long-term safety and efficacy study (Study TV48125-CNS-30051), consisting of 
a 12-month double-blind treatment period and a 6.5-month follow-up period. Patients receiving 
active study drug in the current study will continue receiving the same treatment (ie, monthly sc 
TEV-48125 at 225 mg or quarterly sc TEV-48125 at 675 mg), and patients receiving placebo in the 
current study will be randomized in a 1:1 ratio to receive monthly sc TEV-48125 at 225 mg or 
quarterly sc TEV-48125 at 675 mg during the long-term safety and efficacy study. Patients who 
withdraw from the study before completing the 12-week evaluation period will have EOT visit 
(visit 5) procedures and assessments performed on the last day they receive the study drug or as 
soon as possible thereafter. Those patients who do not enter the long-term safety and efficacy study 
for any reason will be offered to enter the long term safety extension for the purpose of evaluating 
ADA approximately 7.5 months (225 days [the approximate equivalent of 5 half-lives]) after 
administration of the last dose of study drug in this study.
The assessments and procedures performed during each study visit are detailed in Table 1. The 
study schema is presented in Figure 1. 
The end of the study is defined as the date the last patient attends the EOT/early withdrawal visit 
(visit 5).
A total of 768 patients are planned to be randomized in a 1:1:1 ratio (256 patients per treatment 
group) to receive 3 monthly sc doses of TEV-48125 at 225 mg, 1 sc dose of TEV-48125 at 675 mg 
followed by 2 monthly sc doses of matching placebo, or 3 monthly sc doses of matching placebo.


Statistical Analysis Plan with Amendment 02
TV48125-CNS-30050
18
Figure 1:
Overall Study Schema
PBO = placebo; V = visit.
Note: Baseline refers to the 28-day run-in period for headache variables and visit 2 (day 0) for all other variables.


Statistical Analysis Plan with Amendment 01
TV48125-CNS-30050
19
Table 1:
Study Procedures and Assessments
Study period
Pretreatment 
period (incl. 
screening visit 
and run-in 
period)
Double-blind treatment period
Visit number
V1
V2
V3
V4
V5
Month number
Month -1
Month 0
Month 1
Month 2
Month 3
Procedures and assessments (completed before dosing, when applicable,
unless otherwise noted)
Screening
days -28 to -1
Baseline 
dose 1
day 0
(+3 days)
Dose 2
day 28 
(±3 days)
Dose 3
day 56 
(±3 days)
EOT or early 
withdrawal
day 84 
(±3 days)
Informed consent
X
Medical and psychiatric history
X
Prior medication history
X
Record demographic characteristics
X
Inclusion and exclusion criteria
X
X
Randomization
X
Physical examination, including weight and heighta
X
X
X
Triplicate 12-lead ECGb,c
X
X
X
Vital signs measurementb
X
X
X
X
X
Adverse eventsd
X
X
X
X
X
Concomitant medication inquiry
X
X
X
X
X
Clinical laboratory testse
X
X
X
X
X
Serum β-HCG testf
X
Urine β-HCG testf
X
X
X
X
FSHg
X


Statistical Analysis Plan with Amendment 01
TV48125-CNS-30050
20
Study period
Pretreatment 
period (incl. 
screening visit 
and run-in 
period)
Double-blind treatment period
Visit number
V1
V2
V3
V4
V5
Month number
Month -1
Month 0
Month 1
Month 2
Month 3
Procedures and assessments (completed before dosing, when applicable,
unless otherwise noted)
Screening
days -28 to -1
Baseline 
dose 1
day 0
(+3 days)
Dose 2
day 28 
(±3 days)
Dose 3
day 56 
(±3 days)
EOT or early 
withdrawal
day 84 
(±3 days)
Provide electronic headache diaryh
X
Complete electronic headache diary entriesi
X
X
Review electronic headache diary
X
X
X
X
Return headache diary device
X
Blood samples for plasma drug concentrationj
X
X
X
X
Blood samples for serum ADA assessmentk
X
X
X
Blood sample for pharmacogenomic analysisl
X
Blood collection for serum, plasma, and RNA biomarker analysis
X
X
X
Urine collection for biomarker analysis
X
X
X
MIDAS questionnaire
X
X
PHQ-2/PHQ-9m
X
X
MSQOL questionnaire
X
X
X
X
EQ-5D-5L questionnaire
X
X
PGIC scale
X
X
X
WPAI questionnaire
X
X


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Study period
Pretreatment 
period (incl. 
screening visit 
and run-in 
period)
Double-blind treatment period
Visit number
V1
V2
V3
V4
V5
Month number
Month -1
Month 0
Month 1
Month 2
Month 3
Procedures and assessments (completed before dosing, when applicable,
unless otherwise noted)
Screening
days -28 to -1
Baseline 
dose 1
day 0
(+3 days)
Dose 2
day 28 
(±3 days)
Dose 3
day 56 
(±3 days)
EOT or early 
withdrawal
day 84 
(±3 days)
eC-SSRSn
X
X
X
X
Administration of study drug
X
X
X
Injection site assessmentso
X
X
X
Review eligibility for long-term safety study (TV48125-CNS-30051)
X
a Height will only be obtained at screening. 
b Procedure will be performed before other assessments (eg, blood draws and administration of questionnaires).
c Electrocardiograms will be performed in triplicate.
d Inquiries about adverse events will be made before and after study drug administration. Postdose inquiries will be made before the patient leaves the study center.
e Serum chemistry, hematology, coagulation, and urinalysis.
f Women of childbearing potential only.
g Postmenopausal women only.
h Eligible patients will be given an electronic headache diary device and will be trained in its use and compliance requirements on the day of screening.
i Patients will complete electronic headache diary entries about the previous day daily beginning on day -27 through the EOT/early withdrawal visit.
j Blood samples for plasma drug concentration determination will be collected prior to dosing at visits 2, 3, and 4.
k Blood samples for serum ADA assessment will also be collected upon observation of any severe hypersensitivity reaction (eg, anaphylaxis).
l A single blood sample for pharmacogenomic analysis will be collected at visit 2 or any visit thereafter from patients who consent to this procedure. A separate informed consent 
form for pharmacogenomic sampling must be signed by the patient.
m Patients will respond first to the PHQ-2. They will respond to questions 3 through 9 (unique questions) of the PHQ-9 only if PHQ-2 is positive.
n The eC-SSRS Baseline/Screening version will be completed at visit 2, and the eC-SSRS Since Last Visit version will be completed at all other visits.
o Injection sites will be assessed for erythema, induration, ecchymosis, and pain immediately and 1 hour after study drug administration. 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 study drug administration, the patient 
will be reassessed 3 hours after study drug administration and hourly thereafter until the reaction/pain is of moderate or less severity.
ADA=antidrug antibody; β-HCG=beta-human chorionic gonadotropin; ECG=electrocardiogram; eC-SSRS=electronic Columbia-Suicide Severity Rating Scale; 
EOT=end of treatment; EQ-5D-5L=EuroQol-5 Dimension, 5 response level version; FSH=follicle-stimulating hormone; MIDAS=Migraine Disability 
Assessment; MSQOL=Migraine-Specific Quality of Life; PGIC=Patient Global Impression of Change; PHQ-2=2-item Patient Health Questionnaire; 
PHQ-9=9-item Patient Health Questionnaire; V=visit; WPAI=Work Performance and Activity Impairment.


Statistical Analysis Plan with Amendment 02
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2.2.
Primary and Secondary Measures and Endpoints
2.2.1.
Primary Efficacy Endpoint
The primary efficacy endpoint is the mean change from baseline (28-day run-in period) in the 
monthly average number of migraine days during the 12-week period after the 1st dose of study 
drug.
2.2.2.
Secondary Efficacy Endpoints
The secondary efficacy endpoints are as follows:

proportion of patients reaching at least 50% reduction in the monthly average number of 
migraine days during the 12-week period after the 1st dose of study drug

mean change from baseline (28-day run-in period) in the monthly average number of 
days of use of any acute headache medications during the 12-week period after the 
1st dose of study drug 

mean change from baseline (28-day run-in period) in the number of migraine days 
during the 4-week period after the 1st dose of the study drug

mean change from baseline (28-day run-in period) in the monthly average number of 
migraine days during the 12-week period after the 1st dose of study drug in patients not 
receiving concomitant migraine preventive medications

mean change from baseline (day 0) in disability score, as measured by the MIDAS 
questionnaire, at 4 weeks after administration of the last (3rd) dose of study drug
2.2.3.
Exploratory Efficacy Endpoints
The exploratory efficacy endpoints are as follows:

mean change from baseline (28-day run-in period) in the number of headache days of at 
least moderate severity during the 12-week period after the 1st dose of study drug

mean change from baseline (28-day run-in period) in the weekly number of migraine 
days during the 4-week period after the 1st dose of study drug 

proportion of patients reaching at least 75% reduction and total (100%) reduction in the 
monthly average number of migraine days during the 12-week period after the 1st dose 
of study drug

proportion of patients reaching at least 50% reduction and at least 75% reduction in the 
number of migraine days during the 4-week period after the 1st dose of study drug for 
whom this level of effect is sustained throughout the 12-week period after the 1st dose of 
study drug

mean change from baseline (28-day run-in period) in the monthly average number of 
migraine days during the 12-week period after the 1st dose of study drug in patients who 
used topiramate for migraine in the past


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
mean change from baseline (28-day run-in period) in the number of migraine days 
during the 12-week period after the 1st dose of study drug for patients who used 
onabotulinumtoxinA for migraine in the past

mean change from baseline (28-day run-in period) in the number of migraine days 
during the 4-week period after the 2nd dose of the study drug

mean change from baseline (28-day run-in period) in the number of migraine days 
during the 4-week period after the last (3rd) dose of the study drug

mean change from baseline (28-day run-in period) in the monthly average number of 
headache days of any severity during the 12-week period after the 1st dose of study drug

mean change from baseline (28-day run-in period) in the number of headache days of at 
least moderate severity during the 4-week period after each dose of study drug

mean change from baseline (28-day run-in period) in the weekly number of headache 
days of at least moderate severity during the 4-week period after the 1st dose of study 
drug 

proportion of patients reaching at least 50% reduction, at least 75% reduction, and total 
(100%) reduction in the monthly average number of headache days of at least moderate 
severity during the 12-week period after the 1st dose of study drug

proportion of patients reaching at least 50% reduction and at least 75% reduction in the 
number of headache days of at least moderate severity during the 4-week period after the 
1st dose of study drug for whom this level of effect is sustained throughout the 12-week 
period after the 1st dose of study drug

mean change from baseline (28-day run-in period) in the number of headache days of at 
least moderate severity during the 12-week period after the 1st dose of study drug for 
patients not receiving concomitant preventive migraine medications

mean change from baseline (28-day run-in period) in the number of headache days of at 
least moderate severity during the 12-week period after the 1st dose of study drug for 
patients who used topiramate for migraine in the past

mean change from baseline (28-day run-in period) in the number of headache days of at 
least moderate severity during the 12-week period after the 1st dose of study drug for 
patients who used onabotulinumtoxinA for migraine in the past

mean change from baseline (28-day run-in period) in the monthly average number of 
headache hours of any severity during the 12-week period after the 1st dose of study 
drug

mean change from baseline (28-day run-in period) in the monthly average number of 
headache hours of at least moderate severity during the 12-week period after the 1st dose 
of study drug

mean change from baseline (28-day run-in period) in the monthly average number of 
days of use of migraine-specific acute headache medications (triptans and ergot 
compounds) during the 12-week period after the 1st dose of study drug


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
mean change from baseline (28-day run-in period) in the monthly average number of 
days with nausea or vomiting during the 12-week period after the 1st dose of study drug

mean change from baseline (28-day run-in period) in the monthly average number of 
days with photophobia and phonophobia during the 12-week period after the 1st dose of 
study drug

mean change from baseline (day 0) in quality of life, as measured by the MSQOL
questionnaire, at 4 weeks after administration of the last (3rd) dose of study drug

mean change from baseline (day 0) in the health status, as measured by the EQ-5D-5L 
questionnaire at 4 weeks after administration of the last (3rd) dose of study drug

mean change from baseline (day 0) in patient depression status, as measured by the 
PHQ-2 and PHQ-9, at 4 weeks after administration of the last (3rd) dose of study drug

mean change from baseline (day 0) in patient work productivity and activity impairment,
as measured by the WPAI questionnaire, at 4 weeks after administration of the last (3rd) 
dose of study drug

assessment of patient satisfaction, as measured by the PGIC scale, at 4 weeks after 
administration of the 1st dose of study drug, at 4 weeks after the 2nd dose of study drug, 
and at 4 weeks after the last (3rd) dose of study drug
2.2.4.
Safety and Tolerability Endpoints
The safety and tolerability endpoints for this study are as follows:

occurrence of adverse events throughout the study

abnormal standard 12-lead electrocardiogram (ECG) findings

changes from baseline in vital signs (systolic and diastolic blood pressure, pulse, oral 
temperature, and respiratory rate) measurements 

changes from baseline in clinical laboratory (serum chemistry, hematology, coagulation, 
and urinalysis) test results

abnormal physical examination findings

abnormal local injection site tolerability findings (ie, erythema, induration, ecchymosis) 
and occurrence of injection site pain 

suicidal ideation and behavior as suggested by the electronic Columbia-Suicide Severity 
Rating Scale (eC-SSRS)
2.2.5.
Pharmacokinetic/Immunogenicity/Biomarker Endpoints
2.2.5.1.
Pharmacokinetic Endpoints
There are no prespecified pharmacokinetic endpoints.
2.2.5.2.
Immunogenicity Endpoint
There are no prespecified immunogenicity endpoints.


Statistical Analysis Plan with Amendment 02
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25
2.2.5.3.
Biomarker Endpoints
The biomarker assessments and endpoints will be provided in a separate document by Personal 
Medicine and Pharmacogenomics.
2.3.
Sample Size and Power Considerations
A total of 768 patients are planned to be randomized in this study to have 675 completers 
(225 completers per treatment group); a 12% drop-out rate is anticipated. A sample size of 
675 patients (ie, 225 evaluable patients completing the study per treatment group) will provide 
90% power to detect a 1.6 difference in migraine days between an active arm and placebo arm at an 
alpha level of 0.05, assuming a common standard deviation (SD) of 5.2 days.
2.4.
Randomization and Blinding
2.4.1.
Randomization
Patient randomization codes will be maintained in a secure location within Teva Clinical Supply 
Chain. At the time of analysis, when treatment codes are needed, the Teva statistician assigned to 
the study will make a request to unblind and will receive the unblinded codes.
2.4.2.
Blinding/Unblinding
This is a randomized study with stratification based on sex, country, and baseline preventive 
migraine medication use (yes, no). Each patient will undergo randomization in a 1:1:1 ratio within 
the stratum to which he or she belongs to receive 1 of the 2 TEV-48125 dose regimens or placebo, 
as assigned by the IRT. The IRT will manage initial drug supply, maintenance of adequate study 
drug supplies on site, and study randomization centrally. At the time of each study visit, the IRT 
will be queried, and site personnel will retrieve and administer a 1.5-mL volume from each syringe 
contained in the appropriately numbered kit(s).
The sponsor, investigators, study staff (except for staff involved in bioanalytical analyses), and 
patients will be blinded to treatment assignment. A computer-generated master randomization list 
will be provided to drug packaging facilities. Packaging vendor(s) will package active drug and 
placebo into single-visit kits according to Good Manufacturing Practice procedures. Kits will be 
identical in appearance and contain 1 prefilled syringe with active drug or placebo. Adequate kit 
supply for upcoming study visits will be managed by IRT and kept (refrigerated at 2°C to 8°C) on 
site.
In case of a serious adverse event or pregnancy, or in cases when knowledge of the study drug 
assignment is needed to make treatment decisions, the investigator may unblind the patient’s drug 
assignment as deemed necessary, mainly in emergency situations. Individual treatment codes, 
indicating the treatment randomization for each randomized patient, will be available to the 
investigator(s) and/or pharmacist(s) at the study center via the IRT, both via telephone and internet. 
If possible, the sponsor should be notified of the event prior to breaking of the code. If this is not 
possible, the sponsor should be notified immediately afterwards, and the patient’s drug code 
assignment should not be revealed. Breaking of the treatment code can always be performed by the 
site without prior approval by the sponsor.


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26
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 adverse events that are defined as: suspected, unexpected, serious, adverse 
reaction (SUSAR) (ie, reasonable possibility; see protocol Section 7.1.4), Global Patient Safety and 
Pharmacovigilance may independently request that the treatment code be revealed (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, analysis, and reporting of the data.
2.5.
Sequence of Planned Analyses
2.5.1.
Interim Analyses
No interim analysis is planned for this study.
2.5.2.
Final Analyses and Reporting
All final, planned analyses identified in this SAP will be performed after the database lock. The 
study will not be unblinded until the study database lock.


Statistical Analysis Plan with Amendment 02
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27
3.
POPULATIONS / ANALYSIS SETS
3.1.
Intent-to-Treat Population
The intent-to-treat (ITT) population will include all randomized patients. In this population, 
treatment will be assigned based on the treatment to which patients are randomized, regardless of 
which treatment they actually received.
3.2.
Safety Population
The safety population will include all patients who receive at least 1 dose of study drug. In this 
population, treatment will be assigned based upon the treatment patients actually receive, regardless 
of the treatment to which they are randomized. All safety analysis will be based on the safety 
population. 
3.3.
Full Analysis Set 
The full analysis set (FAS) will include all patients in the ITT population who receive at least 1 
dose of study drug and have at least 10 days of post baseline efficacy assessments on the primary 
endpoint. The FAS will be used for all efficacy analysis.
3.4.
Per-Protocol Analysis Set 
The per-protocol 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.


Statistical Analysis Plan with Amendment 02
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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. Descriptive statistics for categorical variables include patient 
counts and percentages. 
Summaries of potentially clinically significant abnormal values will include all post-baseline values 
(including scheduled, unscheduled, and early termination visits).
4.2.
Specification of Baseline Values
Patients will complete electronic headache diary entries daily for 28-day run-in period and enter 
headache information (ie, occurrence of headache, duration of headache, maximum severity of 
headache, and acute migraine-specific medication use) about the previous day into the electronic 
headache diary device. If the run-in period is greater or less than 28 days, the baseline values for 
calculating the change from baseline of the monthly values of the efficacy variables will be 
normalized to 28 days. The baseline value for calculating change from baseline of the weekly 
values will be normalized to 7 days.
The efficacy baseline values during the 28-day run-in period derived from the e-diary include

total number of migraine days

total headache days of at least moderate severity

total number of days of use of any acute headache medication

total headache days of any severity

total number of headache hours of at least moderate severity

total number of headache hours of any severity

total number of days of use of migraine-specific acute headache medications (triptans 
and ergot compounds) for the group of patients who use migraine-specific acute 
headache medications at baseline

total number of days with nausea or vomiting

total number of days with photophobia and phonophobia
Other efficacy baseline values that will be measured on day 0 before the 1st study drug
administration include

disability score, as measured by the MIDAS assessment (Appendix C)

quality of life, as measured by the MSQOL questionnaire (Appendix D)

health status, as measured by the EQ-5D-5L questionnaire (Appendix F)

patient depression status, as measured by the PHQ-2 and the PHQ-9 (Appendix G)


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
patient work productivity and activity impairment, as measured by the WPAI 
questionnaire (Appendix H)
Other baseline will be the last value prior to the 1st dose of study drug. 
4.3.
Region of Pooled Countries
The countries will be pooled to 2 regions as described below in Table 2 for analysis purpose. 
Table 2:
Pooled Countries by Region
Region
Country
United States
United States
Other
Japan, Czech Republic, Poland, Russia, Canada, Spain, Israel, Finland
4.4.
Multiple Comparisons and Multiplicity
A fixed-sequence (hierarchical) testing procedure will be implemented to control the type 1 error 
rate at 0.05. The sequence of comparisons will be as follows:
1. mean change from baseline (28-day run-in period) in the monthly average number of 
migraine days during the 12-week period after the 1st dose of study drug for the TEV-48125
225/225/225 mg treatment group versus the placebo treatment group
2. proportion of patients reaching at least 50% reduction in monthly average number of 
migraine days during 12-week period after the 1st dose of study drug for the TEV-48125 
225/225/225 mg treatment group versus the placebo treatment group
3. mean change from baseline (28-day run-in period) in the monthly average number of 
migraine days during the 12-week period after the 1st dose of study drug for the TEV-48125 
675 mg/placebo/placebo treatment group versus the placebo treatment group
4. mean change from baseline (28-day run-in period) in the number of migraine days during the
4-week period after the 1st dose of the study drug for the TEV-48125 675 
mg/placebo/placebo treatment group versus the placebo treatment group
5. proportion of patients reaching at least 50% reduction in the monthly number of migraine 
days during 12-week period after the 1st dose of study drug for the TEV-48125 675 
mg/placebo/placebo treatment group versus the placebo treatment group
6. mean change from baseline (28-day run-in period) in the monthly average number of days of 
use of any acute headache medications during the 12-week period after the 1st dose of the 
study drug for the TEV-48125 225/225/225 mg treatment group versus the placebo
treatment group
7. mean change from baseline (28-day run-in period) in the monthly average number of days of 
use of any acute headache medications during the 12-week period after the 1st dose of study
drug for the TEV-48125 675 mg/placebo/placebo treatment group versus the placebo 
treatment group


Statistical Analysis Plan with Amendment 02
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8. mean change from baseline (28-day run-in period) in the number of migraine days during the
4-week period after the 1st dose of the study drug for the TEV-48125 225/225/225 mg
treatment group versus the placebo treatment group
9. mean change from baseline (day 0) in disability score, as measured by the MIDAS 
questionnaire, at 4 weeks after administration of the last (3rd) dose of study drug for the 
TEV-48125 225/225/225 mg treatment group versus the placebo treatment group
10. mean change from baseline (day 0) in disability score, as measured by the MIDAS 
questionnaire, at 4 weeks after administration of the last (3rd) dose of study drug for the 
TEV-48125 675 mg/placebo/placebo treatment group versus the placebo treatment group
11. mean change from baseline (28-day run-in period) in the monthly average number of 
migraine days during the 12-week period after the 1st dose of study drug for the TEV-48125 
225/225/225 mg treatment group versus the placebo treatment group in patients not 
receiving concomitant migraine preventive medications
12. mean change from baseline (28-day run-in period) in the monthly average number of 
migraine days during the 12-week period after the 1st dose of study drug for the TEV-48125 
675 mg/placebo/placebo treatment group versus the placebo treatment group in patients not 
receiving concomitant migraine preventive medications
If the resulting 2-sided p-value from the first comparison is ≤0.05, then the next comparison of 
interest will be interpreted inferentially at the alpha level of 0.05. This process will continue either 
until all comparisons of interest 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 p>0.05, no further 
comparisons will be interpreted inferentially.
4.5.
Handling Withdrawals and Missing Data
If a patient has ≥10 days of the e-diary data after 1st dose of the study drug, his/her monthly average 
number of days/hours of efficacy variables during the 12-week period or monthly number of 
days/hours of efficacy variables during the 4-week period will be prorated to 28 days. 
Multiple imputation (MI) method will be applied on the primary variable as sensitivity analyses. 
The methods will be described in detail in Section 6.2.3.
A patient’s monthly number of days/hours of efficacy variables during the 4-week period after each 
dose of study drug will be calculated for months 1, 2, and 3. If a patient has missing diary days in a 
month, the following method will be used to handle the missing data. 

If the patient has 10 or more days of e-diary data for a month, the monthly number of 
days/hours of efficacy variables will be prorated to 28 days for that month. 

If the patient has less than 10 days of e-diary data for a month, the monthly number of 
days/hours of efficacy variables will be considered as missing.  
The weekly number of migraine days and headache days of at least moderate severity will be 
calculated for the patients’ first 28 calendar days of diary data after the 1st dose of study drug. Each 
week is defined as 7 calendar days with week 1 counted from the 1st dose date. If a patient has 
missing diary days in a week, the following method will be used to handle the missing data.


Statistical Analysis Plan with Amendment 02
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31

If the patient has ≥3 days of e-diary data for a week, the weekly number of days of 
efficacy variables will be prorated to 7 days for that week. 

If the patient has <3 days of e-diary data for a week, the weekly number of days of 
efficacy variables will be considered as missing for that week. 
The handling of missing questionnaire items for the MSQOL questionnaire (Appendix D) is 
discussed in Appendix E: scoring instruction for MSQOL. 
4.6.
Study Days and Visit Windows
Study days will be numbered relative to the 1st day of study drug administration. The start of 
treatment (visit 2 or day 1) is defined as the date on which a patient takes the 1st dose of study drug, 
as recorded on the study drug administration CRF. Days will be numbered relative to study drug 
start (ie, ..., –2, –1, 1, 2, ...; with day 1 being the start of study drug and day –1 being the day before 
the start of study drug).
The 4-week (28-day) visit windows for the e-diary based efficacy endpoints will be determined 
based on the actual dosing day. The run-in phase is defined as day -28 to -1 before the 1st injection 
on day 1. Treatment phase including month 1, 2 and 3 is from the beginning of the 1st injection of 
study drug to visit 5/day 84 or the end of treatment visit. The 3-month visit windows are separated 
by each dosing date/time. Month 1 is from the date/time of the 1st dose of study drug administration 
on day 1 to the date/time just before the 2nd dose.  Month 2 is from the date/time of the 2nd dose to 
the date/time just before the 3rd dose.  Month 3 is from the date/time of the 3rd  dose to the end of 
the study on day 84 approximately.   
Throughout this document, all by month efficacy summaries for the headache data will refer to 
these visit windows.
The weekly (7-day) windows for calculating the weekly efficacy endpoints for the first 28 days  
will be determined based on the 1st dosing day. The first week is from day 1 to day 7, the second 
week is from day 8 to day 14, the third week is from day 15 to day 21, and the fourth week is from 
day 22 to day 28. Only the days between the first and the second dose will be included.
For all other 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 assessments at 
the scheduled and unscheduled visits. 
Endpoint for analyses and summaries is the last observed postbaseline data. For patients who 
withdraw from the study, data at the early termination visit will be excluded from the by-visit 
summaries but will be included in the endpoint summaries.


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5.
STUDY POPULATION SUMMARY
5.1.
General
The ITT population will be used for all study population summaries unless otherwise noted.  
Summaries will be presented by treatment group, all TEV-48125 and overall unless otherwise 
noted. 
For continuous variables, descriptive statistics (n, mean, SD, SE, 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.
5.2.
Patient Disposition
Patients screened, screening failures, and the reasons the patients were not randomized will be 
summarized only for the overall group using patient counts.  
Patients randomized (ie, in the ITT set), patients randomized but not treated, patients in the safety, 
full analysis set and per-protocol population, patients who complete the study, and patients who 
withdraw from the study will be summarized using descriptive statistics. Patients who withdraw 
from the study will also be summarized using descriptive statistics by reason for withdrawal.  The 
denominator for calculating the percentages will be the number of ITT population. 
5.3.
Demographics and Baseline Characteristics
The demographic data including date of birth (or year of birth), sex, country, ethnicity and race will 
be collected at the screening after the patient signs informed consent. Patient’s demographics and 
baseline characteristics including age, sex, country, ethnicity and race, weight, height, and body 
mass index, years of migraine, concomitant preventive medication use for migraine, use of 
topiramite or onabotulinumtoxinA for migraine in the past, and any triptans/ergots during baseline
will be summarized for ITT population.
The baseline e-diary efficacy variables listed in Section 4.2, baseline MIDAS scores and MSQOL
scores will be summarized by treatment group for the ITT population. 
For continuous variables, treatment groups will be compared using an analysis of variance with 
treatment as a factor. For categorical variables, treatment groups will be compared using a 
Pearson’s chi-square test (or Fisher’s exact test if cells sizes are too small).
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 by 
system organ class (SOC) and preferred term (PT). Patients are counted only once in each SOC and 
only once in each PT. 


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5.5.
Prior Medications or Therapy
All prior medications or therapy will be coded using the World Health Organization dictionary of 
medical codes (WHO Drug).  The incidence of prior medications or therapy will be summarized 
using descriptive statistics by therapeutic class and PT.  Patients are counted only once in each 
therapeutic class category, and only once in each PT category.  Prior medications will include all 
medications taken prior to the 1st study drug treatment.
The subset of prior medications will be summarized for the following categories.

preventive migraine medication

triptans and ergots

non-steroidal anti-inflammatory drugs (NSAIDs) for migraine/headache

NSAIDs for reasons other than migraine/headache

opioids for migraine/headache 

opioids for reasons other than migraine/headache 

other
5.6.
Electrocardiography
Electrocardiogram findings (normal, abnormal, and missing) at baseline will be summarized using 
descriptive statistics.
5.7.
Physical Examinations
Physical examinations results will be listed. Patients with at least 1 abnormal finding (overall) and 
abnormal findings for each category will be summarized. 
5.8.
Protocol Violations 
Patients with at least 1 protocol violation will be summarized for each category using descriptive 
statistics.
5.9.
Childbearing Potential 
All patients must be of nonchildbearing potential as defined in protocol Section 4.1. Information 
related to childbearing potential will be collected and listed.


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6.
EFFICACY ANALYSIS
6.1.
General
The efficacy data for this study consist of headache related questions responses (e.g., occurrence of 
headache, duration of headache in each day, maximum severity of headache, and acute migraine-
specific medication use) collected daily using an electronic headache diary device. 
In addition, the following questionnaires will be used for the assessments of migraine impairment, 
quality of life and satisfaction of treatment etc. during the study (See Table 1) for the schedule of 
the assessment).

migraine disability assessment test (see Appendix C)

migraine-specific quality of life, as measured by the MSQOL questionnaire (see 
Appendix D)

health status, as measured by the EQ-5D-5L questionnaire (see Appendix F)

patient depression status, as measured by the PHQ-2 and the PHQ-9 (see Appendix G)

patient work productivity and activity impairment, as measured by the WPAI
questionnaire (see Appendix H)

assessment of patient satisfaction, as measured by the PGIC scale (see Appendix I)
The monthly average number of days or hours of efficacy variables (e.g. migraine days, days of 
headache with at least moderate severity, days of headache with any severity, total hours of 
headache with any severity, total hours of headache with at least moderate severity, days of use of 
any acute headache medications, days with nausea or vomiting, days with photophobia and 
phonophobia etc.) during the 12-week period after the 1st dose of study drug will be derived and 
normalized to 28 days equivalent using the following formula.
∑ 	
 ℎ	
 	  
 	
 ℎ 12  
	
∑ ℎ 
	
  ℎ 
 	
 ℎ 12  
	 × 28 (1)
The monthly number of days or hours of efficacy variables during a 4-week period after each dose 
will be derived and normalized to 28 days equivalent using the following formula, where monthly
data separated by each visit of study drug dosing will be used.
∑ 	
 ℎ	
 	  
 
! ℎ 4  
	
∑ ℎ 
	
  ℎ 
 	
 ℎ 4  
	 × 28
(2)
The baseline values will be calculated using all data collected in the run-in period, i.e.,
∑ 	
 ℎ	
 	  
 
! ℎ 
 − 
	
∑ ℎ 
	
  ℎ 
 	
 ℎ 
 − 
	 × 28 (3)
The percentage of reduction in the monthly average number of an efficacy variable will be 
calculated as 
  −	 
 
× 100% (4)


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where the baseline value is calculated by formula (3) and the postbaseline value in the equation is 
calculated by formula (1) for the variables during the 12-week period or by formula (2) for the 
variables during the 4-week period after each dose for months 1, 2 and 3.
The baseline values for calculating the change from baseline of the weekly number of days of the 
efficacy variables will use all data collected in the run-in period and be calculated as
∑ 	  
 
! ℎ 
 − 
	
∑ ℎ 
	
  ℎ 
 	
 ℎ 
 − 
	 × 7 (5)
The weekly number of days of efficacy variables (e.g., days of headache with at least moderate 
severity, migraine days) for each week during the 4-week period after the 1st dose of study drug will 
be derived and normalized to 7 days equivalent using the following formula.
∑ 	  
 
! ℎ 7  
	
∑ ℎ 
	
  ℎ 
 	
 ℎ 7  
	 × 7
(6)
The FAS will be used for all efficacy analyses. Summaries will be presented by treatment group as 
randomized, unless otherwise noted. Descriptive statistics for all efficacy data will be presented by 
month (or week) or visit as appropriate and over 12-week period.
The primary and secondary endpoints analysis listed in Section 4.4 will be repeated for the per-
protocol analysis set.
6.2.
Primary Efficacy Variable(s) and Analysis
For the purpose of this study, a migraine day is endorsed when at least 1 of the following situations 
occur:

A calendar day (0:00 to 23:59) demonstrating at least 2 consecutive hours of a headache 
endorsing criteria for migraine with or without aura

A calendar day (0:00 to 23:59) demonstrating at least 2 consecutive hours of a headache 
endorsing criteria for probable migraine, a migraine subtype where only 1 migraine 
criterion is missing

A calendar day (0:00 to 23:59) demonstrating a headache of any duration that was 
treated with migraine specific medications (triptans and ergot compounds)
The derivation logic is presented in Appendix B.
6.2.1.
Variable Definition
The primary efficacy variable is the change from baseline in the monthly average number of 
migraine days during the 12-week period after the 1st dose of study drug.  The baseline values will 
be derived using formula (3). The postbaseline values will be derived using formula (1), and the
change is calculated as *+,-./,01230 4/150 −./,01230 4/150.


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6.2.2.
Primary Analysis
The hypothesis testing for the primary analysis is     
2
1
2
1
:
:






a
o
H
vs
H
where 
1and 
2
are the estimates of mean change from baseline in the monthly average number of 
migraine days for the TEV-48125 treatment group and the placebo group respectively. The 
estimated difference of each TEV-48125 dose vs. placebo will be tested following the pre-specified 
fixed sequence as specified in Section 4.4.
An analysis of covariance (ANCOVA) method will be applied for the primary analysis. The model 
will include treatment, sex, region (Table 2) , and baseline preventive migraine medication use
(yes/no) as fixed effects; the baseline number of migraine days and years since onset of migraine as 
covariates. The least square (LS) means for the treatment groups, LS mean and corresponding 95% 
confidence intervals for the treatment differences (TEV-48125 – placebo), and associated p-value 
will be provided. 
The following sample SAS code pertains to the primary efficacy analysis.
ODS OUTPUT DIFFS=XXX LSMEANS=XXX TESTS3=XXX;
PROC MIXED DATA=XXX; 
CLASS TREAT SEX BMU REGION;
MODEL CHG=BASE YOD BMU SEX TREAT REGION/S;
LSMEANS TREAT/PDIFF CL ALPHA=0.05;
RUN;
The normality of the residuals from the ANCOVA model will be checked using Shapiro Wilk’s 
normality test. In case that the Shapiro Wilk’s test has a p value ≤0.01, Wilcoxon rank-sum test 
will be conducted as the primary analysis using SAS procedure NPAR1WAY for each active 
treatment group and placebo group. P value based on normal approximation from this procedure 
will be selected for the treatment comparison. The ANCOVA analysis will be performed as a 
supportive analysis.
6.2.3.
Sensitivity Analysis
6.2.3.1.
MMRM Analysis
A mixed-effects repeated measures (MMRM) analysis model will be implemented to estimate the 
mean change from baseline in the monthly average number of migraine days for the overall 3 
months treatment period and by each month to support the primary analysis. 
Each patient’s monthly number of migraine days during the 4-week period for month 1, month 2 
and month 3 will be calculated by formula (2) in Section 6.1 based on the e-diary responses for that 
month. If a patient is early terminated or has intermittent missing days and has less than 10 days of 
e-diary entries for a month, that month’s value will be considered as missing as described 
in Section 4.5.


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The MMRM model will include baseline value, treatment, sex, region, baseline preventive migraine 
medication use (yes/no), years since onset of migraines, month and treatment-by-month interaction 
as fixed effects, and patient in the repeated statement as a random effect. The unconstructed 
covariance structure will be used for the repeated observations within a patient. LS means for the 
treatment groups, LS means for the treatment differences (TEV-48125 - placebo), and 
corresponding 95% confidence intervals and associated p-values will be calculated by month and 
for the overall treatment period. 
The following SAS code pertains to the MMRM analysis.
ODS OUTPUT DIFFS=XXX LSMEANS=XXX TESTS3=XXX;
PROC MIXED DATA=XXX METHOD=REML; 
CLASS USUBJID MONTH TREAT SEX BMU REGION;
MODEL CHG=BASE YOD BMU SEX TREAT MONTH TREAT*MONTH/S;
REPEATED MONTH/SUBJECT=USUBJID TYPE=UN R;
LSMEANS TREAT TREAT*MONTH/PDIFF CL ALPHA=0.05;
RUN;
The LS means ±SE of monthly change from baseline values estimated by MMRM will be plotted 
by month for each treatment group.
6.2.3.2.
Analysis with Multiple Imputation Method 
Multiple imputation (MI) method will be applied to impute the monthly missing data. The data will 
be processed by the following steps.

If a patient has partial e-diary data for a month, ie, <10 days of data, that month value 
will be considered missing before the MI procedure. 

For the patients in the active treatment group who are early terminated with reasons of 
adverse event or lack of efficacy, they will be assigned to placebo group so their missing 
values will be imputed using data from the placebo treated patients 

Run SAS PROC MI procedure to create 10 complete datasets. 

Within each imputed data set, for a patient who has partial, say X days (X<10) , e-diary 
data in a month, the monthly value will be replaced by 
∑(	
 !
  ) + (28 −7) ∗ /28

The monthly average number of migraine days during the 12-week period after the 1st
dose of study drug will be the average of month 1, month 2 and month 3 values. 
Each dataset will be analyzed using the same ANCOVA model as described in Section 6.2.2. The 
LS means and standard errors from each analysis will be output to a SAS data set. SAS 
MIANALYZE procedure will be used to generate the final LS means (±SE) for the treatment 
groups and the treatment differences (TEV-48125 - placebo) as well as p-values associated with 
treatment differences. The 95% confidence intervals for the treatment differences will also be 
constructed.


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6.3.
Secondary Efficacy Variables and Analysis
The secondary efficacy endpoints are as follows:

proportion of patients reaching at least 50% reduction in the monthly average number of 
migraine days during the 12-week period after the 1st dose of study drug

mean change from baseline (28-day run-in period) in the monthly average number of 
days of use of any acute headache medications during the 12-week period after the 
1st dose of study drug 

mean change from baseline (28-day run-in period) in the number of migraine days 
during the 4-week period after the 1st dose of the study drug

mean change from baseline (28-day run-in period) in the monthly average number of 
migraine days during the 12-week period after the 1st dose of study drug in patients not 
receiving concomitant migraine preventive medications 

mean change from baseline (day 0) in disability score, as measured by the MIDAS 
questionnaire, at 4 weeks after administration of the last (3rd) dose of study drug
6.3.1.
Variable Definition
6.3.1.1.
Electronic Headache Diary Data
The change from baseline in the monthly average number of days of secondary efficacy variables 
(e.g. migraine days, days of use of any acute headache medications etc.) during the 12-week period 
after the 1st dose of study drug will be derived similar to the primary variables using the e-diary data 
collected through the corresponding headache diary questions (Appendix A). The baseline values 
and the postbaseline values will be calculated using formula (3) and (1) respectively.  The change
is calculated as postbaseline value – baseline value.
The percent reduction in the monthly average number of migraine days during the 12-week period
after the 1st dose of study drug will be calculated by formula (4) in Section 6.1. The patient is 
considered as a responder if the percent reduction is 50% or more. If a patient is early discontinued 
from the study, he/she will be counted as a non-responder. 
The change from baseline (run-in period) in the number of migraine days during the 4-week period
after the 1st dose of study drug will be derived similar to the primary endpoint using only the 1st
month diary data. 
6.3.1.2.
Migraine Disability Assessment (MIDAS)
The MIDAS questionnaire is a 5-item instrument developed to assess headache-related disability 
based on lost days of activity in 3 domains (work, household work, and nonwork) over the previous
3 months. Patients will complete the MIDAS questionnaire at baseline (visit 2) and the EOT visit 
(visit 5). The total score, ie, the sum of the first 5 questions, is used for grading of disability, with 
scores of 0 to 5, 6 to 10, 11 to 20, and ≥21 interpreted as disability grades 1 (little or no disability), 
2 (mild disability), 3 (moderate disability), and 4 (severe disability), respectively.


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6.3.2.
Analysis of Secondary Efficacy Variables
An ANCOVA method, which is similar to the primary analysis setup, will be used for the analysis 
of the mean change from baseline in the monthly average number of days of secondary efficacy 
variables during the 12-week period derived from headache diary data. The model will include 
treatment, sex, region, and baseline preventive migraine medication use (yes/no) as fixed effects; 
the baseline values and years since onset of migraines as covariates. The LS means for the treatment 
groups, LS means and 95% confidence intervals for the treatment differences (TEV-48125 –
placebo), and associated p-values will be provided. 
If a patient has less than 10 days of e-diary data entries after the 1st dose of study drug, the missing 
data handling method for the primary variable discussed in Section 6.2.1 will be applied for the 
monthly average number of days of secondary efficacy variables during the 12-week period. 
Similar to the sensitivity analysis for the primary efficacy variable described in Section 6.2.3.1 an
MMRM model will be implemented to estimate the mean change from baseline for the following 
endpoint by month and for overall 3 months after the 1st dose of study drug. 

mean change from baseline (28-day run-in period) in the monthly average number of 
days of use of any acute headache medications 
LS means for the treatment groups, LS mean and corresponding 95% confidence intervals for the 
treatment differences (TEV-48125 - placebo), and associated p-values will be calculated by month 
and for the overall treatment period.
The LS means ±SE of e-diary efficacy variables estimated by MMRM will be plotted by month for 
each treatment group.
Cochran Mantel-Haenszel test stratified by baseline preventive migraine medication use (yes/no) 
will be used for analyzing the proportion of patients reaching at least 50% reduction in the monthly 
average number of migraine days during the 12-week period after the 1st dose of study drug. The 
SAS Proc FREQ will be used to carry out this analysis.
The change from baseline values in the MIDAS total scores will be analyzed using the same 
ANCOVA method as described above.
Patients not receiving concomitant preventive medication constitute the sub-population who don’t 
take any preventive migraine medications listed in APPENDIX B of the protocol during the study, 
ie, with baseline preventive migraine medication use = No.
For all relevant secondary endpoints, the normality of the residuals from each ANCOVA model 
will be checked using Shapiro Wilk’s normality test. In case that the Shapiro Wilk’s test has a p 
value ≤0.01, Wilcoxon rank-sum test will be conducted as the primary analysis. The ANCOVA 
analysis will be considered as a supportive analysis.


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6.4.
Exploratory Efficacy Variables and Analysis
The exploratory efficacy endpoints are described in Section 2.2.3.
6.4.1.
Variable Definition
6.4.1.1.
Electronic Headache Diary Data
A headache day of at least moderate severity will be defined as a calendar day (00:00 to 23:59) 
where the patient reports:

a day with headache pain that lasts ≥4 hours with a peak severity of at least moderate 
severity
or

a day when the patient used acute migraine-specific medication (triptans or ergots) to 
treat a headache of any severity or duration
The percent reduction in the monthly average number of migraine days during the 12-week period 
after the 1st dose of study drug will be calculated by formula (4) in Section 6.1. The patient is 
considered as a responder reaching 50%, 75% or 100% reduction if his/her percent reduction is 
50% or more, 75% or more, or 100% respectively. Similar definition will be applied to calculate the 
proportion of patients reaching at least 50%, 75% or 100% reduction in the monthly average 
number of headache days of at least moderate severity during the 12-week period after the 1st dose 
of study drug. If a patient is early discontinued from the study, he/she will be counted as a non-
responder. 
The percent reduction in the monthly number of migraine days during the 4-week period after each 
dose for months 1, 2, and 3 will be calculated by formula (4) where the postbaseline value will be 
the number of headache days of at least moderate severity prorated to 28 days for month 1, month 
2, and month 3, respectively. If the patient has 50% reduction or more in month 1, he/she will be 
considered responder during the 4-week period after 1st dose of study drug. In addition if the patient 
also has 50% reduction or more in month 2 and 3, he/she is a responder for months 2 and 3, and the 
level of effect is sustained throughout the 12-week period after the 1st dose of study drug for this 
patient. Similar definition will be applied to calculate the proportion of sustained responders 
reaching at least 75% reduction. The proportion of sustained responders reaching at least 50% and 
75% reduction in the number of headache days of at least moderate severity will be derived 
similarly.  
The headache day of any severity will be defined as a calendar day (00:00 to 23:59) with headache 
pain that lasts ≥4 hours of any severity or a day when the patient used acute migraine-specific 
medication (triptans or ergots) to treat a headache of any severity or duration.
The change from baseline in the monthly average number of days or hours of exploratory efficacy 
variables (e.g. days with at least moderate severity, days with any severity, total hours of headache 
with at least moderate severity, total hours of headache with any severity, days of use of migraine-
specific acute medications, days with nausea or vomiting, days with photophobia and phonophobia 
etc.) during the 12-week period after the 1st dose of study drug will be derived similar to the 
primary variables using the e-diary data collected through the corresponding headache diary 
questions (Appendix A). The baseline values and the postbaseline values will be derived using 


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formula (3) and (1) respectively, and the change is calculated as postbaseline value – baseline 
value.
The change from baseline in the monthly number of days or hours of exploratory efficacy variables
(e.g. days of headache with at least moderate severity, days of headache with any severity, total 
hours of headache with at least moderate severity, total hours of headache with any severity, days of 
use of migraine-specific acute medications, days with nausea or vomiting, days with photophobia 
and phonophobia etc.) during the 4 week period after the each dose of study drug will be calculated
using formula (2) using the month 1, month 2 and month 3 diary data respectively.
The change from baseline in weekly number of headache days of at least moderate severity or 
migraine days for week 1 (Day 1-7), week 2 (Day 8-14), week 3 (Day15-21) and week 4 (Day 22-
28) after the 1st dose of study drug will be derived using the 1st 28-day diary data. The baseline 
values and the postbaseline values will be derived using formula (5) and (6) in Section 6.2.1
respectively, and the change is calculated as postbaseline value – baseline value.
6.4.1.2.
Migraine-Specific Quality of Life 
The 14-item MSQOL (see Appendix D) questionnaire is designed to measure how migraines affect 
and/or limit daily functioning across three domains: Role Function-Restrictive domain comprising 7 
items assessing how migraines limit one’s daily social and work-related activities; Role Function-
Preventive domain comprising 4 items assessing how migraines prevent these activities, and 
Emotional Function domain comprising 3 items assessing the emotions associated with migraines. 
Raw dimension scores are computed as a sum of item responses and rescaled to a 0 to 100 scale 
such that higher scores indicate better quality of life. Appendix E  provides the scoring instructions 
on how to rescale the raw score to the scales that will be used for analysis.
6.4.1.3.
EuroQol-5 Dimension Questionnaire
The EQ-5D-5L questionnaire (Appendix F) is a standardized questionnaire that assesses overall 
state of health. The EQ-5D-5L consist 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.
6.4.1.4.
Patient Health Questionnaire 
The PHQ (Appendix G) is a 9-item questionnaire with each item corresponding to 1 criterion of the 
Diagnostic and Statistical Manual for Mental Disorders 4th edition diagnostic criteria for major 
depressive disorder. Each of the items is scored on a scale of 0 (“not at all”), 1 (“several days”), 2 
(“more than half the days”), and 3 (“nearly every day”) based on the frequency of symptoms during 
the past 2 weeks (Spitzer et al 1999). The PHQ-2 was developed from the PHQ-9 to rapidly screen 
for depression and consists of the first 2 questions of the PHQ-9. The PHQ-2 and the PHQ-9 are 
validated measures for detecting and monitoring depression, anxiety, and somatization (Kroenke et 
al 2010).


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Patients will complete the PHQ-2 at baseline (visit 2) and the EOT visit (visit 5). If the PHQ-2 is 
positive (ie, the total score of the 2 items is ≥3), the patient will complete questions 3 thought 9 
(unique questions) of the PHQ-9. 
6.4.1.5.
Work Productivity and Activity Impairment Questionnaire: General Health V2.0 
The generic version of the WPAI: General Health (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. This assessment will be done at baseline (visit 2) 
and the EOT visit (visit 5).
The following scores (in percentages) will be derived based on the WPAI:GH questionnaire. 

percent work item missed due to health:  
:;
:;<:=x100

percent impairment while working due to health:  
>?
@A x100

percent overall work impairment due to health:  {
:;
:;<:= + BC1 −
:;
:;<:=D ×
:?
@AE}x100

percent activity impairment due to health:   
>F
@Ax100
6.4.1.6.
Patient’s Global Impression of Change 
The PGIC scale (Appendix I) is a validated generic tool for assessment of overall change in the 
severity of illness following treatment. Patients will rate how they feel now compared with how 
they felt before receiving study drug on a 7-point scale where 0 is “No change” and 7 is “A great 
deal better”.
Based on the PGIC assessment, a dichotomous scale of “ Yes” or “No” will be derived. A favorable 
change is score of 5-7 = ’Yes’, which means there is significant improvement with the treatment. If 
the response is 1-4 = ’No’, it is considered no significant change. 
6.4.2.
Exploratory Efficacy Analysis
6.4.2.1.
Electronic Headache Diary Data
Cochran Mantel-Haenszel test stratified by baseline preventive migraine medication use (yes/no)
will be implemented for analyzing the responder type of exploratory efficacy endpoints. The SAS 
Proc FREQ will be used to carry out this analysis.
An ANCOVA method defined in Section 6.2.2 and an MMRM model defined Section 6.2.3.1 will 
be implemented for the following exploratory endpoints analysis.

mean change from baseline (28-day run-in period) in the number of headache days of at 
least moderate severity during the 12-week period after the 1st dose of study drug

mean change from baseline (28-day run-in period) in the monthly average number of 
headache days of any severity during the 12-week period after the 1st dose of study drug


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
mean change from baseline (28-day run-in period) in the monthly average number of 
headache hours of any severity during the 12-week period after the 1st dose of study 
drug

mean change from baseline (28-day run-in period) in the monthly average number of 
headache hours of at least moderate severity during the 12-week period after the 1st dose 
of study drug

mean change from baseline (28-day run-in period) in the monthly average number of 
days with nausea or vomiting during the 12-week period after the 1st dose of the study

mean change from baseline (28-day run-in period) in the monthly average number of 
days with photophobia and phonophobia during the 12-week period after the 1st dose of 
study drug
Similar to the sensitivity analysis for the primary efficacy variable described in Section 6.2.3.1, an 
MMRM model will be implemented to estimate the mean change from baseline for the following 
endpoints by week after the 1st dose of study drug. 

mean change from baseline in the weekly number of headache days of at least moderate 
severity

mean change from baseline in the weekly number of migraine days 
LS means for the treatment groups, LS means and corresponding 95% confidence intervals for the 
treatment differences (TEV-48125 - placebo), and associated p-values will be calculated by week.
The LS means ±SE of e-diary efficacy variables estimated by MMRM will be plotted by week for 
each treatment group.
6.4.2.2.
Migraine-Specific Quality of Life 
The transformed scores for the three domains (i.e., Role Function-Restrictive, Role Function-
Preventive and Emotional Function) of MSQOL will be derived for baseline (visit 2), visit 3, visit 
4, and visit 5. The change from baseline values after the 3rd injection will be analyzed by ANCOVA 
method as described in Section 6.2.2 and MMRM method as described in Section 6.2.3.1.
6.4.2.3.
EuroQol-5 Dimension Questionnaire
The number and percentage of patients rating their scale of 1 to 5 for the 5 domains will be
presented before and after treatment. The change from baseline values on the visual analogue scale
will be analyzed using the same ANCOVA method as described in Section 6.2.2.
6.4.2.4.
Patient Health Questionnaire
The change from baseline in total PHQ-9 score will be analyzed using the same ANCOVA method 
as described in Section 6.2.2.
6.4.2.5.
Work Productivity and Activity Impairment Questionnaire : General Health V2.0 
For the patients who are currently employed, their scores of

percent work item missed due to health


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
percent impairment while working due to health 

percent overall work impairment due to health

percent activity impairment due to health
will be analyzed using the same ANCOVA method as described in Section 6.2.2 .
6.4.2.6.
Patient’s Global Impression of Change Scale
The percentage of patients’ dichotomous scale of “ Yes” or “No” rated by PGIC assessments at 4-
week after each dose will be analyzed by Cochran Mantel-Haenszel test stratified by baseline 
preventive migraine medication use (yes/no) as described in Section 6.3.2.
6.5.
Subgroup Analysis
The primary analysis with ANCOVA method defined in Section 6.2.2 and MMRM method defined 
in Section 6.2.3.1 will also be applied to the following subgroups for the change from baseline 
values in the number of migraine days and the monthly average number of headache days of at least 
moderate severity.

patients receiving or not receiving any concomitant preventive treatment at baseline

patients who used topiramate for migraine in the past

patients who used onabotulinumtoxinA for migraine in the past  

patients in different age groups (18-45, >45 years old)

patients in different race groups (caucasian, non-caucasian)

patients by sex


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7.
SAFETY ANALYSIS
7.1.
General
The safety population will be used for all safety analyses. Summaries will be presented by treatment 
group and all TV48125 as actually received unless specified otherwise. 
7.2.
Study Drug Administration
Following the baseline assessments, eligible patients will be randomly assigned with stratification 
based on sex, country, and baseline use of preventive migraine medication (yes, no) to receive 
monthly TEV-48125 at 225 mg, TEV-48125 at 675 mg followed by monthly placebo, or monthly 
placebo.
Study drug will be administered by qualified study personnel as sc injections approximately every 
28 days for a total of 3 doses, as follows:

Patients randomized to receive monthly TEV-48125 225 mg will receive 1 active and 2 
placebo injections at visit 2 and 1 active injection (225 mg/1.5 mL) at visits 3 and 4. 

Patients randomized to receive TEV-48125 675 mg/placebo/placebo will receive 
3 active injections (225 mg/1.5 mL) at visit 2 and 1 placebo injection at visits 3 and 4. 

Patients randomized to receive placebo will receive 3 placebo injections at visit 2 and 1
single placebo injection at visits 3 and 4. 
Duration of treatment (days treated) is the number of days on treatment based on the 1st study drug 
administration day and end of treatment (EOT) visit day/early withdrawal day (EOT visit day – first 
day of study drug + 1). For subjects who are lost to follow-up, the EOT date is defined as the last 
study drug administration date +27. 
Number (%) of patient receiving 1 dose, 2 doses, and 3 doses will be summarized using descriptive 
statistics by treatment group.  Duration of treatment (days) will also be summarized using 
descriptive statistics for each treatment group.  
7.3.
Adverse Events
All adverse events will be coded using the MedDRA version 18.1. 
For adverse event recording, the study period is defined for each patient as the time period from 
signature of the informed consent form through completion of visit 5 or the early withdrawal visit 
for patients who withdraw from the study for any reason.
Adverse events will be collected at each visit via adverse event inquiry. 
The following are considered protocol-defined adverse events of special interest to be sent to the 
sponsor’s 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), or Hy’s Law events, as well anaphylaxis and 
hypersensitivity reactions. Hypersensitivity reactions will be monitored using the diagnostic criteria 
for anaphylaxis as outlined by the 2006 Joint National Institute of Allergy and Infectious 


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Disease/Food Allergy and Anaphylaxis Network Second Symposium on Anaphylaxis (Sampson et 
al, 2006). In the event of suspected anaphylaxis, vital signs, including oxygen saturation and 
respiration rate, will be measured.
Summaries by treatment group will be presented for treatment emergent adverse events (overall and 
by severity), treatment emergent adverse events determined by the investigator to be treatment-
related adverse events (overall and by severity), serious adverse events, adverse events causing 
discontinuation from the study, non-serious treatment emergent adverse events and prior to 
treatment adverse events. Additionally, the injection site reactions recorded as adverse events and 
protocol defined adverse events will be summarized by treatment group separately. 
The incidence of adverse event will be summarized using descriptive statistics by SOC, PT, and 
severity of the adverse event. Each patient will be counted only once within a SOC or a PT by using 
the adverse events with the highest severity within each category. Treatment-related adverse event 
summaries will include adverse events related to study drug and adverse events with missing 
relationship to study drug.  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.
Listings for deaths, serious adverse events, adverse events leading to discontinuation, injection site 
related adverse event, and protocol defined adverse events will be presented. All information 
pertaining to adverse events noted during the study will be listed by subject, detailing verbatim 
given by the investigator, PT, SOC, date of onset, date of resolution, severity, and relationship to 
treatment. The onset of adverse events will also be shown relative (in number of days) to the 1st day 
of treatment. In addition, MedDRA dictionary terms for adverse event descriptions, and adverse 
event preferred terms by patient number and treatment group will be presented.
7.4.
Injection Site Assessments
Injection site assessments will be performed immediately and 1 hour after administration of each 
dose of study drug (Table 1). The injection site(s) will be assessed for erythema, induration, 
ecchymosis, and pain, and severity 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).
Injection-site pain will be measured as summarized in Table 3.
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 study drug 
administration, the patient will be reassessed at 3 hours after study drug administration and hourly 
thereafter until the reaction/pain is of moderate or less severity.
Number (%) of patients having injections and their post injection assessments for erythema, 
induration, ecchymosis, and pain of each grade will be summarized by visits and timepoints for 
each treatment group. 


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Table 3:
Severity of Pain Scale for Injection Site Assessments
Grade
Assessments
0
No pain
1
Mild
2
Moderate
3
Severe
4
Worst possible
To differentiate between assessments at active treatment (TEV 48125) injection sites and placebo 
injection sites for subjects who receive 225 mg TEV 48125 (1 active, 2 placebo injections) at visit 
2, summaries for these treatments will be presented by treatment type (TEV-48125 or placebo). 
Subjects are only counted once for each treatment type, and if multiple sites with the same 
treatment type (TEV-48125 or placebo)  present with different severities, the most severe reaction 
will be summarized.
7.5.
Deaths
If any patient dies during the study all relevant information will be discussed in the patient’s 
narratives included in CSR. 


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7.6.
Clinical Laboratory Tests
Clinical laboratory tests (serum chemistry, hematology, coagulation, and urinalysis) will be 
performed at the time points detailed in Table 1 using the central laboratory. Specific laboratory 
tests to be performed are listed below in Table 4.
Table 4:
Clinical Laboratory Test
Serum Chemistry
Hematology
Coagulation
Urinalysis
• calcium
• phosphorus
• sodium
• potassium
• chloride
• carbon dioxide
• magnesium
• glucose
• blood urea nitrogen
• creatinine
• ALT
• AST
• total bilirubin
• direct bilirubin
• lactate dehydrogenase
• GGT
• ALP
• albumin
• creatine phosphokinase
• total protein
• hemoglobin
• hematocrit
• RBC count 
• RBC indices
-
mean corpuscular 
volume
-
mean corpuscular  
hemoglobin 
concentration
-
RBC distribution width
• platelet count
• WBC count and differential 
count (absolute values and 
percentages)
-
neutrophils
-
lymphocytes
-
eosinophils
-
monocytes
-
basophils
• prothrombin time
• partial thromboplastin 
time
• INR
• color and appearance
• specific gravity
• pH
• blood (hemoglobin)
• glucose
• albumin
• protein
• ketones
• leukocyte esterase
• nitrite
• direct bilirubin
• microscopic
-
bacteria
-
RBCs
-
WBCs
-
casts
-
crystals
ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; GGT=gamma- glutamyl 
transpeptidase; INR=international normalized ratio; RBC=red blood cell; WBC=white blood cell.
Laboratory tests results and changes from baseline for chemistry, hematology, urinalysis, and 
coagulation laboratory tests will be summarized by visits for each treatment group using descriptive 
statistics. Shifts (below, within, and above the normal range) from baseline to each visit and 
endpoint will be summarized using patient counts. Listings of all individual patients’ laboratory test 
results will be presented.  
The incidence of potentially clinically significant abnormal results will be summarized using 
descriptive statistics with the criteria specified in Table 5. The potentially clinically significant 
abnormal laboratory values will include all postbaseline values (including scheduled, unscheduled, 
and early termination visits) for the summaries. Listings of patients who have potentially clinically 
significant abnormal laboratory data will be presented.


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Table 5:
Criteria for Potentially Clinically Significant Laboratory Values
Test
Criterion value
Serum chemistry
ALT
3x ULN
AST
3x ULN
ALP
3x ULN
GGT
3x ULN
LDH
3x ULN
BUN
10.71 mmol/L
Creatinine
177 mol/L
Uric acid
Men
625 mol/L
Women
506 mol/L
Bilirubin (total)
34.2 mol/L
Hematology
Hematocrit
Men
<0.37 L/L
Women
<0.32 L/L
Hemoglobin
Men
115 g/L
Women
95 g/L
WBC counts
3 x 109/L 
20 x 109/L
Eosinophils
10%
ANC
1 x 109/L
Platelet counts
75 x 109/L 
700 x 109/L
Urinalysis
HGB
2 unit increase from baseline
Glucose
2 unit increase from baseline
Ketones
2 unit increase from baseline
Total protein
2 unit increase from baseline
ULN=upper limit of normal range.
ALP=alkaline phosphatase; ALT=alanine aminotransferase; ANC=absolute neutrophil count AST=aspartate 
aminotransferase; BUN=blood urea nitrogen; GGT=gamma- glutamyl transpeptidase; HGB=hemoglobin; 
INR=international normalized ratio; LDH=lactate dehydrogenase; RBC=red blood cell; ULN=upper limit of normal 
range; WBC=white blood cell
Serum β-HCG tests will be performed for all women of childbearing potential at screening (visit 1), 
and urine β-HCG tests will be performed for women of childbearing potential at visits 2 through 5. 
Positive pregnancy test results will be listed.


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7.7.
Vital Signs
Vital signs (pulse, systolic and diastolic blood pressure, body temperature, and respiratory rate) will 
be measured before other assessments (eg, blood draws and administration of questionnaires) at the 
time points detailed in Table 1.
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.
Vital signs values and changes from baseline to each visit and endpoint will be summarized using 
descriptive statistics.  The incidence of potentially clinically significant abnormal values will be 
summarized for selected vital signs using descriptive statistics.
Table 6 specifies the criteria for identifying vital signs as potentially clinically significant abnormal.  
Note that in order to be identified as potentially clinically significant abnormal, a value would need 
to meet both conditions below:  i.e., have a value beyond the criterion value and a change of at least 
the magnitude specified in the change from baseline column. The potentially clinically significant 
abnormal vital signs values will include all postbaseline values (including scheduled, unscheduled, 
and early termination visits) for the summaries.
Table 6:
Criteria for Potentially Clinically Significant Vital Signs
Vital Sign
Criterion value
Change relative to baseline
Pulse
120 bpm
Increase of 15
50 bpm
Decrease of 15
Systolic blood pressure
180 mm Hg
Increase of 20
90 mm Hg
Decrease of 20
Diastolic blood pressure
105 mm Hg
Increase of 15
50 mm Hg
Decrease of 15
Respiratory rate
<10 breaths/min
Body temperature
≥38.3C
Change of 1.1C
bpm=beats per minute
A listing for potentially clinically significant abnormal vital signs will be presented.
7.8.
Electrocardiography 
Twelve-lead ECGs will be conducted before other assessments (eg, blood draws and administration 
of questionnaires) at the time points detailed in Table 1.
The ECGs will be performed in triplicate, with approximately 1 minute between recordings. The
average of the recorded measurements will be calculated for each visit.
Any ECG finding that is judged by the investigator as a potentially clinically significant change 
(worsening) compared with the baseline value will be considered an adverse event.


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Shifts (normal and abnormal) from baseline to the endpoint will be summarized using patient 
counts and percentages. ECG variables results and changes from baseline to EOT/EOS will be 
summarized using descriptive statistics. 
7.9.
Physical Examinations
Physical examinations, including height (to be obtained at the screening visit only) and weight will 
be performed at the time points detailed in Table 1.
A complete physical examination will include the following organ systems: general appearance; 
head, eyes, ears, nose, and throat; chest and lungs; heart; abdomen; musculoskeletal; skin; lymph 
nodes; and neurological. Any physical examination finding that is judged by the investigator as a 
potentially clinically significant change (worsening) compared with a baseline value will be 
considered an adverse event. 
Abnormal physical examination findings will be listed.
7.10.
Electronic Columbia-Suicide Severity Rating Scale
The electronic columbia-suicide severity rating scale (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 2, and the eC-SSRS ‘Since 
Last Visit version’ will be completed by the patient at all other time points, as described in Table 1.
Any positive findings on the eC-SSRS ‘Since Last Visit version’ require evaluation by a physician 
or doctoral-level psychologist.
Patients having positive findings will be listed.
7.11.
Concomitant Therapy or Medication
All concomitant medications will be coded using the WHO dictionary of medical codes. The 
concomitant medication will include all medications taken after the 1st study drug administration. 
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 subset of concomitant pain medication and medication or therapy for migraine/headache will 
be summarized by the following indication categories.

migraine/headache preventive medication

opioids for reasons other than migraine/headache 

opioids for migraine/headache 

triptans and ergots

NSAIDs for reasons other than migraine/headache

NSAIDs for migraine/headache

other


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8.
PHARMACOKINETIC ANALYSIS
There are no prespecified pharmacokinetic endpoints. 
Summary of plasma concentration of the study drug will be based on the safety population and will 
be presented by visit for each of the active treatment groups (samples from patients who received 
placebo will not be analyzed). The plasma concentration will be listed by active treatments, 
scheduled visits and timepoints. 
9.
BIOMARKER ANALYSIS
The biomarker analysis is not included in this SAP. A separate planned analysis will be conducted.


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10.
STATISTICAL SOFTWARE
All data listings, summaries, and statistical analyses will be generated using SAS®.


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11.
CHANGES TO PROTOCOL SPECIFIED ANALYSES
The FAS definition is modified per the FDA feedback. The original definition was “all patients in 
the ITT population who receive at least 1 dose of study drug and have at least 1 post baseline 
efficacy assessment on the primary endpoint”.  The modified definition is “all patients in the ITT 
population who receive at least 1 dose of study drug and have at least 10 days of post baseline 
efficacy assessments on the primary endpoint”.
The first 4-week efficacy data for at least moderate severity headache days and migraine days will 
be explored by week using descriptive method and MMRM method.


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12.
REFERENCES
Classification Committee of the International Headache Society. The International Classification of 
Headache Disorders, 3rd edition (beta version). Cephalalgia 2013;33(9):629-808.
Kroenke K, Spitzer RL, Williams JB, Löwe B. The Patient Health Questionnaire somatic, anxiety, 
and depressive symptom scales: a systematic review. Gen Hosp Psychiatry 2010;32(4):345-59.
Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, et al. The Columbia 
Suicide Severity Rating Scale: initial validity and internal consistency findings from three multisite 
studies with adolescents and adults. Am J Psychiatry 2011;168(12):1266-77.
Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF, Jr., Bock SA, Branum A, et al. 
Second symposium on the definition and management of anaphylaxis: summary report-Second 
National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network 
symposium.[reprint in Ann Emerg Med. 2006 Apr;47(4):373-80; PMID:16546624]. Journal of 
Allergy & Clinical Immunology. 2006 Feb;117(2):391-7.
Silberstein S, Holland S, Freitag F, Dodick DW, Argoff C, Ashma E. Evidence-based guideline 
update: pharmacologic treatment of episodic migraine prevention in adults. Neurology 
2012;78:1337-45.
Spitzer RL, Kroenke K, Williams JB. Validation and utility of self-report version of PRIME MD: 
the PHQ primary care study. Primary care evaluation of metal disorders. Patient health 
questionnaire. JAMA 1999;282(18):1737-44.


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APPENDIX A. E-DIARY QUESTIONNAIRE
The following questions are referring to yesterday
(00:00 - 23:59)
A1
Did you experience a headache of any severity yesterday?
A2
Did you have at least four (4) consecutive hours of headache yesterday?
A3
Did you have at least two (2) consecutive hours of headache yesterday?
A4
What was the greatest severity that your headache reached yesterday at anytime?
A5
How many total hours did you have a headache(s) of any severity yesterday? 
A6
How many total hours did you have a headache(s) of moderate or severe intensity yesterday?
The following questions are referring to yesterday
(00:00 - 23:59) AT THE TIME WHEN YOUR HEADCAHE REACHED THE WORST SEVERITY
B1
Was it worse on one side of the head than on the other, and/or limited to one side of the head?
B2
Was it pounding, pulsating, or throbbing?
B3
Was it made worse by routine activities such as walking or climbing stairs?
B4
Did you have nausea, or get sick to your stomach?
B5
Did light bother you more than when you didn't have a headache (did you experience 
photophobia)? 
B6
Did sounds bother you more than when you didn't have a headache (did you experience 
phonophobia)? 
The following questions are referring to yesterday
(00:00 - 23:59) 
B7
Did you experience something like seeing spots, stars, lines, flashing lights, zigzag lines, or 
"heat waves" around the time of your headache? (This is different from "light bothers you") 
B8
Did you have feelings such as numbness or tingling in any part of your body or face around the 
time of your headache? 
B9
Did you experience something like seeing spots, stars, lines, flashing lights, zigzag lines, or 
"heat waves" similar to those you may have seen when you have a headache? (This is different 
from "light bothers you") 
B10
Did you have feelings such as numbness or tingling in any part of your body or face, similar to 
what you may have felt when you have a headache? 


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C0
Did you take any medications yesterday for your headache/migraine?
C1
Were any of the following Medications taken yesterday? 
Local list of Triptans, Ergots and Opioid combinations, Presented in groups of 5 per screen, with 
Yes / No option to answer.
For the following questions please do not consider any medications you listed in the 
above questions.
D1
Did you use any other prescription medications (i.e. opioids) in an effort to get relief from your 
headache/migraine? 
D5
Did you use any other over the counter medications in an effort to get relief from your 
headache/migraine?
E1
Did you have problems falling sleep last night?
E2
Which of the following situations best describe your work/school performance yesterday, when 
you did not have a headache?  
E3
What would better describe in general, how did you feel yesterday?
E4
How much of the time yesterday did you find it difficult to
concentrate on what you needed to do? 
E5
On average, how much of the time yesterday were you very tired, asleep, or feeling drained? 
E6
Which of the following situations best describe your ability to perform household chores 
yesterday, when you did not have a headache? 
E7
How engaged were you with your partner's or children's activities yesterday, when you didn't 
have a headache? 
E8
Overall, how interested were you in doing daily activities yesterday? 


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APPENDIX B. LOGICS FOR ENDPOINTS DERIVATION 
EM migraine day: 1 of the following 5 options
OPTION 1
OPTION 2
Part 1
1
A1
YES
1
A1
YES
2*
A2 or A3
YES
2
C0
YES
AND
3
C1
YES
4
C1
ERGOT OR TRIPTAN
TWO OF THE FOLLOWING
OPTION 3
Part 2
1
A4
Mod-
S
2
B1
YES
1
A1
YES
3
B2
YES
2
C0
YES
4
B3
YES
3
D1
YES
AND
4
D1
ERGOT OR TRIPTAN
ONE OF THE FOLLOWING
OPTION 4
Part 3
1
B4
YES
1
A1
YES
2
B5
YES
AND
ONE OF THE 
FOLLOWING
AND
1
B7
YES
B6
YES
2
B8
YES
* For eligibility evaluation, replace A2 or A3 = YES with A2='YES'.
OPTION 5: PROBABLE MIGRAINE
If Part 1 and Part 2 met, Part 3 needs ONLY one of the following:
Part 3
B5
YES
B6
YES
If Part 1 and Part 3 met, Part 2 needs ONLY one of the following:
Part 2
1
A4
Mod-
S
2
B1
YES
3
B2
YES
4
B3
YES
If Part 2 and Part 3 met, Part 1 needs ONLY the following:
Part 1
1
A1
YES


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APPENDIX C. THE MIGRAINE DISABILITY ASSESSMENT


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APPENDIX D. MIGRAINE-SPECIFIC QUALITY OF LIFE
QUESTIONNAIRE (MSQ) (VERSION 2.1)


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APPENDIX E. SCORING INSTRUCTIONS FOR MSQ (VERSION 2.1)


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APPENDIX F.
EQ-5D-5L AND EQ VAS


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APPENDIX G. PATIENT HEALTH QUESTIONNAIRE (PHQ-2) AND (PHQ-
9) 


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


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APPENDIX I.
PATIENT’S GLOBAL IMPRESSION OF CHANGE (PGIC) 
SCALE