Clinical trial NCT03965091
Conditions: Fibromyalgia
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc.
Start date: 2019-07-31; Completion date: 2022-01-19
Enrollment: 189 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of the study is to estimate the treatment effect of fremanezumab administered subcutaneously (SC) in reducing pain in adult participants with fibromyalgia (FM). A secondary objective is to evaluate the effect of fremanezumab on other efficacy measures, including pain, quality of life, sleep, fatigue, improvement in health, physical functioning, and mood. Another secondary objective is to evaluate the safety and tolerability of fremanezumab administered SC in adult participants with FM.

The total duration of participant participation in the study is planned to be 21 weeks, consisting of a screening period of up to 5 weeks (ranging from 17 to 35 days), and a double-blind treatment period of 16 weeks.

Detailed description:

Arms: arm 1: Participants will receive placebo matching to fremanezumab SC on Days 1, 29, 57, and 85. arm 2: Participants will receive fremanezumab SC on Days 1, 29, and 57 and placebo matched to fremanezumab SC on Day 85. arm 3: Participants will receive fremanezumab SC on Days 1, 29, and 57 and placebo matched to fremanezumab SC on Day 85.
Interventions: intervention 1: Fremanezumab intervention 2: Placebo
Intervention descriptions: intervention 1: Fremanezumab will be administered per dose and schedule specified in the arm description. intervention 2: Placebo matching to fremanezumab will be administered per schedule specified in the arm description.

Protocol documents:
Prot_000.pdf: 
 
 
 
Clinical Study Protocol 
 
 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Proof of Concept 
Study of the Efficacy and Safety of Fremanezumab for Treatment of Patients with 
Fibromyalgia 
 
 
Study Number TV48125-PN-20028 
 
 
NCT03965091 
 
 
Protocol with Amendment 05 Approval Date: 10 August 2021 


Placebo-Controlled Study–Fibromyalgia
Clinical Study Protocol with Amendment 05
Study TV48125-PN-20028
1
 
Clinical Study Protocol with Amendment 05
Study Number TV48125-PN-20028
A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Proof of Concept Study of the 
Efficacy and Safety of Fremanezumab for Treatment of Patients with Fibromyalgia
(Concealed version)
Proof of Concept Study (Phase 2)
IND number: 141519; BLA number: 761089
Protocol Approval Date: 06 December 2018
Protocol with Amendment 01 Approval Date: 08 February 2019
Protocol with Amendment 02 Approval Date: 16 April 2019
Protocol with Amendment 03 Approval Date: 22 July 2019
Protocol with Amendment 04 Approval Date: 16 June 2020
Protocol with Amendment 04 with Revision 01 Approval Date: 25 June 2020
Protocol with Amendment 05 Approval Date: 10 August 2021
Sponsor:
Teva Branded Pharmaceutical Products R&D, Inc.
145 Brandywine Parkway
West Chester, Pennsylvania 19380
United States of America
Information regarding clinical laboratories and other departments and institutions is 
found in Appendix A
This clinical study will be conducted in accordance with current Good Clinical Practice (GCP) as directed 
by the provisions of the International Council for Harmonisation (ICH); United States (US) Code of 
Federal Regulations (CFR), and European Union (EU) Directives and Regulations (as applicable in the 
region of the study); national country legislation; and the sponsor’s Standard Operating Procedures 
COVID-19 pandemic-related operational updates are provided in Appendix O.
Confidentiality Statement
This document contains confidential and proprietary information (including confidential 
commercial information pursuant to 21CFR§20.61) and is a confidential communication of Teva 
Branded Pharmaceutical Products R&D, Inc. and/or its affiliates. The recipient agrees that no 
information contained herein may be published or disclosed without written approval from the 
sponsor.
© 2021 Teva Branded Pharmaceutical Products R&D, Inc. All rights reserved.


Placebo-Controlled Study–Fibromyalgia
Clinical Study Protocol with Amendment 05
Study TV48125-PN-20028
2
AMENDMENT HISTORY
The protocol for Study TV48125-PN-20028 (original protocol dated 06 December 2018) has 
been amended and reissued as follows:
Amendment 05
10 August 2021
153 patients have been randomized/enrolled to
date
The following sections are affected:
Preface
Table 1 Study Procedures and Assessments
Section 4.1 Patient Inclusion Criteria
Section 4.2 Patient Exclusion Criteria 
Section 5.7.1 Permitted Concomitant Medication 
or Therapy
Section 5.11 Total Blood Volume
Section 7.4.2.2 Urine Drug Screen
Section 9.6.4.2 Sensitivity Analysis
Section 9.15 Planned Interim Analysis
Appendix B Study Procedures and Assessments 
by Visit
Appendix I. List of Prohibited Medications and 
Therapeutic Interventions
Appendix J. Total Blood Volume
Appendix O. Management of Study Activities 
During COVID-19


Placebo-Controlled Study–Fibromyalgia
Clinical Study Protocol with Amendment 05
Study TV48125-PN-20028
3
Amendment 04, Revision 01
25 June 2020
68 patients have been randomized/enrolled to date
The protocol amendment 04 was approved on 
16 June 2020. However, it was not distributed 
externally and was immediately followed by 
protocol amendment 4 revision 01, with the 
addition of an interim analysis. Protocol 
amendment 04 revision 01 was submitted to health 
authorities.
The following sections are affected:
Section 9.15 Planned Interim Analysis
Amendment 04
16 June 2020
68 patients have been randomized/enrolled to date
The management of study activities during the 
COVID-19 pandemic are detailed in Appendix O.
The following sections are affected:
Section 3.1 General Study Design and Study 
Schematic Diagram
Section 4.5 Rescreening
Section 5.1.1.2 Dosing Visits and Dose 
Modification
Appendix D. Quality Control and Quality 
Assurance
Appendix E. Ethics
Amendment 03
22 July 2019
No patients have been randomized/enrolled to date
Amendment 02
16 April 2019
No patients have been randomized/enrolled to date
Amendment 01
08 February 2019
No patients have been randomized/enrolled to date
The Summary of Changes to the Protocol includes the corresponding reason/justification for 
each change and is provided in Section 16.


Placebo-Controlled Study–Fibromyalgia
Clinical Study Protocol with Amendment 05
Study TV48125-PN-20028
4
INVESTIGATOR AGREEMENT
Original Protocol Dated 06 December 2018
Clinical Study Protocol with Amendment 05
IND number: 141519;
NDA number: Not Applicable; BLA number: 761089;
EudraCT number: Not Applicable
A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Proof of Concept Study of the 
Efficacy and Safety of Fremanezumab for Treatment of Patients with Fibromyalgia (Concealed 
version)
Principal Investigator: 
Title:
Tel:
I have read the protocol with Amendment 05 and agree that it contains all necessary details for 
carrying out this study. I am qualified by education, experience, and training to conduct this 
clinical research study. The signature below constitutes agreement with this protocol and 
attachments and provides assurance that this study will be conducted according to all stipulations 
of the protocol, including all statements regarding confidentiality, and according to national or 
local legal and regulatory requirements and applicable regulations and guidelines.
I will make available the protocol and all information on the investigational medicinal product 
(IMP) that were furnished to me by the sponsor to all physicians and other study personnel 
reporting to me who participate in this study and will discuss this material with them to ensure 
that they are fully informed regarding the IMP and the conduct of the study. I agree to keep 
records on all patient information, IMPs shipment and return forms, and all other information 
collected during the study, in accordance with national and local Good Clinical Practice (GCP) 
regulations as well as all other national and international laws and regulations.
Executed signature pages are maintained within the Investigator Site File and the Trial 
Master File.
Principal Investigator
Signature
Date


Placebo-Controlled Study–Fibromyalgia
Clinical Study Protocol with Amendment 05
Study TV48125-PN-20028
5
SPONSOR PROTOCOL APPROVAL
Sponsor’s Authorized 
Representative
 
 
 
Signature
Date
Executed signature pages are maintained within the Trial Master File.


Placebo-Controlled Study–Fibromyalgia
Clinical Study Protocol with Amendment 05
Study TV48125-PN-20028
6
COORDINATING INVESTIGATOR AGREEMENT
Original Protocol Dated 06 December 2018
Clinical Study Protocol with Amendment 05
IND number: 141519; NDA number: Not Applicable; BLA number: 761089; 
EudraCT number: Not Applicable
A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Proof of Concept Study of the 
Efficacy and Safety of Fremanezumab for Treatment of Patients with Fibromyalgia (Concealed 
version)
I have read the protocol with Amendment 05 and agree that it contains all necessary details for 
carrying out this study. I am qualified by education, experience, and training to conduct this 
clinical research study. The signature below constitutes agreement with this protocol and 
attachments and provides assurance that this study will be conducted according to all stipulations 
of the protocol, including all statements regarding confidentiality, and according to national and 
local legal and regulatory requirements and applicable regulations and guidelines.
I will make available the protocol and all information on the investigational medicinal product 
(IMP) that were furnished to me by the sponsor to all physicians and other study personnel 
reporting to me who participate in this study and will discuss this material with them to ensure 
that they are fully informed regarding the IMP and the conduct of the study. I agree to keep 
records on patient information, IMPs shipment and return forms, and other information collected 
during the study, in accordance with my responsibilities under the function of the coordinating 
investigator and in accordance with national and local Good Clinical Practice (GCP) regulations 
as well as all other national and international laws and regulations. In addition, I will assume the 
responsibility of the coordinating investigator according to a separate contract.
Coordinating Investigator
Title:
Address of Investigational Center:
Tel:
Coordinating Investigator
Signature
Date
Executed signature pages are maintained within the Investigator Site File and the Trial 
Master File.


Placebo-Controlled Study–Fibromyalgia
Clinical Study Protocol with Amendment 05
Study TV48125-PN-20028
7
CLINICAL STUDY PROTOCOL SYNOPSIS
with Amendment 05
Study TV48125-PN-20028
Title of Study: A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Proof of 
Concept Study of the Efficacy and Safety of Fremanezumab for Treatment of Patients with 
Fibromyalgia (Concealed version)
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc.
Investigational New Drug (IND) Number: 141519
New Drug Application Number: Not 
Applicable 
Biological License Application (BLA) Number: 761089 EudraCT 
Number: Not Applicable
EMA Decision number of Pediatric Investigation Plan: Not Applicable
Article 45 or 46 
of 1901/2006 does not apply
Name of Test Investigational Medicinal Product (IMP) or Device: Fremanezumab, a 
recombinant humanized immunoglobulin G (IgG) 2Δa/kappa monoclonal antibody (mAb) 
against calcitonin gene-related peptide (CGRP)
EudraVigilance (EV) code for the IMP, if applicable: Not Applicable
Type of the Study: Proof of Concept Study
Indication: Fibromyalgia (FM)
Is this study conducted to investigate the New Use of an approved, marketed product? Yes
Number of Investigational Centers Planned: The study is planned to be conducted at 
approximately 40 investigational centers.
Countries Planned: The study is planned to be conducted in the United States.
Planned Study Period: The planned study period is from May 2019 until approximately 
July 2022.
Number of Patients Planned (total): Approximately 240 patients will be randomized.
Study Population: ≥18- to 75-year-old male and female patients with FM


Placebo-Controlled Study–Fibromyalgia
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Study TV48125-PN-20028
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Primary and Secondary Objectives and Endpoints
Objectives
Endpoints
The primary objective of the 
study is to estimate the 
treatment effect of 
fremanezumab administered 
subcutaneously in reducing 
pain in adult patients with FM.
The primary efficacy endpoint is the change from baseline up 
to week 16 in the weekly average of the daily average Pain 
Intensity-Numerical Rating Scale (PI-NRS) score over the past 
24 hours.
A secondary objective is to 
evaluate the effect of 
fremanezumab on other 
efficacy measures, including 
pain, quality of life, sleep, 
fatigue, improvement in health, 
physical functioning, and 
mood.
The secondary efficacy endpoints are as follows:

change from baseline up to week 16 in the 
individual components of the Fibromyalgia Impact 
Questionnaire Revised (FIQR): symptom subscore, 
impact subscore, and functional subscore score

responder rate of the Patient Global Impression of 
Change (PGIC) rating (percentage of patients much 
improved or very much improved) up to week 16

the percentage of patients who experience a 
≥30% reduction in the weekly average of the daily 
average PI-NRS score up to week 16

the percentage of patients who experience a 
≥50% reduction in the weekly average of the daily 
average PI-NRS score up to week 16

change from baseline up to week 16 in the weekly 
average of the daily worst PI-NRS score over the 
past 24 hours

change from baseline up to week 16 in the Patient-
Reported Outcomes Measurement Information 
System (PROMIS) Sleep Disturbance Short Form 
(SF) 8a score

change from baseline up to week 16 in the 
PROMIS Physical Function SF12a score

change from baseline up to week 16 in the 
PROMIS Fatigue SF8a score

number (%) of patients who did not complete the 
treatment (Kaplan-Meier Survival Analysis) due to 
lack of efficacy


Placebo-Controlled Study–Fibromyalgia
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Study TV48125-PN-20028
9
Objectives
Endpoints
A secondary objective of the 
study is to evaluate the safety 
and tolerability of 
fremanezumab administered 
subcutaneously in adult 
patients with FM.
The safety and tolerability endpoints are as follows:

occurrence of adverse events

change from randomization up to week 16 in the 
clinical laboratory tests (serum chemistry, 
hematology, and urinalysis)

change from baseline up to week 16 in vital signs 
(pulse, respiratory rate, systolic and diastolic blood 
pressure, and oral body temperature measurements 
at each visit)

clinically significant changes in physical 
examination, including body weight

abnormal standard 12-lead electrocardiogram 
(ECG) findings

tolerability at the injection site including but not 
limited to pain, erythema, induration, and 
ecchymosis

occurrence of hypersensitivity/anaphylaxis 
reactions using standardized criteria (Appendix C)

suicidal ideation and behavior as measured by the 
Columbia-Suicide Severity Rating Scale (C-SSRS)

number (%) of patients who did not complete the 
treatment (Kaplan-Meier Survival Analysis) due to 
adverse events


Placebo-Controlled Study–Fibromyalgia
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Study TV48125-PN-20028
10
 
 
 
 
 
 
 
 
 
 
 
Immunogenicity Objective and Endpoint:
Objectives
Endpoints
To evaluate the 
immunogenicity of 
fremanezumab and the impact 
of anti-drug antibodies (ADAs) 
on clinical outcomes

incidence and characteristics of ADAs (eg, titers, 
kinetics, and neutralizing activities)


Placebo-Controlled Study–Fibromyalgia
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11
General Study Design: This is a 21-week, multicenter, randomized, double-blind, 
placebo-controlled, parallel-group study to evaluate the efficacy and safety of fremanezumab in 
adult patients with FM. Fremanezumab 225 mg, fremanezumab 675 mg, or placebo will be 
administered subcutaneously (sc) for 4 total doses (1 dose [3 injections] administered each 
month). Patients will receive either placebo or 1 of 2 fremanezumab dose levels at Visits 3, 4, 5, 
and 6. All patients will receive either placebo or 1 of 2 fremanezumab dose levels for a total of 
3 sc injections at each dosing visit. The study consists of the following:

17- to 35-day screening period (Visit 1, phone contact, and Baseline Assessment 
Period Start [BAPS] Visit [Visit 2])

16-week double-blind treatment period (Visits 3, 4, 5, 6, and 7)
Patients enrolled in the study will be male or female patients with FM. Patients will be required 
to washout all prohibited concomitant medication(s) prior to the start of the BAPS Visit (Visit 2).
No study assessments or procedures will be conducted until informed consent has been obtained. 
The screening period includes the following:

Screening Visit (Visit 1) during which the informed consent will be reviewed and 
signed, and the screening procedures will occur.

Phone contact no later than day -15 to inform the patient how to safely taper off 
prohibited concomitant medications and schedule the BAPS Visit (Visit 2).

BAPS Visit (Visit 2) at which point patients will receive electronic diaries (e-diaries) 
to record their daily average pain intensity score and daily worst pain intensity score 
using the PI-NRS in the e-diary every evening at approximately the same time 
(between 1800 and 2200 hours). The PI-NRS score must also be recorded in the 
e-diary prior to taking rescue medication.
Training on tablet assessments and the e-diary will occur at the Screening Visit (Visit 1) and the 
BAPS Visit (Visit 2). As needed throughout the study, subsequent retraining on tablet 
assessments and the e-diary will be completed.
The duration of the washout period will be 7 to 19 days; suggested washout periods for 
commonly used analgesics are listed in Table 4. The baseline assessment period is 14 days (from 
Visit 2 to Visit 3) during which patients must complete at least 12 of 14 days of e-diary entries. 
The average of the daily average pain score using the PI-NRS during the baseline assessment 
period (ie, from day -14 to day -1) will be used to qualify the patient for randomization.
Patients meeting study eligibility requirements will be randomly assigned to 1 of 3 treatments in 
a 1:1:1 ratio. For the purposes of reducing bias, improving scientific integrity, and increasing 
assay sensitivity, a Concealed Protocol approach will be used. The Concealed Protocol will not 
specify eligibility criteria for randomization, treatment randomization, nor the timing of the 
primary endpoint. Investigators, site personnel, and study staff (ie, contract research organization 
[CRO]) will work from the Concealed Protocol.
Study procedures, assessments, and administration of the first dose of IMP will occur at Visit 3 
(day 1). Patients will return to the study center approximately every 4 weeks (Visits 4, 5, and 6) 
for blinded administration of the IMP, and for vital signs, efficacy, safety, and blood samples for 
pharmacokinetic analysis, immunogenicity, and biomarkers at various time points.


Placebo-Controlled Study–Fibromyalgia
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Study TV48125-PN-20028
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Before the Randomization Visit (Visit 3) and during the 16-week double-blind treatment period, 
patients will record their daily average pain intensity score and daily worst pain intensity score 
using the PI-NRS in the e-diary every evening between 1800 and 2200 hours. During the 
16-week double-blind treatment period, each week, patients will record their sleep score using 
the PROMIS Sleep Disturbance SF8a once weekly (in the morning) in the e-diary. Patients will 
be permitted to take acetaminophen as rescue medication (as needed) and record their pain 
intensity score before taking rescue medication in the e-diary. At least 75% compliance with 
e-diary recordings on a weekly basis is expected after the randomization visit. Site personnel will 
monitor patients’ compliance that e-diary entry is at least 75% every week during the 
double-blind treatment period.
At monthly visits during the double-blind treatment period, end-of-treatment (EOT), and at the 
time points described in Table 1, the IMD, FIQR, EQ-5D-5L, PGIC, PROMIS Physical Function 
SF12a, PROMIS Fatigue SF8a, HADS, and C-SSRS questionnaires will be completed at study 
sites. The PROMIS Sleep Disturbance SF8a will be completed weekly by the patient in the 
morning in the e-diary. Patients who both discontinue treatment and terminate early from the 
study before completing the 16-week double-blind treatment period will have the 
EOT/end-of-study (EOS) or early termination (ET) Visit (Visit 7) procedures and assessments 
performed as soon as possible thereafter. The e-diaries will be collected at the week 16 visit 
(Visit 7).
The procedures and assessments will include collection of adverse events, concomitant 
medication information, vital signs, C-SSRS, and samples for pharmacokinetic analysis, 
biomarker analysis, and immunogenicity analysis at the time points included in Table 1.
Patients who complete all scheduled visits will have final procedures and assessments performed 
at the EOT/EOS or ET Visit (Visit 7), approximately 4 weeks after administration of the final 
dose of the IMP (Visit 6).
Study procedures and assessments with their time points are shown in Table 1. The study 
schematic diagram is shown in Figure 1.
Brief Summary of Study Design for the Trial Registry(s):
This is a 21-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group 
study to evaluate the efficacy and safety of fremanezumab 225 mg sc or 675 mg sc against 
placebo sc administered monthly for 4 doses in adult patients with FM. The study will consist of 
a 17- to 35-day screening period (Visit 1, phone contact, and BAPS Visit [Visit 2]) and a 
16-week double-blind treatment period (Visits 3, 4, 5, 6, and 7. Patients enrolled in the study will 
be male or female patients with FM. Patients will be required to wash out of all prohibited 
concomitant medication(s) prior to the BAPS Visit (Visit 2).
Method of Randomization and Blinding: The sponsor, investigators, study staff (ie, CRO; 
except for staff involved in bioanalytical analyses), and patients will be blinded to treatment 
assignment throughout the study. A computer-generated master randomization list will be 
provided to drug packaging facilities. Packaging vendor(s) will package active drug and placebo 
according to Good Manufacturing Practice procedures. Kits will be identical in appearance. 
Adequate kit supply for upcoming study visits will be managed by the Randomization and Trial 
Supply Management (RTSM) system. The IMP will be kept refrigerated at 2°C to 8°C on site.


Placebo-Controlled Study–Fibromyalgia
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Study TV48125-PN-20028
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Patients will be randomized in a 1:1:1 ratio to either of 2 dose regimens (225 mg sc or 675 mg 
sc) or placebo sc by the RTSM system. Patients will be stratified by sex (male/female) and age at 
FM onset (<40 years old and ≥40 years old). The RTSM system will manage initial drug supply, 
maintenance of adequate IMP supplies on site, and study randomization centrally.
Investigational Medicinal Products: Dose, Pharmaceutical Form, Route of Administration, 
and Dosing Regimen
The prespecified treatments with fremanezumab or placebo will be administered by qualified 
study personnel as sc injection approximately every 4 weeks (28 days) for a total of 4 doses, 
on days 1, 29, 57, and 85.
Test IMP: Fremanezumab; recombinant humanized IgG2Δa/kappa mAb against CGRP
Reference IMP: None
Placebo IMP: Fremanezumab placebo. This is the same vehicle as the test IMP formulation 
but does not contain active fremanezumab.
Duration of Patient Participation and Maximal Exposure to IMP: The total duration of 
patient participation in the study is planned to be 21 weeks, consisting of a screening period of 
up to 5 weeks (ranging from 17 to 35 days), and a double-blind treatment period of 16 weeks.
Study Duration: May 2019 until approximately July 2022.
End-of-Study: EOS is defined as completion of the last visit of the last patient.
Plans for Treatment or Care after the Patient Has Ended Participation in the Study:
There are currently no plans to make the treatment available after completion of this study. After 
Visit 7, all subsequent clinical care will be determined by or at the discretion of the treating 
physician.
Inclusion Criteria: Patients may be randomized/enrolled in the study only if they meet all of the 
following criteria:
a.
approved for study participation by the Fibromyalgia Eligibility Review Committee 
(Section 5.8.1)
b. capable of giving signed informed consent
c.
agree to comply with the requirements and restrictions listed in this protocol, 
including remaining at the clinic for the duration of each required visit during the 
study period to complete all scheduled procedures and assessments
d. male or female ≥18 to 75 years old at screening (inclusive) with FM
e.
willing to comply with recording of once-daily scores using the PI-NRS, completed 
every evening (approximately the same time each day) starting at the BAPS Visit 
(Visit 2) and continuing to the EOT/EOS or ET Visit (Visit 7). A minimum of 12 of 
14 daily average pain intensity ratings AND daily worst pain intensity ratings are 
required to be recorded in an e-diary during the baseline assessment period.


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Study TV48125-PN-20028
14
f.
all of the following diagnostic criteria for FM according to 2016 American College of 
Rheumatology (Wolfe et al 2016) are met at the Screening Visit:

Generalized pain, defined as pain in at least 4 of 5 regions, is present.

Symptoms have been present at a similar level for at least 3 months.

Widespread pain index (WPI) ≥7 and a symptom severity (SS) scale score ≥5 OR 
WPI of 4 to 6 and SS scale score ≥9.

A diagnosis of FM is valid irrespective of other diagnoses. A diagnosis of FM 
does not exclude the presence of other clinically important illnesses.
g. PI-NRS score ≥4 in average daily FM pain assessed by self-report over the past week 
at Screening Visit
h. body mass index of 18.5 to 45 kg/m2 and a body weight ≥45 kg
i.
agree to use only acetaminophen as rescue medication for FM-related pain (up to 
1000 mg per dose and not to exceed 3000 mg/day for any indication throughout the 
study period)
j.
non-pharmacologic interventions (including normal daily exercise routines, 
chiropractic care, physical therapy, psychotherapy, and massage therapy) are 
unchanged for a minimum of 30 days prior to screening and will remain unchanged 
throughout the study
k. agree not to initiate or modify any non-pharmacologic or pharmacologic interventions 
for FM from washout through the EOT/EOS or ET Visit
l.
agree to maintain a usual and unchanged physical exercise regimen
m. [Revision 1] must meet the following pregnancy-related criteria:

females must have a negative serum beta-human chorionic gonadotropin (β-HCG) 
test at screening or be sterile or postmenopausal; definitions of sterile and 
postmenopausal are provided in Appendix F

females of childbearing potential whose male partners are potentially fertile (ie, 
no vasectomy) must use highly effective birth control methods for the duration of 
the study (ie, starting at screening) and for 6 months after the last dose of the 
IMP; further details are provided in Appendix F

males who are potentially fertile/reproductively competent (not surgically [eg, 
vasectomy] or congenitally sterile), and their female partners are of childbearing 
potential, should use highly effective birth control methods for the duration of the
study (ie, starting at screening); further details are provided in Appendix F
n. must agree not to participate in another interventional study from the screening period 
through the EOT/EOS or ET Visit


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Study TV48125-PN-20028
15
Exclusion Criteria: Patients will not be randomized/enrolled in this study if they meet any of 
the following criteria:
a.
unable or unwilling to discontinue/washout of prohibited medications (Appendix I); 
Note: Medications used to treat depression or anxiety are permitted provided they 
were started at least 90 days prior to screening, have been used at a stable dose for at 
least 90 days, and will be maintained at that dose for the duration of the study. 
Therefore, both over-the-counter medications used to treat depression or anxiety and 
selective serotonin reuptake inhibitors (SSRIs; with the exception of ≥60 mg/day of 
fluoxetine) are permitted.
b. in the investigator’s opinion, history of no meaningful improvement to an adequate 
trial of 2 or more different pharmacological classes of medications indicated for FM 
adequately dosed for an adequate period of time
c.
ongoing pain that would confound or interfere with the assessment of the patient’s 
FM pain or require excluded therapies during the patient’s participation in this study. 
Other sources of pain may include, but are not limited to, neuropathic pain 
attributable to an identifiable cause, post-herpetic neuralgia, traumatic injury, prior 
surgery, complex regional pain syndrome or failed back syndrome, infections or 
inflammatory arthritis (eg, rheumatoid arthritis [RA], ankylosing spondylitis, 
psoriatic arthritis, gout), other autoimmune diseases (eg, systemic lupus 
erythematosus), and other widespread rheumatic diseases (widespread osteoarthritis 
[OA]). Localized OA is permitted as long as it is subclinical (which does not require 
treatment with an analgesic[s]).
d. surgery planned during the study period
e.
receiving prophylactic treatment for migraine-related disorders, including topiramate, 
valproic acid, onabotulinumtoxinA, amitriptyline, and nortriptyline
f.
known history of clinically significant or unstable hematologic, cardiac, or 
thromboembolic events (ie, arterial or venous thrombotic or embolic events, including 
cerebrovascular accident [including transient ischemic attacks]; deep vein thrombosis 
or pulmonary embolism); renal, endocrine, pulmonary, gastrointestinal, genitourinary, 
or neurologic disorders [exclusive of FM]; infectious, hepatic, or ocular disease, at 
the discretion of the investigator, as determined by a medical and psychiatric history; 
and physical examination, 12-lead ECG, serum chemistry, hematology, coagulation, 
and urinalysis). Abnormal test results may be repeated for confirmation.
g. moderate or severe major depressive symptoms as assessed by the HADS Depression 
Subscore >14 (at the Screening Visit and/or the BAPS Visit)
h. known history of suicide attempt, suicidal behavior, or suicidal ideation within the 
last 12 months (a response of “yes” to questions 4 or 5 on the suicidal ideation portion 
of the Columbia-Suicide Severity Rating Scale) or have been assessed as a significant 
risk to commit suicide at the Screening Visit or Randomization Visit
i.
lifetime history of any psychotic and/or bipolar disorder as assessed by the 
Mini-International Neuropsychiatric Interview (MINI)


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Study TV48125-PN-20028
16
j.
current, untreated, moderate or severe major depressive disorder and/or anxiety 
disorders as assessed by the MINI. Patients with currently treated major depressive 
disorder and/or anxiety disorder can be included, provided that according to the 
investigator’s judgment, there have been no clinically significant changes in 
symptoms while on a stable dose of allowed antidepressants or antianxiety 
medications for at least 90 days prior to screening, and that the dosage of 
antidepressant or antianxiety medication will be maintained for the duration of the 
study.
k. current eating disorders as assessed by the MINI 
l.
known infection or history of human immunodeficiency virus, tuberculosis, or 
chronic hepatitis B or C infection or are antigen positive for hepatitis B at screening
m. past or current history of cancer in the past 5 years, except for appropriately treated 
non-melanoma skin carcinoma (basal carcinoma)
n. known history of hypersensitivity reactions to injected proteins, including mAbs and 
animal venoms, or a history of Stevens-Johnson Syndrome/toxic epidermal necrolysis 
syndrome
o. known history of hypersensitivity or intolerance to the use of acetaminophen
p. known hypersensitivity or intolerance to the components in the formulation of 
fremanezumab
q. participation in an interventional clinical study of a chemical entity or device within 
2 months or 5.5 half-lives (whichever is longer) prior to IMP administration
r.
participation in an interventional clinical study of a mAb within 3 months or 
5.5 half-lives (whichever is longer) prior to IMP administration
s.
any prior exposure to mAbs targeting the CGRP pathway (including erenumab, 
eptinezumab, galcanezumab, or fremanezumab) at any time. If the patient has 
participated in a clinical study with any of these mAbs, it has to be confirmed that the 
patient received placebo in order to be eligible for this study.
t.
clinically significant elevations in hepatic enzymes (alanine aminotransferase or 
aspartate aminotransferase) based on the upper limit of normal (ULN) or investigator 
judgment, which have been reconfirmed on a repeat test 
u. suspected hepatocellular damage that fulfills criteria for Hy’s law at screening
v. serum creatinine >1.5× ULN, clinically significant proteinuria, or evidence of renal 
disease at screening
w. known history of alcohol and/or drug abuse within the past 12 months per the MINI 
or have a positive urine drug screen for illegal drugs of abuse at the Screening Visit, 
BAPS Visit, or prior to randomization
x. [Revision 1] if using marijuana (cannabis), meets the MINI (v.7.0.2) criteria for 
greater than mild substance use disorder for marijuana (cannabis), cannabidiol, or 
other cannabinoids during the preceding 12 months; and/or the investigator is 
concerned that the use of marijuana (cannabis), cannabidiol, or other cannabinoids


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could interfere with a subject’s ability to provide reliable data or comply with the 
protocol
y. diagnosed with uncontrolled sleep apnea 
z. employee of Teva Pharmaceuticals, the CRO involved, or the investigative site 
personnel directly affiliated with this study and/or immediate family members 
(spouse, parent, child, or sibling, whether biological or legally adopted, or legal 
guardian/custodian)
aa. involved in an active workers compensation case or is currently filing or seeking a 
work disability claim for any reason or condition
bb. currently experiencing acute, severe psychosocial stress (ie, recent death of a loved 
one, divorce)
cc. any condition or situation (ie, shift work) that, in the investigator’s opinion, makes the 
patient unsuitable for study participation
dd. [New criterion] has received any CGRP pathway targeting treatment or compound 
(anti-CGRP antibodies, anti-CGRP receptor antibodies, or CGRP receptor 
antagonists/oral gepants) for migraine
ee. [New criterion] the patient is a pregnant or nursing female or plans to become 
pregnant during the study, including the 6-month period after the administration of 
the IMP
Statistical Considerations
Sample Size Rationale: The sample size of 80 subjects per treatment group was selected based 
on expert consensus agreement at a scientific advisory board meeting; this sample size is 
expected to provide sufficient precision to estimate the treatment effect of fremanezumab versus 
placebo. Moreover, assuming a standard deviation of 2.2 for change from baseline in the weekly 
average of the daily average PI-NRS score, 80 patients per treatment group will provide at least 
90% probability to observe the half length of the 95% confidence interval of the treatment 
difference between fremanezumab 225 mg sc or fremanezumab 675 mg sc and placebo less than 
0.74. In total, 240 patients will be enrolled in this study in a 1:1:1 randomization ratio.
Primary Efficacy Analysis: The primary efficacy variable, the change from baseline to week 16
in the weekly average of the daily average PI-NRS scores over the past 24 hours, will be 
analyzed using a Mixed Model Repeated Measures (MMRM) model with change from baseline 
in the weekly average of the daily average PI-NRS scores at each week as the dependent 
variable; sex, age group at FM onset, week, treatment, and treatment by week interaction as fixed 
factors; and baseline PI-NRS scores as a covariate. The heterogeneous autoregressive correlation 
structure for repeated observations within patients will be used; the denominator degrees of 
freedom will be estimated using Kenward-Roger’s approximation. An adjustment for missing 
data due to lack of efficacy or adverse event assumes that the PI-NRS scores will, on average,
return to baseline values. Missing data will be imputed 500 times to generate 500 complete data 
sets by using the SAS procedure PROC MI following the 3 steps below:

Step 1: The monotone missing pattern will be induced by the Markov Chain Monte 
Carlo method in the PROC MI procedure using seed number 4751523.


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
Step 2: The remaining missing data at subsequent weeks will be imputed using the 
regression method for the monotone pattern with seed number 4751523 and 
adjustment for covariates including treatment groups, randomization strata, relevant 
baseline, and all values at preceding visits.

Step 3: The initially missing and now imputed data for patients discontinued from the 
study treatment due to lack of efficacy or adverse event will be center adjusted at the 
mean baseline value for that treatment group, ie, the final imputed score will be equal 
to the imputed score under missing at random minus (mean change from baseline 
score at the post-baseline time point for the treatment group).
Each imputed data set will be analyzed using the MMRM described above. The results from the 
500 analyses will be combined using Rubin’s formulae (PROC MIANALYZE). The least 
squares mean estimates for the mean change from baseline to each time point, as well as the 
difference of the estimates between the fremanezumab and placebo groups, with the 
corresponding standard error, p-value, and associated 95% confidence interval will be calculated.
Sensitivity Analysis: Sensitivity analyses will be included to address the assumptions in the 
primary model. The primary analysis will be repeated; however, the daily average pain scores 
measured on the days where the patient took rescue medication will be replaced with his or her 
PI-NRS score at the time of rescue medication use before the weekly average PI-NRS scores are 
derived. On days where a patient uses rescue medication more than once, the mean PI-NRS score 
at the time of rescue mediation use will be used as the pain score in place of the average pain 
intensity score for that day.
Three new sensitivity analyses will be conducted as part of the planned second interim analysis.
Details of the new sensitivity analyses will be specified in the interim analysis statistical analysis 
plan.
Secondary Efficacy Analysis: The change from baseline to week 16 in the weekly average of 
the daily worst PI-NRS score over the past 24 hours and the change from baseline of the 
individual components of the FIQR score and total FIQR score will be analyzed in the same 
manner as the primary efficacy endpoint; however, the baseline pain intensity over the past 
24 hours and the baseline FIQR score, respectively, will be used as a covariate in the MMRM 
model instead of the baseline PI-NRS score.
PGIC data will be dichotomized, where a patient who responds as either “much improved” or 
“very much improved” will be considered improved, and all other responses will be considered 
not improved. The response variable will be analyzed using a logistic regression model with the 
treatment, age group at FM onset, and sex as explanatory factors. In addition, PGIC data will be 
summarized as categorical variables by week and treatment group using descriptive statistics. 
The percentage of patients who experience a ≥30% reduction and ≥50% reduction in the weekly 
average of the daily average PI-NRS score will be analyzed using a generalized estimating 
equation method, where the dependent variable experience ≥30% reduction and ≥50% reduction 
(Yes/No) will be modeled through the binomial link function, with treatment, sex, age group at 
FM onset, week, and treatment by week interaction as explanatory factors. In addition, a plot of 
percentage of improvement versus percentage of patients meeting the improvement level 
throughout the study will be presented by treatment group.


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All other secondary efficacy endpoints will be analyzed in the same manner as the primary 
efficacy endpoint with the respective baseline assessment as a covariate in the MMRM model.
Other Efficacy Analysis: Statistical modeling to be used for other efficacy endpoints will be 
described and detailed in the statistical analysis plan as appropriate.
Multiple Comparisons and Multiplicity: No multiplicity adjustment is planned for this study.
 
 
Safety Analyses: The safety analysis set will include all randomized patients who receive at 
least 1 dose of IMP.
In the safety analysis set, treatment will be assigned based on the treatment patients actually 
received, regardless of the treatment to which they were randomized, unless otherwise specified.
Tolerability Analysis: Local tolerability findings (eg, erythema, induration, ecchymosis, and 
occurrence of injection site pain) will be listed and summarized descriptively.
Pharmacokinetic Analysis: Plasma concentrations will be tabulated at each planned sampling 
time point by treatment group. In addition, the most appropriate population pharmacokinetic
model will be developed; covariates that may affect pharmacokinetic parameters will be tested 
for inclusion in the model. This analysis will be reported separately from the CSR; individual 
pharmacokinetic concentration data will be summarized and listed in the CSR.
Pharmacokinetic/Pharmacodynamic Analysis: If appropriate, further 
pharmacokinetic/pharmacodynamic relationship may be estimated by compartmental techniques. 
The pharmacokinetic parameters will be based on fremanezumab concentrations. The 
pharmacodynamic endpoint will be the efficacy and/or safety response(s).
The pharmacokinetic/pharmacodynamic relationship may be estimated using the most 
appropriate model after comparing different candidate models for their quality of fit. Covariates 
that may affect the pharmacokinetic/pharmacodynamic relationship will be tested for inclusion in 
the model.
Biomarker Analysis: Blood samples (approximately 19.0 mL) will be collected on day 1, prior 
to randomization and at the times specified in Table 1,
 
 
 
 
Immunogenicity Analysis: A summary of immunogenicity results will be provided, and the 
incidence of immunogenicity and the antibody titers will be calculated.
Ancillary Studies Analysis: No ancillary analyses are planned for this study.


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Planned Interim Analysis: Interim analyses are planned for this study.


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TABLE OF CONTENTS
TITLE PAGE...................................................................................................................................1
AMENDMENT HISTORY .............................................................................................................2
INVESTIGATOR AGREEMENT...................................................................................................4
SPONSOR PROTOCOL APPROVAL ...........................................................................................5
COORDINATING INVESTIGATOR AGREEMENT...................................................................6
CLINICAL STUDY PROTOCOL SYNOPSIS...............................................................................7
LIST OF ABBREVIATIONS........................................................................................................29
1.
INTRODUCTION AND BACKGROUND INFORMATION ..................................32
1.1.
Introduction.................................................................................................................32
1.2.
Findings from Nonclinical and Clinical Studies.........................................................34
1.2.1.
Nonclinical Studies.....................................................................................................34
1.2.2.
Clinical Studies...........................................................................................................34
1.3.
Known and Potential Benefits and Risks to Patients..................................................35
1.3.1.
Known and Potential Benefits and Risks of the Test Investigational 
Medicinal Product(s) ..................................................................................................35
1.3.2.
Overall Benefit and Risk Assessment for This Study ................................................36
2.
STUDY OBJECTIVES AND ENDPOINTS..............................................................37
2.1.
Primary and Secondary Study Objectives and Endpoints ..........................................37
2.1.1.
Justification of Primary Endpoint...............................................................................38
2.2.
.......................................................................39
2.3.
Immunogenicity Objective and Endpoint...................................................................39
3.
STUDY DESIGN .......................................................................................................40
3.1.
General Study Design and Study Schematic Diagram ...............................................40
3.2.
Planned Number of Patients and Countries................................................................41
3.3.
Justification for Study Design and Selection of Population.......................................41
3.4.
Stopping Rules for the Study......................................................................................42
3.5.
Schedule of Study Procedures and Assessments........................................................43
3.6.
e-Diary and Tablet Data Collection............................................................................51
3.6.1.
e-diary.........................................................................................................................51
3.6.2.
Tablet ..........................................................................................................................52
4.
SELECTION AND EARLY TERMINATION OF PATIENTS................................53
4.1.
Patient Inclusion Criteria ............................................................................................53


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4.2.
Patient Exclusion Criteria...........................................................................................54
4.3.
Discontinuation from IMP/Early Termination from Study Criteria and 
Procedures for the Patient...........................................................................................57
4.4.
Replacement of Patients .............................................................................................58
4.5.
Rescreening.................................................................................................................59
4.6.
Screen Failure .............................................................................................................59
5.
TREATMENTS..........................................................................................................60
5.1.
Investigational Medicinal Products Used in the Study...............................................60
5.1.1.
Test Investigational Medicinal Product......................................................................60
5.1.1.1.
Starting Dose and Dose Levels...................................................................................60
5.1.1.2.
Dosing Visits and Dose Modification.........................................................................60
5.1.2.
Placebo Investigational Medicinal Product ................................................................60
5.2.
Preparation, Handling, Labeling, Storage, and Accountability for IMPs...................62
5.2.1.
Storage and Security...................................................................................................62
5.2.2.
Labeling......................................................................................................................62
5.2.3.
Accountability.............................................................................................................62
5.3.
Justification for Investigational Medicinal Products..................................................63
5.3.1.
Justification for Dose of Test Investigational Medicinal Product ..............................63
5.3.2.
Justification for Use of Placebo Investigational Medicinal Product ..........................64
5.4.
Other Medicinal Products/Non-Investigational Medicinal Products..........................64
5.5.
Treatment after the End of the Study..........................................................................64
5.6.
Restrictions .................................................................................................................64
5.6.1.
Activity .......................................................................................................................65
5.6.2.
Blood Donation...........................................................................................................65
5.7.
Prior and Concomitant Medication or Therapy..........................................................65
5.7.1.
Permitted Concomitant Medication or Therapy .........................................................65
5.7.2.
Prohibited Medication or Therapy..............................................................................65
5.7.3.
Recommended Washout Periods................................................................................66
5.8.
Procedures for Monitoring Patient Compliance .........................................................68
5.8.1.
Fibromyalgia Eligibility Review Committee..............................................................68
5.9.
Randomization and Blinding......................................................................................68
5.10.
Maintenance of Randomization and Blinding............................................................68
5.10.1.
Maintenance of Randomization..................................................................................68


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5.10.2.
Blinding and Unblinding ............................................................................................69
5.10.3.
Independent Data Monitoring Committee..................................................................69
5.11.
Total Blood Volume ...................................................................................................70
6.
ASSESSMENT OF EFFICACY ................................................................................71
6.1.
Assessments of Efficacy.............................................................................................71
6.1.1.
Pain Intensity-Numerical Rating Scale.......................................................................71
6.1.2.
Fibromyalgia Impact Questionnaire Revised .............................................................71
6.1.3.
EuroQol-5 Dimension Questionnaire .........................................................................71
6.1.4.
Patient Global Impression of Change.........................................................................71
6.1.5.
Patient-Reported Outcomes Measurement Information System ................................72
6.1.5.1.
PROMIS Sleep Disturbance Short Form 8a...............................................................72
6.1.5.2.
PROMIS Physical Function Short Form 12a..............................................................72
6.1.5.3.
PROMIS Fatigue Short Form 8a ................................................................................72
6.1.6.
Hospital Anxiety and Depression Scale .....................................................................72
6.1.7.
Inventory of Medical Diagnoses.................................................................................72
7.
ASSESSMENT OF SAFETY.....................................................................................74
7.1.
Adverse Events ...........................................................................................................74
7.1.1.
Definition of an Adverse Event..................................................................................74
7.1.2.
Recording and Reporting of Adverse Events .............................................................75
7.1.3.
Severity of an Adverse Event .....................................................................................75
7.1.4.
Relationship of an Adverse Event to the Investigational Medicinal Product.............75
7.1.5.
Serious Adverse Events..............................................................................................76
7.1.5.1.
Definition of a Serious Adverse Event .......................................................................76
7.1.5.2.
Expectedness...............................................................................................................77
7.1.5.3.
Reporting a Serious Adverse Event............................................................................77
7.1.6.
Protocol-Defined Adverse Events of Special Interest ................................................79
7.1.7.
Protocol Deviations Because of an Adverse Event ....................................................80
7.2.
Pregnancy ...................................................................................................................80
7.3.
Medication Error and Special Situations Related to the Investigational 
Medicinal Products.....................................................................................................80
7.4.
Clinical Laboratory Tests ...........................................................................................81
7.4.1.
Serum Chemistry, Hematology, and Urinalysis .........................................................82
7.4.2.
Other Clinical Laboratory Tests .................................................................................82


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7.4.2.1.
Beta-human Chorionic Gonadotropin Tests ...............................................................83
7.4.2.2.
Urine Drug Screen ......................................................................................................83
7.5.
Physical Examinations................................................................................................83
7.6.
Vital Signs ..................................................................................................................83
7.7.
Electrocardiography....................................................................................................84
7.8.
Immunogenicity..........................................................................................................84
7.9.
Assessment of Local Tolerability and Pain ................................................................84
7.10.
Assessment of Suicidality...........................................................................................84
8.
ASSESSMENT OF PHARMACOKINETICS / BIOMARKERS / 
IMMUNOGENICITY / ANCILLARY STUDIES.....................................................85
8.1.
Pharmacokinetic Assessment......................................................................................85
8.2.
Pharmacodynamics Assessment.................................................................................85
8.3.
Immunogenicity Testing.............................................................................................85
8.4.
85
9.
STATISTICS ..............................................................................................................87
9.1.
Study Design and Randomization ..............................................................................87
9.2.
Sample Size and Power Considerations .....................................................................87
9.3.
Analysis Sets...............................................................................................................87
9.3.1.
Intent-to-Treat Analysis Set........................................................................................87
9.3.2.
Modified Intent-to-Treat Analysis Set........................................................................87
9.3.3.
Safety Analysis Set.....................................................................................................88
9.3.4.
Per-Protocol Analysis Set...........................................................................................88
9.3.5.
Pharmacokinetic Analysis Set ....................................................................................88
9.4.
Data Handling Conventions........................................................................................88
9.4.1.
Handling Early Terminations and Missing Data ........................................................88
9.5.
Study Population.........................................................................................................88
9.5.1.
Patient Disposition......................................................................................................88
9.5.2.
Demographic and Baseline Characteristics ................................................................89
9.6.
Efficacy Analysis........................................................................................................89
9.6.1.
Primary Endpoint........................................................................................................89
9.6.2.
Secondary Endpoints ..................................................................................................89
9.6.3.
89
9.6.4.
Planned Method of Analysis.......................................................................................90


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9.6.4.1.
Primary Efficacy Analysis..........................................................................................90
9.6.4.2.
Sensitivity Analysis ....................................................................................................90
9.6.4.3.
Secondary Efficacy Analysis......................................................................................91
9.6.4.4.
Other Efficacy Analysis..............................................................................................92
9.6.4.5.
....................................................................................92
9.7.
Multiple Comparisons and Multiplicity......................................................................92
9.8.
Safety Analysis ...........................................................................................................92
9.8.1.
Safety Variables..........................................................................................................92
9.8.2.
Safety Analysis ...........................................................................................................93
9.8.3.
Tolerability Analysis ..................................................................................................93
9.9.
Pharmacokinetic Analysis ..........................................................................................93
9.10.
Pharmacodynamic Analysis........................................................................................94
9.11.
Pharmacokinetic/Pharmacodynamic Analysis............................................................94
9.12.
Biomarker Analysis ....................................................................................................94
9.13.
Immunogenicity Analysis...........................................................................................94
9.14.
Ancillary Studies Analysis .........................................................................................94
9.15.
Planned Interim Analysis............................................................................................94
9.16.
Reporting Deviations from the Statistical Plan ..........................................................94
10.
QUALITY CONTROL AND QUALITY ASSURANCE .........................................96
11.
COMPLIANCE STATEMENT..................................................................................97
12.
DATA MANAGEMENT AND RECORD KEEPING ..............................................98
13.
FINANCING AND INSURANCE.............................................................................99
14.
PUBLICATION POLICY ........................................................................................100
15.
REFERENCES .........................................................................................................101
16.
SUMMARY OF CHANGES TO PROTOCOL .......................................................105
16.1.
Amendment 05 Dated 09 August 2021 ....................................................................105
16.2.
Amendment 04 with Revision 01 Dated 25 June 2020 ............................................113
16.3.
Amendment 04 Dated 16 June 2020.........................................................................114
16.4.
Administrative Letter 01 Dated 28 February 2020...................................................134
16.5.
Amendment 03 Dated 22 July 2019 .........................................................................135
16.6.
Amendment 02 Dated 16 April 2019........................................................................144
16.7.
Amendment 01 Dated 08 February 2019..................................................................151


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APPENDIX A.
CLINICAL LABORATORIES AND OTHER DEPARTMENTS AND 
INSTITUTIONS.......................................................................................................161
APPENDIX B.
STUDY PROCEDURES AND ASSESSMENTS BY VISIT.........................163
APPENDIX C.
CLINICAL CRITERIA FOR DIAGNOSING ANAPHYLAXIS...................169
APPENDIX D.
QUALITY CONTROL AND QUALITY ASSURANCE ..............................170
APPENDIX E.
ETHICS............................................................................................................172
APPENDIX F.
BIRTH CONTROL METHODS AND PREGNANCY TESTING.................173
APPENDIX G.
LOST TO FOLLOW-UP.................................................................................175
APPENDIX H.
HANDLING, LABELING, STORAGE, AND ACCOUNTABILITY 
FOR IMP(S)..............................................................................................................176
APPENDIX I.
LIST OF PROHIBITED MEDICATIONS AND THERAPEUTIC 
INTERVENTIONS...................................................................................................178
APPENDIX J.
TOTAL BLOOD VOLUME.............................................................................182
APPENDIX K.
PRODUCT COMPLAINTS............................................................................183
APPENDIX L.
DATA MANAGEMENT AND RECORD KEEPING....................................185
APPENDIX M.
PUBLICATION POLICY ..............................................................................188
APPENDIX N.
RELEVANT MEDICATIONS ALLOWED FOR THE DURATION 
OF THE STUDY......................................................................................................189
APPENDIX O.
MANAGEMENT OF STUDY ACTIVITIES DURING COVID-19 .............190


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LIST OF TABLES
Table 1:
Study Procedures and Assessments............................................................................44
Table 2:
Investigational Medicinal Products Used in the Study...............................................61
Table 3:
Other Medicinal Products Used in the Study .............................................................64
Table 4:
List of Recommended Washout Periods for Common Medications ..........................66
Table 5:
The Relationship of an Adverse Event to the IMP.....................................................76
Table 6:
Clinical Laboratory Tests ...........................................................................................82


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LIST OF FIGURES
Figure 1:
Overall Study Schematic Diagram .............................................................................41


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LIST OF ABBREVIATIONS
Abbreviation
Term
β-HCG
beta-human chorionic gonadotropin
ACR
American College of Rheumatology
ADA
anti-drug antibody
ADL
activities of daily living
ALT
alanine aminotransferase (SGPT)
AST
aspartate aminotransferase (SGOT)
AUC
area under the plasma concentration-time curve
BAPS
Baseline Assessment Period Start
BLA
Biological License Application
BP
blood pressure
CA
Competent Authority
CDMS
clinical data management system
CFR
Code of Federal Regulations (US)
CGRP
calcitonin gene-related peptide
CH
cluster headache
CM
chronic migraine
COVID-19
Coronavirus Disease 2019
CRO
contract research organization
CSR
clinical study report
C-SSRS
Columbia-Suicide Severity Rating Scale
ECG
electrocardiogram
eCRF
electronic case report form
e-diary
electronic diary
EM
episodic migraine
EOS
end-of-study
EOT
end-of-treatment
EQ VAS
EQ Visual Analogue Scale
EQ-5D-5L
EuroQol-5D-5L
ET
early termination
EudraCT
European Clinical Trials
FIQR
Fibromyalgia Impact Questionnaire Revised


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Abbreviation
Term
FM
fibromyalgia
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GLP
Good Laboratory Practice
GPSP
Global Patient Safety and Pharmacovigilance
HADS
Hospital Anxiety and Depression Scale
HBsAg
Hepatitis B surface antigen
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
ICF
informed consent form
ICH
The International Council on Harmonisation
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
IgG
immunoglobulin G
IHS
International Headache Society
IMP
investigational medicinal product
IMD
Inventory of Medical Diagnoses
IND
Investigational New Drug
IRB
Institutional Review Board
ITT
intent-to-treat
iv
intravenous
LSO
local safety officer
mAb
monoclonal antibody
MCMC
Markov Chain Monte Carlo
MINI
Mini-International Neuropsychiatric Interview
mITT
modified intent-to-treat
MMRM
mixed model repeated measures
n
number
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NDA
New Drug Application
NIH
National Institutes of Health
OA
osteoarthritis
OTC
over-the-counter
PEF
peak expiratory flow


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Abbreviation
Term
PGIC
Patient Global Impression of Change
PI-NRS
Pain Intensity-Numerical Rating Scale
PP
per-protocol
PROC MI
SAS procedure
PROMIS
Patient-Reported Outcomes Measurement Information System
RA
rheumatoid arthritis
RIM
reserpine induced model
RTSM
Randomization and Trial Supply Management
sc
subcutaneous
SF
Short Form
SOP
Standard Operating Procedure
SS
symptom severity
SSRI
selective serotonin reuptake inhibitor
SUSAR
suspected unexpected serious adverse reaction
TNFα
tumor necrosis factor alpha
ULN
upper limit of normal
US
United States (of America)
WOCBP
women of childbearing potential
WPI
widespread pain index


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1.
INTRODUCTION AND BACKGROUND INFORMATION
1.1.
Introduction
Fremanezumab (TEV-48125 [formerly PF-04427429, RN307, and LBR-101]), a humanized 
immunoglobulin G (IgG) 2Δa/kappa monoclonal antibody (mAb) derived from a murine 
precursor, is currently approved in the United States (US) for the preventive treatment of 
migraine in adults and marketed under the trade name AJOVY®. Fremanezumab is under 
development for chronic pain indications. Fremanezumab is a potent, selective calcitonin 
gene-related peptide (CGRP) binder and does not bind to the closely related family members 
such as amylin, calcitonin, adrenomedullin, or intermedin peptides. Fremanezumab binds both 
α- and β-CGRP and inhibits CGRP from binding to the CGRP receptor.
Calcitonin gene-related peptide and its receptor are widely expressed in the somatosensory and 
autonomic peripheral nerves as well as in the enteric system (Iyengar et al 2017). Dorsal root 
ganglion sensory neurons are pseudounipolar, and both their central and peripheral axonal 
endings release CGRP (Raddant and Russo 2011). Calcitonin gene-related peptide is found in the 
central nervous system primarily in the dorsal horn of the spinal cord. There is also a prominent 
localization of CGRP in sensory Aδ- and C-fiber neurons of peripheral nerves (Iyengar et al 
2017, Poyner et al 2002, Pozo-Rosich et al 2015). Stimulation of sensory nerves can elicit an 
axon reflex, releasing CGRP and substance P from adjacent axonal branches. This results in 
evoked release of proinflammatory mediators that leads to sensitization of peripheral nerves and, 
with further stimulation, amplification of pain signals, which is manifested clinically as 
hyperalgesia and allodynia (Basbaum et al 2009, Willis 1999, Woolf 2011). In addition, satellite 
glia surrounding dorsal root ganglia release proinflammatory factors such as tumor necrosis 
factor alpha (TNFα) that promote CGRP release from nociceptive neurons, which in turn 
stimulates further release of proinflammatory factors from satellite glia in a positive-feedback 
loop. Furthermore, with inflammation, local mast cells may release both TNFα and CGRP, 
further driving the positive-feedback loop (Raddant and Russo 2011).
Chronic nerve injury or nerve inflammation may lead to a neuroplastic phenomenon termed pain 
sensitization, in which afferent nociceptive neurons display increased excitability in response to 
stimuli (eg, lower threshold for activation, repetitive discharges, and increased synaptic efficacy) 
(Iyengar et al 2017). Both central and peripheral pain sensitization essentially represent a 
reprogramming of the sensory nervous system that may occur with chronic nociceptive pain as 
well as chronic neuropathic pain. Although CGRP does not itself mediate pain, it plays an 
important role in both peripheral as well as central sensitization, phenomena that manifest 
clinically as allodynia and hyperalgesia, and which are prominent concomitant symptoms of 
migraine (photophobia, phonophobia, and cutaneous allodynia) [Cornelison et al 2016, Durham 
2016, Iyengar et al 2017, Raddant and Russo 2011, Russell et al 2014]. Given the efficacy seen 
in treating migraine as well as the associated allodynia, by analogy, an anti-CGRP antibody has 
the potential to block or reduce pain sensitization in a variety of chronic pain indications in 
which sensitization has been shown to play a role, such as fibromyalgia (FM), osteoarthritis 
(OA), neuropathic pain, and visceral pain.


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Fibromyalgia is a common cause of chronic widespread musculoskeletal pain, often 
accompanied by fatigue, cognitive disturbance, psychiatric symptoms, and multiple somatic 
symptoms. The prevalence of the condition ranges from 1.2% to 5.4% and is dependent on 
criteria used to diagnose FM (Jones et al 2015). 
The diagnosis of FM is based primarily on the patient’s symptoms of widespread pain, typically 
reported in the muscles and joints, and findings of multiple tender points in characteristic soft 
tissue locations, in the absence of evidence on physical examination and laboratory testing of 
joint or muscle inflammation that would explain the patient’s symptoms. According to the 
2016 American College of Rheumatology FM diagnostic criteria (Wolfe et al 2016), FM may be 
diagnosed when all of the following criteria are met:
1. Generalized pain, defined as pain in at least 4 of 5 regions, is present.
2. Symptoms have been present at a similar level for at least 3 months.
3. There is a widespread pain index (WPI) ≥7 and a symptom severity (SS) scale score ≥5 
OR WPI of 4 to 6 and SS scale score ≥9.
4. A diagnosis of FM is valid irrespective of other diagnoses. A diagnosis of FM does not 
exclude the presence of other clinically important illnesses.
Fibromyalgia often occurs with other conditions currently considered to have a similar 
underlying pathophysiology (eg, irritable bowel syndrome, interstitial cystitis, and tension 
headache) or as a comorbidity in individuals with diseases characterized by ongoing peripheral 
damage or inflammation (eg, autoimmune disorders and osteoarthritis) (Clauw 2014).
The approach toward the treatment of FM integrates pharmacological and non-pharmacological 
interventions. Non-pharmacologic interventions include patient education (eg, regarding the 
importance of good sleep, treating common comorbidities), adhering to an exercise program, 
psychological interventions and cognitive behavioral therapy for pain management, and 
addressing the treatment of other common comorbidities (Clauw 2014, Macfarlane et al 2017).
If non-pharmacologic interventions do not yield a satisfactory improvement in FM, 
pharmacotherapy is often initiated. In the US, there are 3 drugs with an approved indication for 
the treatment of FM: 2 serotonin and norepinephrine reuptake inhibitors (SNRIs), duloxetine 
(CYMBALTA®) and milnacipran (SAVELLA®), and the anti-seizure medication pregabalin 
(LYRICA®). Other analgesic classes that have been used commonly in the treatment of FM 
include tricyclic antidepressants (eg, amitriptyline), anti-seizure medications (eg, gabapentin 
[NEURONTIN®]), muscle relaxants (eg, cyclobenzaprine, tizanidine [ZANAFLEX®]), or OTCs,
including acetaminophen and nonsteroidal anti-inflammatory drugs. To date, these 
pharmacologic treatment options produce only marginal effectiveness and are accompanied by 
side effects necessitating the need to develop new treatments for patients with FM.
The etiology of the syndrome is unknown, and the pathophysiology is uncertain (Clauw 2014).
Fibromyalgia is considered a pain amplification syndrome characterized by widespread 
musculoskeletal pain with comorbidities of fatigue, cognitive/emotional, and poor sleep quality 
related symptoms (Staud and Rodriguez 2006, Wolfe et al 1995). Research over the past 
2 decades has delivered consistent evidence to suggest abnormal nervous system findings in 
patients with FM (Clauw et al 2011). In addition to pain-related changes, patients with FM 
manifest hyperalgesia and allodynia with respect to mechanical and thermal stimuli, a composite 


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of reduced tolerance and abnormal brain processing of non-painful sensory stimuli (Carrillo-de-
la-Pena et al 2006, Geisser et al 2008, Gibson et al 1994, Hollins et al 2009, Kosek et al 1996, 
Lόpez-Solá et al 2014, Wilbarger and Cook 2011). Central and/or peripheral mechanisms of 
nociception are altered in FM (Carrillo-de-la-Pena et al 2006, Geisser et al 2008, Gibson et al 
1994, Hollins et al 2009, Kosek et al 1996, Lόpez-Solá et al 2014, Sann and Pierau 1998, Staud 
and Smitherman 2002, Wilbarger and Cook 2011). Studies suggest that pain in FM may be 
associated with hyperexcitability of the nociceptive system (ie, increased transmission 
[Oaklander et al 2013, Serra et al 2014, Üçeyler et al 2013], peripheral and central amplification 
[Cook et al 2004, Gracely et al 2002, Pujol et al 2014], reduced inhibitory control mechanisms 
[Julien et al 2005, Kosek and Hansson 1997]), and reduced opponent non-nociceptive sensory 
processing (Ichesco et al 2013, Lόpez-Solá et al 2014, Montoya et al 2006, Ozgocmen et al 2003, 
Pujol et al 2014).
Refer to the current Investigator’s Brochure (IB) for detailed information on the background, 
pharmaceutical particulars, nonclinical experience, and clinical experience with fremanezumab.
1.2.
Findings from Nonclinical and Clinical Studies
1.2.1.
Nonclinical Studies
Fremanezumab was evaluated in nonclinical pharmacology, pharmacokinetics, and toxicology 
studies. Pivotal studies were conducted under Good Laboratory Practice (GLP) via the 
intravenous (iv) and subcutaneous (sc) routes of administration with once-weekly dosing for up 
to 6 months.
No toxicological concerns were identified following chronic dosing to experimental animals at 
dose levels up to 300 mg/kg/week. The calculated safety margin is 54-fold higher than the 
expected clinical exposure following 675 mg sc monthly.
In a GLP embryo-fetal development study in rabbits, sc injection of fremanezumab to pregnant 
rabbits was well tolerated and did not induce any obvious maternal toxicity or embryo-fetal 
toxicity in any dose group.
Based on the absence of findings in the safety pharmacology studies, no concerns were identified 
for fremanezumab to cause any biologically significant changes in the cardiovascular, 
respiratory, and central nervous systems.
The pharmacokinetics of fremanezumab 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 elimination half-life. Exposure increased linearly across doses following single and 
repeated weekly dosing. Following sc administration, mean systemic exposure ranged from 65% 
to 92% of the equivalent iv doses, demonstrating reasonably high sc bioavailability.
The overall nonclinical safety data (see also the IB) support the safe, repeated (monthly) 
administration of fremanezumab in human subjects for the duration of the Phase 3 pivotal trials 
(3 months) and the long-term safety extension (1 year).
1.2.2.
Clinical Studies
As of 30 August 2019, approximately 4972 subjects/patients (4062 adult patients with migraine, 
15 pediatric patients with migraine, 380 patients with cluster headache [CH], 37 patients with 


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persistent post-traumatic headache, an estimated 4 patients with FM, and 474 healthy subjects) 
have been exposed to fremanezumab. The fremanezumab clinical program comprises 24 clinical 
studies (10 Phase 1; 6 Phase 2, 2b, or 2b/3; and 8 Phase 3 studies), of which 19 have been 
completed.
The safety and tolerability of fremanezumab was studied in all of the 24 studies in the clinical 
program (ie, 10 Phase 1, 2 Phase 2, 2 Phase 2b, 2 Phase 2b/3, and 8 Phase 3 studies). Based on 
the safety results of the completed studies, the safety profile was assessed to include the 
following events as identified risks qualifying as adverse drug reactions: injection site induration, 
injection site erythema, injection site pruritus, injection site pain, and injection site rash. None of 
the identified risks was serious or considered as a clinically meaningful risk. No serious adverse 
reaction is considered expected by the sponsor for the purpose of expedited reporting of 
suspected unexpected serious adverse reactions (SUSAR) reporting.
1.3.
Known and Potential Benefits and Risks to Patients
1.3.1.
Known and Potential Benefits and Risks of the Test Investigational Medicinal
Product(s)
Benefits
Despite the available nonpharmacologic and pharmacologic interventions (approved and 
non-approved), acceptable pain relief in patients with FM is often inadequate. In a large 
proportion of patients, symptoms of FM are refractory to treatment and pharmacological 
treatments that have a minimal or moderate effect on pain. Patients do not experience acceptable 
efficacy and/or cannot tolerate the adverse effects of these medications, and therefore, FM 
continues to pose a clinically significant unmet medical need (Ablin and Häuser 2016, 
Macfarlane et al 2017). Fremanezumab inhibits the interaction of CGRP with its receptor and 
may alleviate pain and perhaps other symptoms associated with FM, based on the involvement of 
CGRP pathway in this condition; however, the benefits of fremanezumab in FM remain to be 
determined.
Risks
Fremanezumab (sc) has generally been well tolerated over the range of doses evaluated (single 
doses of 0.02 to 2000 mg in healthy subjects, multiple doses of 30 to 300 mg in healthy 
volunteers, and multiple doses of 225 to 900 mg sc in patients with migraine). The most common 
treatment-emergent adverse events in patients with migraine were mild to moderate transient 
general administration site disorders/reactions. Other commonly reported treatment-emergent 
adverse events were upper respiratory tract infection, back pain, nausea, and dizziness. Based on 
the exposure and body of evidence from Teva’s studies of fremanezumab in other indications, 
the benefit and risk assessment for fremanezumab is expected to be favorable.
Known risks that do not impact the risk-benefit profile are as follows:

injection site induration

injection site erythema

injection site pruritus


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
injection site pain

injection site rash
None of these risks are considered clinically meaningful.
Severe hypersensitivity reactions are regarded as a potential risk for fremanezumab based on the 
following considerations: mild and moderate drug hypersensitivity events were observed 
infrequently albeit with similar incidence in placebo and fremanezumab in the clinical 
development program for migraine, but no anaphylaxis or severe hypersensitivity reactions 
related to the investigational medicinal product (IMP) were seen. While no severe 
hypersensitivity or anaphylactic reactions occurred as a result of fremanezumab administration in 
the clinical development program for migraine, a small number of severe hypersensitivity 
reactions, including anaphylaxis, have been reported in the postmarketing period. One patient, 
who was taking multiple concomitant medications including lamotrigine and treated with 
fremanezumab, was reported to have Stevens-Johnson Syndrome. This reaction has also been 
rarely reported to occur in patients taking other anti-CGRP pathway monoclonal antibodies, 
along with concomitant medications including lamotrigine.
Because CGRP is a vasodilator, there is a theoretical risk of unfavorable cardiovascular effects 
with CGRP inhibition. Extensive research conducted with the CGRP ligand antagonists has not 
identified relevant safety cardiovascular concerns in humans. Dedicated studies conducted in 
monkey and humans using fremanezumab have not identified clinically relevant changes in heart 
rate, blood pressure, or other cardiovascular parameters. No relevant cardiovascular event has 
been seen in the completed studies.
Refer to the current IB for additional information regarding benefits and risks to patients.
1.3.2.
Overall Benefit and Risk Assessment for This Study
The efficacy of fremanezumab in the treatment of FM is unknown. This study serves as a proof 
of concept study. The benefit of fremanezumab in treating pain associated with FM remains to be 
determined.


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2.
STUDY OBJECTIVES AND ENDPOINTS
2.1.
Primary and Secondary Study Objectives and Endpoints
The primary and secondary study objectives and endpoints are as follows:
Objectives
Endpoints
The primary objective of the 
study is to estimate the 
treatment effect of 
fremanezumab administered 
subcutaneously in reducing 
pain in adult patients with FM.
The primary efficacy endpoint is the change from baseline up 
to week 16 in the weekly average of the daily average Pain 
Intensity-Numerical Rating Scale (PI-NRS) score over the past 
24 hours.
A secondary objective is to 
evaluate the effect of 
fremanezumab on other 
efficacy measures, including 
pain, quality of life, sleep, 
fatigue, improvement in health, 
physical functioning, and 
mood.
The secondary efficacy endpoints are as follows:

change from baseline up to week 16 in the 
individual components of the Fibromyalgia Impact 
Questionnaire Revised (FIQR): symptom subscore, 
impact subscore, and functional subscore score

responder rate of the Patient Global Impression of 
Change (PGIC) rating (percentage of patients much 
improved or very much improved) up to week 16

the percentage of patients who experience a 
≥30% reduction in the weekly average of the daily 
average PI-NRS score up to week 16

the percentage of patients who experience a 
≥50% reduction in the weekly average of the daily 
average PI-NRS score up to week 16

change from baseline up to week 16 in the weekly 
average of the daily worst PI-NRS score over the 
past 24 hours

change from baseline up to week 16 in the 
Patient-Reported Outcomes Measurement 
Information System (PROMIS) Sleep Disturbance 
Short Form (SF) 8a score

change from baseline up to week 16 in the 
PROMIS Physical Function SF12a score

change from baseline up to week 16 in the 
PROMIS Fatigue SF8a score

number (%) of patients who did not complete the 
treatment (Kaplan-Meier Survival Analysis) due to 


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Objectives
Endpoints
lack of efficacy
A secondary objective of the 
study is to evaluate the safety 
and tolerability of 
fremanezumab administered 
subcutaneously in adult 
patients with FM.
The safety and tolerability endpoints are as follows:

occurrence of adverse events

change from randomization up to week 16 in the 
clinical laboratory tests (serum chemistry, 
hematology, and urinalysis)

change from baseline up to week 16 in vital signs 
(pulse, respiratory rate, systolic and diastolic blood 
pressure, and oral body temperature measurements 
at each visit)

clinically significant changes in physical 
examination, including body weight

abnormal standard 12-lead electrocardiogram 
(ECG) findings

tolerability at the injection site including but not 
limited to pain, erythema, induration, and 
ecchymosis

occurrence of hypersensitivity/anaphylaxis 
reactions using standardized criteria (Appendix C)

suicidal ideation and behavior as measured by the 
Columbia-Suicide Severity Rating Scale (C-SSRS)

number (%) of patients who did not complete the 
treatment (Kaplan-Meier Survival Analysis) due to 
adverse events
2.1.1.
Justification of Primary Endpoint
The change from baseline in the weekly average of the daily average PI-NRS score over the past 
24 hours is a well-established and Food and Drug Administration-accepted endpoint in clinical 
studies of chronic pain, including FM. The PI-NRS is a validated numerical pain rating 
scale-based outcome measure (Arnold et al 2015, Farrar et al 2010).


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2.2.
 
 
 
 
 
 
 
 
 
 
 
2.3.
Immunogenicity Objective and Endpoint
The immunogenicity objective and endpoint are as follows:
Objective
Endpoint
To evaluate the immunogenicity 
of fremanezumab and the 
impact of anti-drug antibodies 
(ADAs) on clinical outcomes 

incidence and characteristics of ADAs (eg, titers, 
kinetics, and neutralizing activities)


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3.
STUDY DESIGN
3.1.
General Study Design and Study Schematic Diagram
This is a 21-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group 
study to evaluate the efficacy and safety of fremanezumab in adult patients with FM. 
Fremanezumab 225 mg, fremanezumab 675 mg, or placebo will be administered sc for 
4 monthly doses. The study will consist of a 17- to 35-day screening period (Visit 1, phone 
contact, and Baseline Assessment Period Start [BAPS] Visit [Visit 2]), and a 16-week 
double-blind treatment period (Visits 3, 4, 5, 6, and 7). Patients enrolled in the study will be male 
or female patients with FM. Patients will be required to wash out of all prohibited concomitant 
medication(s) prior to the BAPS Visit (Visit 2).
Therefore, the total duration of patient participation in the study is planned to be 21 weeks, 
consisting of the screening period of up to 5 weeks (ranging from 17 to 35 days) and the 
double-blind treatment period of 16 weeks; details are given in Section 5.
The end-of-study (EOS) is defined as completion of the last visit of the last patient.
The study duration will be from May 2019 until approximately July 2022.
For Coronavirus Disease 2019 (COVID-19) updates, see Appendix O.
The study schematic diagram is presented in Figure 1.


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Figure 1:
Overall Study Schematic Diagram
a The screening period is up to 5 weeks and can range from 17 to 35 days. The duration of the washout period will be 
7 to 19 days; suggested washout periods for commonly used analgesics are listed in Table 4.
Note: For Visits 4 and 5 (when at-home dosing is available), home visits are permitted for patients who are not able 
to go to the investigational center or if the investigational center staff are not able to see patients at the 
investigational center (see Section 3.5).
BAPS = Baseline Assessment Period Start; COVID-19 = Coronavirus Disease 2019; e-diary = electronic diary; 
EOS = end-of-study; EOT = end-of-treatment; PK = pharmacokinetic; sc = subcutaneous; V = visit. 
3.2.
Planned Number of Patients and Countries
Approximately 240 patients will be randomized.
The study is planned to be conducted in the United States of America in approximately 
40 investigational centers. 
3.3.
Justification for Study Design and Selection of Population
The 2016 ACR Classification Criteria for diagnosis of FM will be utilized to ensure that the 
study’s patient population is representative of current practice. Although these have been less 
widely used than past criteria, specifically within clinical studies of FM, these current criteria 
avoid regional pain disorder misclassification and eliminate the restriction of diagnosis to 


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patients who have no other condition that would explain their widespread pain (Wolfe et al 
2016).
A randomized, double-blind, placebo-controlled, parallel-group design has been chosen because 
this study design best controls for bias. A crossover study design is not feasible given the long 
half-life of fremanezumab. The use of placebo is necessary because there is no alternative 
method for controlling for placebo effects. In order to assess a possible dose response, both a 
225-mg and a 675-mg dose regimen have been included.
To maintain full blinding, reduce bias, improve scientific integrity, and increase assay sensitivity, 
a Concealed Protocol approach will be used. All study sites and staff will be blinded to eligibility 
criteria for randomization, treatment randomization, and the timing of the primary endpoint. 
Investigators, site personnel, and study staff (ie, contract research organization [CRO]) will work 
from the Concealed Protocol.
Patients will be randomly assigned to treatment groups by means of a computer-generated 
randomization list. This system will be used to ensure a balance across treatment groups; no 
effort will be made to maintain a balance among treatment groups within a study site.
The doses planned for administration at Visits 3 (1st dose), 4, 5, and 6 for patients randomized to 
receive fremanezumab 225 mg, fremanezumab 675 mg, or placebo will require administration of 
three 1.5-mL sc injections. In order to blind the treatment groups based on both dose volume and 
number of injections, patients will receive the following injection schedule:
Fremanezumab
225 mg
Fremanezumab
675 mg
Placebo
Visits 3 to 6
1× 1.5 mL sc 225 mg 
active drug
2× 1.5 mL sc placebo
3× 1.5 mL sc 225 mg 
active drug
3× 1.5 mL sc placebo
3.4.
Stopping Rules for the Study
There are no formal rules for early termination of this study. During the conduct of the study, 
serious adverse events will be reviewed (Section 7.1.5) as they are reported from the 
investigational centers to identify safety concerns.
The study may be terminated by the sponsor for any reason at any time. For example, the 
sponsor should terminate the study in the event of:

new toxicological or pharmacological findings or safety issues that invalidate the 
earlier positive benefit-risk assessment

discontinuation of the development of the IMP
If the whole study or specific arms of the study will be stopped, the patients that are terminated 
early will be followed according to Section 4.3.


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3.5.
Schedule of Study Procedures and Assessments
Study procedures and assessments with their time points are presented in Table 1. Detailed 
descriptions of each method of procedures and assessments are provided in Section 6 (efficacy 
assessments), Section 7 (safety assessments), and Section 8 (pharmacokinetic and other 
assessments). Study procedures and assessments by visit are listed in Appendix B.
Central surveillance monitoring will be carried out in real time, and a data review coordinator 
will perform daily review of the blinded data (eg, e-diary) to identify missing or conflicting data 
so that corrective action may be implemented as quickly as possible.
For Visits 4 and 5 (when at-home dosing is available), home visits are permitted for patients who 
are not able to go to the investigational center or if the investigational center staff are not able to 
see patients at the investigational center. Home visits may be completed by a Home Care 
Visiting Service Provider (ie, home care, visiting nurse, or other medical professional) under 
supervision by the investigational center staff, as required, to complete assessments/procedures. 
The Home Care Visiting Service Provider will be a centralized provider identified by the 
sponsor. The investigational center must contact the sponsor before any home visits are initiated. 
Home visits will be documented.
Visits should be conducted in accordance with the timelines specified in the protocol (see 
Table 1), whenever feasible. Averting a missed visit is considered a high priority. Therefore, if 
additional time is required beyond the specified visit window to complete the visit, the Medical 
Monitor should be contacted, and the visit window may be extended for appropriate reasons. In 
such instances, the reasons for deviation in the date of the visit will be clearly documented.


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Table 1:
Study Procedures and Assessments
Study Period
Screening Period
(up to 5 weeks [17 to 35 days])a
Double-Blind Treatment Period (16 weeks)
Screening 
Visit
Phone 
Contact
(Washout)b
Baseline 
Assessment 
Period
Randomization
(Dose 1)
Dose 2
Dose 3
Dose 4
Visit number
V1
Phone 
Contact
V2
(BAPS Visit)
V3
V4c
V5c
V6
V7 
(EOT/EOS or ET)
Day and allowed time 
windows
Week -5
Day -35
Day -33 
through
Day -15
Day -14
(±2 days)
Day 1
Day 29
±7 days
Day 57
±7 days
Day 85
±7 days
Day 113
±7 days
Procedures and 
assessmentsd, e
Screening
Scheduling 
and 
Instructionsf
BAPS Visit
W 1
W 4
W 8
W 12
W 16
Informed consent
X
Inclusion and exclusion 
criteria
X
X
X
Medical and psychiatric 
history
X
Record demographic 
characteristics
X
Pain reporting (tablet) 
trainingg
X
X
X
X
X
X
E-diary trainingh
X
X
X
X
X
X
Dispense/account/
collect rescue medication 
(APAP)i
X
X
X
X
X
X
X
Prior medication tapering
X
Assign randomization/ 
treatment number
X


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Study Period
Screening Period
(up to 5 weeks [17 to 35 days])a
Double-Blind Treatment Period (16 weeks)
Screening 
Visit
Phone 
Contact
(Washout)b
Baseline 
Assessment 
Period
Randomization
(Dose 1)
Dose 2
Dose 3
Dose 4
Visit number
V1
Phone 
Contact
V2
(BAPS Visit)
V3
V4c
V5c
V6
V7 
(EOT/EOS or ET)
Day and allowed time 
windows
Week -5
Day -35
Day -33 
through
Day -15
Day -14
(±2 days)
Day 1
Day 29
±7 days
Day 57
±7 days
Day 85
±7 days
Day 113
±7 days
Procedures and 
assessmentsd, e
Screening
Scheduling 
and 
Instructionsf
BAPS Visit
W 1
W 4
W 8
W 12
W 16
PI-NRSj
X
X
X
ACR 2016 WPIk
X
ACR 2016 SSk
X
MINI
X
Prior medication and 
treatment history
X
X
X
Clinical laboratory tests 
(serum chemistry, 
hematology, and 
urinalysis)l
X
X
X
X
Urine drug screen
X
X
X
X
X
X
X
Alcohol (social history)m
X
Marijuana (cannabis), 
cannabidiol, or other 
cannabinoids (medicinal 
and social history)
X
Physical examinationn, o
X
X
X
X
X
X
X


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Study Period
Screening Period
(up to 5 weeks [17 to 35 days])a
Double-Blind Treatment Period (16 weeks)
Screening 
Visit
Phone 
Contact
(Washout)b
Baseline 
Assessment 
Period
Randomization
(Dose 1)
Dose 2
Dose 3
Dose 4
Visit number
V1
Phone 
Contact
V2
(BAPS Visit)
V3
V4c
V5c
V6
V7 
(EOT/EOS or ET)
Day and allowed time 
windows
Week -5
Day -35
Day -33 
through
Day -15
Day -14
(±2 days)
Day 1
Day 29
±7 days
Day 57
±7 days
Day 85
±7 days
Day 113
±7 days
Procedures and 
assessmentsd, e
Screening
Scheduling 
and 
Instructionsf
BAPS Visit
W 1
W 4
W 8
W 12
W 16
Electrocardiographyp, q
X
X
X
X
Vital signs measurementr
X
X
X
X
X
X
X
Serum β-HCG test for 
women
X
Urine pregnancy test for 
WOCBPs
X
X
X
X
X
X
FSHt
X
Inform patients of study 
restrictions and 
compliance requirements
X
X
X
X
X
X
Assess concomitant 
medication
X
X
X
X
X
X
X
X
Provide e-diary
X
Review study complianceu
X
X
X
X
X
X
EQ-5D-5L (tablet)
X
X
X
X
X
X
HADS (tablet)
X
X
X
X
X
X
X


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Study Period
Screening Period
(up to 5 weeks [17 to 35 days])a
Double-Blind Treatment Period (16 weeks)
Screening 
Visit
Phone 
Contact
(Washout)b
Baseline 
Assessment 
Period
Randomization
(Dose 1)
Dose 2
Dose 3
Dose 4
Visit number
V1
Phone 
Contact
V2
(BAPS Visit)
V3
V4c
V5c
V6
V7 
(EOT/EOS or ET)
Day and allowed time 
windows
Week -5
Day -35
Day -33 
through
Day -15
Day -14
(±2 days)
Day 1
Day 29
±7 days
Day 57
±7 days
Day 85
±7 days
Day 113
±7 days
Procedures and 
assessmentsd, e
Screening
Scheduling 
and 
Instructionsf
BAPS Visit
W 1
W 4
W 8
W 12
W 16
FIQR (tablet)
X
X
X
X
X
X
PGIC (tablet)
X
X
PROMIS Physical 
Function SF12a (tablet)
X
X
X
X
X
X
PROMIS Fatigue SF8a
(tablet)
X
X
X
X
X
X
PROMIS Sleep 
Disturbance SF8a 
(e-diary)v
X
IMD (tablet)w
X
X
X
Blood samples for plasma 
concentration of IMPx
X
X
X
Blood samples for serum 
ADA concentrationy
X
X
X
 
 
X
X
X


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Study Period
Screening Period
(up to 5 weeks [17 to 35 days])a
Double-Blind Treatment Period (16 weeks)
Screening 
Visit
Phone 
Contact
(Washout)b
Baseline 
Assessment 
Period
Randomization
(Dose 1)
Dose 2
Dose 3
Dose 4
Visit number
V1
Phone 
Contact
V2
(BAPS Visit)
V3
V4c
V5c
V6
V7 
(EOT/EOS or ET)
Day and allowed time 
windows
Week -5
Day -35
Day -33 
through
Day -15
Day -14
(±2 days)
Day 1
Day 29
±7 days
Day 57
±7 days
Day 85
±7 days
Day 113
±7 days
Procedures and 
assessmentsd, e
Screening
Scheduling 
and 
Instructionsf
BAPS Visit
W 1
W 4
W 8
W 12
W 16
Adverse events inquiryaa
X
X
X
X
X
X
X
C-SSRSbb
X
X
X
X
X
X
X
Administration of IMP
X
X
X
X
Review e-diaries
X
X
X
X
X
X
Collect patient e-diary
X
a The Screening Visit should occur no more than 35 days before randomization. The screening period should be a minimum duration of 17 days (if no washout 
period is required), and the length of the screening period will be contingent on the duration of the washout period for the prohibited medication.
b Patients will be instructed to start the washout period during the screening period phone contact. The duration of the washout period will be 7 to 19 days; 
suggested washout periods for commonly used analgesics are listed in Table 4. Laboratory values will be checked prior to the phone call by the investigator. 
Visit 2 will be scheduled and the monitoring plan for washout will be defined by the investigator. The washout period will need to be completed before the 
BAPS Visit (Visit 2). Training and Instructions will be provided to patients regarding the monitoring of withdrawal symptoms during the washout period.
c For Visits 4 and 5 (when at-home dosing is available), home visits are permitted for patients who are not able to go to the investigational center or if the 
investigational center staff are not able to see patients at the investigational center (see Section 3.5).
d All assessments listed before IMP administration in the Study Procedures and Assessments are to be performed before IMP administration.
e For unscheduled visits, procedures and assessments will be completed as needed, at the investigator’s discretion. For further details, see Appendix B. 
f Patients who do not require a washout may be scheduled for the BAPS Visit (Visit 2) following review by the Fibromyalgia Eligibility Review Committee 
(Section 5.8.1).
g Training patients on accurate pain reporting and placebo response reduction on the site’s tablet will occur at Screening (Visit 1), the BAPS Visit (Visit 2), and 
as needed for subsequent retraining throughout the study.


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h Training for the e-diary will occur at Screening (Visit 1), the BAPS Visit (Visit 2), and as needed for subsequent retraining throughout the study. Site personnel 
will also instruct patients on the requirement for timely and daily completion of the e-diary. During the BAPS Period, a minimum of 12 of 14 days’ compliance 
with e-diary recording is required. At least 75% compliance with e-diary recordings on a weekly basis is expected after the randomization period. Site 
personnel will monitor patients’ compliance that e-diary entry is at least 75% every week during the double-blind treatment period. If weekly 75% compliance 
is not maintained, a reminder and any other corrective actions, as deemed necessary, will be issued to the patient.
i Rescue medication will need to be brought back to the investigational center (or reviewed in the patient’s home if a home visit is conducted at Visit 4 and/or 
Visit 5) for pill counts at each visit. Collect, perform accountability, and re-dispense at all visits. Final collection is at the EOT/EOS or ET Visit (Visit 7) or at 
the Randomization Visit (Visit 3) if the patient is not randomized. From the BAPS Visit (Visit 2) onward, if the patient needs rescue medication, their pain 
intensity score should be entered into the e-diary before taking the rescue medication.
j At screening, patients will record their average pain over the past 7 days using the site’s tablet. For the baseline assessment period (ie, between the BAPS Visit 
[Visit 2] and the Randomization Visit [Visit 3]) and the double-blind treatment period, patients will record their daily average pain intensity score and daily 
worst pain intensity score using the PI-NRS in the e-diary every evening at approximately the same time between 1800 and 2200 hours. Pain intensity scores 
will be entered in the e-diary prior to every use of rescue medication.
k The 2016 ACR diagnostic criteria for fibromyalgia (Wolfe et al 2016) must be met at the Screening Visit.
l Clinical laboratory tests will include serum chemistry, hematology, urinalysis, and urine drug screen. HIV, HBsAg, hepatitis C antibody, and TSH will also be 
completed only at the Screening Visit (Visit 1).
m Alcohol screening will be done by query of alcohol consumption history.
n Height and weight will be obtained at the Screening Visit. Weight only will be obtained during each physical examination.
o A full physical examination will be conducted at Screening (Visit 1). Physical examinations will be abbreviated and supplemented by the collection of AEs and 
SAEs at Visits 2 to 7.
p A single ECG will be performed.
q Procedure will be performed before other assessments (eg, blood draws and administration of questionnaires).
r Vital signs, including heart rate, respiratory rate, oral body temperature, and blood pressure, will be measured after ECGs and before scheduled blood draws, 
when applicable. Additionally, vital signs must be recorded immediately in case of suspected anaphylaxis and severe hypersensitivity.
s A serum pregnancy test may be completed as a confirmatory test, if warranted. In the event pregnancy is confirmed, the IMP will not be administered, and the 
patient will undergo early termination from the study.
t Postmenopausal women only (at least 1 year since last menses and FSH level above 35 U/L).
u Review of study compliance includes review of e-diary recordings, rescue medication use, concomitant medication use, and use of non-pharmacologic 
therapies (including normal daily exercise routines, chiropractic care, physical therapy, psychotherapy, and massage therapy).
v The PROMIS Sleep Disturbance SF8a (e-diary) should be performed weekly on awakening. Collection of the PROMIS Sleep Disturbance SF8a will start the 
day of the BAPS Visit (Visit 2) to assess the previous week’s sleep and is completed in the e-diary. 
w At the Screening Visit (Visit 1), the IMD (tablet) will be administered by the investigator; any condition that the patient has been diagnosed with will be 
recorded. At Visit 6 and the EOT/EOS or ET Visit (Visit 7), the IMD will be administered by the investigator; any condition recorded at Visit 1 will be 
assessed for improvement or non-improvement.
x Blood samples (4 mL) for plasma drug concentration will be collected at designated visits. Blood samples will be collected before dosing when IMP is 
administered. Samples from patients who were randomized to receive placebo will not be analyzed.
y Blood samples (5 mL) for serum ADA assessment will be collected prior to dosing at the designated visits, as well as upon observation of any severe 
hypersensitivity reaction or anaphylaxis. Samples from patients who were randomized to receive placebo will not be analyzed.


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z
 
aaAdverse events will be captured from the time informed consent is signed until end-of-study. Postdose inquiries will be made before the patient leaves the 
investigational center.
bbThe C-SSRS Baseline/Screening version will be completed at Visit 1, and the C-SSRS Since Last Visit version will be completed at all other time points.
ACR = American College of Rheumatology; ADA = anti-drug antibody; AE = adverse event; APAP = acetaminophen; β-HCG = beta-human chorionic 
gonadotropin; BAPS = Baseline Assessment Period Start; C-SSRS = Columbia-Suicide Severity Rating Scale; ECG = electrocardiogram; e-diary = electronic 
diary; EOS = end-of-study; EOT = end-of-treatment; EQ-5D-5L = EuroQol-5D-5L; ET = early termination; FIQR = Fibromyalgia Impact Questionnaire 
Revised; FSH = follicle-stimulating hormone; HADS = Hospital Anxiety and Depression Scale; HBsAg = hepatitis B surface antigen; HIV = human 
immunodeficiency virus; IMD = Inventory of Medical Diagnoses; IMP = investigational medicinal product; MINI = Mini-International Neuropsychiatric 
Interview; PGIC = Patient Global Impression of Change; PI-NRS = Pain Intensity-Numerical Rating Scale; PROMIS = Patient-Reported Outcomes Measurement 
Information System; SAE = serious adverse event; SF = Short Form; SS = symptom severity; TSH = thyroid stimulating hormone; V = visit; WOCBP = women 
of childbearing potential; WPI = widespread pain index.


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3.6.
e-Diary and Tablet Data Collection
The primary data collection tools that will be used in this study are the e-diary and the tablet, 
administered by 
 (Appendix A).
3.6.1.
e-diary
The e-diary will be dispensed to each patient at the BAPS Visit (Visit 2). The e-diary will be 
used to record the following data:

Average PI-NRS rating

Worst PI-NRS rating

At-the-moment PI-NRS rating

Rescue medication use

Amount of rescue medication used for a specific breakthrough pain episode

Time of rescue medication used for a specific breakthrough pain episode

PROMIS Sleep Disturbance SF8a (Morning Report only)
The e-diary will be completed per the Study Procedures and Assessments (Table 1). The e-diary 
will contain the following reports, which will guide the patient through completion of the 
necessary data collection on any respective day during the study: Evening Report, Make-up 
Evening Report, Morning Report, and Make-up Morning Report. The Evening Report will be 
available to patients each evening for completion between 1800h and 2200h. The Evening 
Report will have audible alarms that will sound at 3 different times before the entry window 
expires or upon completion of the report. If a patient cannot complete or forgets to complete the 
Evening Report, a Make-up Evening Report will become available for completion between 
0300h and 1300h the next day. The Make-up Evening Report will also have audible alarms that 
will sound 3 times during this interval but will cease to sound upon completion of the report.
The Morning Report will be available to patients for completion between 0300h and 1300h on 
the respective day as scheduled in Table 1. The Morning Report will have audible alarms that 
will sound at 3 different times during this interval but will cease to sound upon completion of the 
report. If a patient cannot complete or forgets to complete the Morning Report, a Make-up 
Morning Report will become available for completion between 1800h and 2200h the same day. 
The Make-up Morning Report will not have separate audible alarms because it becomes 
available during the same time interval as the Evening Report for that day, which does have 
audible alarms.
The Rescue Medication tab will be available to patients 24 hours per day; tapping this tab will 
automatically display all required information for the patient to complete. The e-diary main 
menu will have tabs for each of the aforementioned reports, which the patient will tap to access 
the respective report. Patients will be trained by the site staff on the use of the e-diary at Visits 1 
and 2, and as needed for subsequent retraining throughout the study. Additional information on 
the e-diary can be found in the Study Manual.


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3.6.2.
Tablet
The tablet will be dispensed to each clinical site. Patients and study site staff will use the tablet at 
their visits to complete the required assessments. The tablet will be used to record the following 
information:

FIQR

PGI-C

PROMIS 12a Physical Function

PROMIS Fatigue SF8a

EQ-5D-5L

HADS

IMD
The tablet assessments will be completed per the Study Procedures and Assessments (Table 1). 
Additional information collected on the tablet only at the Screening Visit includes the 
patient-reported average PI-NRS rating over the past 7 days. The tablet main menu will contain 
individual tabs for each of the visits. Assessments will be completed by study site staff and/or the 
patient at the study site in the same order. Patients will be trained by the site staff via the tablet 
on accurate pain reporting and placebo response reduction at Visits 1 and 2, and as needed for 
subsequent retraining throughout the study. Additional information on the tablet can be found in 
the Study Manual.


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4.
SELECTION AND EARLY TERMINATION OF PATIENTS
Prospective waivers (exceptions) from study inclusion and exclusion criteria to allow patients to 
be randomized/enrolled will not be granted by Teva or the Medical Monitor.
Changes to inclusion or exclusion criteria are indicated below and detailed in Section 16.
4.1.
Patient Inclusion Criteria
Patients may be randomized/enrolled in this study only if they meet all of the following criteria:
a.
approved for study participation by the Fibromyalgia Eligibility Review Committee 
(Section 5.8.1)
b. capable of giving signed informed consent
c.
agree to comply with the requirements and restrictions listed in this protocol, 
including remaining at the clinic for the duration of each required visit during the 
study period to complete all scheduled procedures and assessments
d. male or female between ≥18 to 75 years old at screening (inclusive) with FM
e.
willing to comply with recording of once daily scores using the PI-NRS, completed 
every evening (approximately the same time each day) starting at the BAPS Visit 
(Visit 2) and continuing to the end-of-treatment (EOT)/EOS or early termination (ET) 
Visit (Visit 7). A minimum of 12 of 14 daily average pain intensity ratings AND daily 
worst pain intensity ratings are required to be recorded in an e-diary during the 
baseline assessment period (Section 3.6.1).
f.
all of the following diagnostic criteria for FM according to 2016 American College of 
Rheumatology (Wolfe et al 2016) are met at the Screening Visit:

Generalized pain, defined as pain in at least 4 of 5 regions, is present.

Symptoms have been present at a similar level for at least 3 months.

WPI ≥7 and SS scale score ≥5 OR WPI of 4 to 6 and SS scale score ≥9.

A diagnosis of FM is valid irrespective of other diagnoses. A diagnosis of FM 
does not exclude the presence of other clinically important illnesses.
g. PI-NRS score ≥4 in average daily FM pain assessed by self-report over the past week 
at Screening Visit
h. body mass index of 18.5 to 45 kg/m2 and a body weight ≥45 kg
i.
agree to use only acetaminophen as rescue medication for FM-related pain (up to 
1000 mg per dose and not to exceed 3000 mg/day for any indication throughout the 
study period)
j.
non-pharmacologic interventions (including normal daily exercise routines, 
chiropractic care, physical therapy, psychotherapy, and massage therapy) are 
unchanged for a minimum of 30 days prior to screening and will remain unchanged 
throughout the study


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k. agree not to initiate or modify any non-pharmacological or pharmacological 
interventions for FM from washout through the EOT/EOS or ET Visit
l.
agree to maintain a usual and unchanged physical exercise regimen
m. [Revision 1] must meet the following pregnancy-related criteria:

females must have a negative serum beta-human chorionic gonadotropin (β-HCG) 
test at screening or be sterile or postmenopausal; definitions of sterile and 
postmenopausal are provided in Appendix F

females of childbearing potential whose male partners are potentially fertile (ie, 
no vasectomy) must use highly effective birth control methods for the duration of 
the study (ie, starting at screening) and for 6 months after the last dose of the 
IMP; further details are provided in Appendix F

males who are potentially fertile/reproductively competent (not surgically [eg, 
vasectomy] or congenitally sterile), and their female partners are of childbearing 
potential, should use highly effective birth control methods for the duration of the 
study (ie, starting at screening); further details are provided in Appendix F
n. must agree not to participate in another interventional study from the screening period 
through the EOT/EOS or ET Visit 
4.2.
Patient Exclusion Criteria
Patients will not be randomized/enrolled in this study if they meet any of the following criteria:
a.
unable or unwilling to discontinue/washout of prohibited medications (Appendix I);
Note: Medications used to treat depression or anxiety are permitted provided they 
were started at least 90 days prior to screening, have been used at a stable dose for at 
least 90 days, and will be maintained at that dose for the duration of the study. 
Therefore, both over-the-counter (OTC) medications used to treat depression or 
anxiety and selective serotonin reuptake inhibitors (SSRIs; with the exception of 
≥60 mg/day of fluoxetine) are permitted.
b. in the investigator’s opinion, history of no meaningful improvement to an adequate 
trial of 2 or more different pharmacological classes of medications indicated for FM 
adequate dosing for an adequate period of time
c.
ongoing pain that would confound or interfere with the assessment of the patient’s 
FM pain or require excluded therapies during the patient’s participation in this study. 
Other sources of pain may include, but are not limited to, neuropathic pain 
attributable to an identifiable cause, post-herpetic neuralgia, traumatic injury, prior 
surgery, complex regional pain syndrome or failed back syndrome, infections or 
inflammatory arthritis (eg, rheumatoid arthritis [RA], ankylosing spondylitis, 
psoriatic arthritis, gout), other autoimmune diseases (eg, systemic lupus 
erythematosus), and other widespread rheumatic diseases (widespread osteoarthritis 
[OA]). Localized OA is permitted as long as it is subclinical (which does not require 
treatment with an analgesic[s]).
d. surgery planned during the study period


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e.
receiving prophylactic treatment for migraine-related disorders, including topiramate, 
valproic acid, onabotulinumtoxinA, amitriptyline, and nortriptyline
f.
known history of clinically significant or unstable hematological, cardiac, or 
thromboembolic events (ie, arterial or venous thrombotic or embolic events, including 
cerebrovascular accident [including transient ischemic attacks], deep vein thrombosis, 
or pulmonary embolism); renal, endocrine, pulmonary, gastrointestinal, genitourinary, 
or neurologic disorders [exclusive of FM]; infectious, hepatic, or ocular disease, at 
the discretion of the investigator, as determined by a medical and psychiatric history; 
and physical examination, 12-lead ECG, serum chemistry, hematology, coagulation, 
and urinalysis). Abnormal test results may be repeated for confirmation.
g. moderate or severe major depressive symptoms as assessed by the HADS Depression 
Subscore >14 (at the Screening Visit and/or the BAPS Visit)
h. known history of suicide attempt, suicidal behavior, or suicidal ideation within the 
last 12 months (a response of “yes” to questions 4 or 5 on the suicidal ideation portion 
of the C-SSRS), or have been assessed as a significant risk to commit suicide at the 
Screening Visit or Randomization Visit
i.
lifetime history of any psychotic and/or bipolar disorder as assessed by the MINI
j.
current, untreated, moderate or severe major depressive disorder and/or anxiety 
disorder as assessed by the MINI. Patients with currently treated major depressive 
disorder and/or anxiety disorder can be included, provided that according to the 
investigator’s judgment, there have been no clinically significant changes in 
symptoms while on a stable dose of allowed antidepressants or antianxiety 
medications for at least 90 days prior to screening, and that the dosage of 
antidepressant or antianxiety medication will be maintained for the duration of the 
study.
k. current eating disorders as assessed by the MINI
l.
known infection or history of human immunodeficiency virus, tuberculosis, or 
chronic hepatitis B or C infection, or are antigen positive for hepatitis B at screening
m. past or current history of cancer in the past 5 years, except for appropriately treated 
non-melanoma skin carcinoma (basal carcinoma)
n. known history of hypersensitivity reactions to injected proteins, including mAbs and 
animal venoms, or a history of Stevens-Johnson Syndrome/toxic epidermal necrolysis 
syndrome
o. known history of hypersensitivity or intolerance to the use of acetaminophen
p. known hypersensitivity or intolerance to the components in the formulation of 
fremanezumab
q. participation in an interventional clinical study of a chemical entity or device within 
2 months or 5.5 half-lives (whichever is longer) prior to IMP administration
r.
participation in an interventional clinical study of a mAb within 3 months or 
5.5 half-lives (whichever is longer) prior to IMP administration


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s.
any prior exposure to mAbs targeting the CGRP pathway (including erenumab, 
eptinezumab, galcanezumab, or fremanezumab) at any time. If the patient has 
participated in a clinical study with any of these mAbs, it has to be confirmed that the 
patient received placebo in order to be eligible for this study.
t.
clinically significant elevations in hepatic enzymes (alanine aminotransferase [ALT] 
or aspartate aminotransferase [AST]) based on the upper limit of normal (ULN) or 
investigator judgment, which have been reconfirmed on a repeat test 
u. suspected hepatocellular damage that fulfills criteria for Hy's law at screening
v. serum creatinine >1.5× ULN, clinically significant proteinuria, or evidence of renal 
disease at screening
w. known history of alcohol and/or drug abuse within the past 12 months per the MINI 
or have a positive urine drug screen for illegal drugs of abuse at the Screening Visit, 
BAPS Visit, or prior to randomization
x. [Revision 1] if using marijuana (cannabis), meets the MINI (v.7.0.2) criteria for 
greater than mild substance use disorder for marijuana (cannabis), cannabidiol, or 
other cannabinoids during the preceding 12 months; and/or the investigator is 
concerned that the use of marijuana (cannabis), cannabidiol, or other cannabinoids
could interfere with a subject’s ability to provide reliable data or comply with the 
protocol
y. diagnosed with uncontrolled sleep apnea
z. employee of Teva Pharmaceuticals, the CRO involved, or the investigative site 
personnel directly affiliated with this study and/or immediate family member (spouse, 
parent, child, or sibling, whether biological or legally adopted, or legal 
guardian/custodian)
aa. involved in an active workers compensation case or is currently filing or seeking a 
work disability claim for any reason or condition
bb. currently experiencing acute, severe psychosocial stress (ie, recent death of a loved 
one, divorce)
cc. any condition or situation (ie, shift work) that, in the investigator’s opinion, makes the 
patient unsuitable for study participation
dd. [New criterion] has received any CGRP pathway targeting treatment or compound 
(anti-CGRP antibodies, anti-CGRP receptor antibodies, or CGRP receptor 
antagonists/oral gepants) for migraine
ee. [New criterion] the patient is a pregnant or nursing female or plans to become 
pregnant during the study, including the 6-month period after the administration of 
the IMP


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4.3.
Discontinuation from IMP/Early Termination from Study Criteria 
and Procedures for the Patient
There are no study-specific patient discontinuation/early termination criteria and procedures. The 
following general criteria apply.
Each patient is free to terminate from the study or discontinue from IMP at any time, without 
prejudice to their continued care. Patients must undergo early termination from the study if any 
of the following events occur:
1. Patient withdraws consent or requests discontinuation from the IMP or early termination 
from the study for any reason.
2. Patient develops an illness that would interfere with his/her continued participation.
3. Patient is noncompliant with the study procedures and assessments or administration of 
IMPs in the opinion of the investigator.
4. Patient takes prohibited concomitant medications as defined in this protocol.
5. A female patient has a confirmed pregnancy during the study based on a positive 
pregnancy test result (positive urine pregnancy tests will need a blood β-HCG 
confirmation of the result).
6. Patient experiences an adverse event or other medical condition, which indicates to the 
investigator that continued participation is not in the best interest of the patient.
7. The investigator and/or sponsor may terminate an individual patient from the study at any 
time for any reason (eg, lack of efficacy, protocol deviation, noncompliance, or adverse 
event). In addition, patients with hypersensitivity reactions, positive C-SSRS, positive 
HADS findings, or abnormal hepatic laboratory values along with bilirubin increases that 
are consistent with hepatic injury may meet criteria for discontinuation from the IMP.
Efficacy endpoints (primary, secondary, 
) will be derived from subjective pain 
ratings collected daily using an e-diary. Eligible patients will receive comprehensive training
from site personnel on the correct use of the e-diary. Site personnel will also instruct patients on 
the requirement for timely and daily completion of the e-diary. At least 75% compliance with 
e-diary recordings on a weekly basis is expected after the randomization visit. Site personnel will 
monitor patients’ compliance that e-diary entry is at least 75% every week during the double-
blind treatment period. If weekly 75% compliance is not maintained, a reminder and any other 
corrective actions, as deemed necessary, will be issued to the patient (Section 3.6.1).
In the following circumstances, the IMP will be discontinued immediately:
1. any increase in ALT or AST to ≥3× the ULN, combined with INR >1.5× the ULN or 
total bilirubin >2× the ULN
2. 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)


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3. any increase in ALT or AST to levels ≥5 but <8× the ULN, which is persistent for 
≥2 weeks of repeated measurements
4. any increase in ALT or AST to levels ≥8× the ULN
5. in any case where monitoring of liver enzymes cannot be performed according to the 
protocol guidance
Patients should be treated with standard of care after discontinuation from IMP or early 
termination of the study, as appropriate. All protocol-specified procedures/assessments should be 
performed at the EOT/EOS or ET Visit (Visit 7) (see Table 1).
Investigators should attempt to obtain information on patients in the case of early termination 
from the study or discontinuation from IMP (EOT/early termination; see Appendix B). Results of 
any evaluations and observations, together with a narrative describing the reason(s) for early 
termination from the study or discontinuation from IMP, must be recorded in the source 
documents. The electronic case report form (eCRF) must document the primary reason for early 
termination from the study or discontinuation from IMP.
See Appendix G for information regarding how the study will define and address lost to 
follow-up patients to help limit the amount and impact of missing data.
If the reason for early termination from the study or discontinuation from IMP is an adverse 
event and/or clinically significant abnormal laboratory test result, monitoring will be continued 
as applicable (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 IMP or study 
procedure is made). The specific event or test result (including repeated test results, as 
applicable) must be recorded both on the source documentation and in the eCRF; both the 
adverse events page and the relevant page of the eCRF will be completed at that time.
The investigator must inform the Study Leader as soon as possible of each patient who is being 
considered for early termination due to adverse events. Additional reports must be provided 
when requested.
If a patient early terminates from the study or discontinues IMP for multiple reasons that also 
include adverse events, the relevant page of the eCRF should indicate that the early termination 
was related to an adverse event. An exception to this requirement will be the occurrence of an 
adverse event that in the opinion of the investigator is not severe enough to warrant early 
termination by itself, but that requires the use of a prohibited medication, thereby requiring early 
termination of the patient. In such a case, the reason for termination would be “need to take a 
prohibited medication”, not the adverse event.
In the case of patients lost to follow-up, attempts to contact the patient must be made and 
recorded in the patient’s medical records and entered into the eCRF.
4.4.
Replacement of Patients
A patient who is terminated early from the study will not be replaced.


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4.5.
Rescreening
Rescreening will not be routinely allowed for patients who are screened but not enrolled 
(eg, because eligibility criteria were not met [inclusion criteria not met and/or exclusion criteria 
met]). However, patients who were screened but not enrolled due to technical issues (eg, diary 
malfunction) or are out of Visit 2 window due to urgent extenuating circumstances (eg, public 
health emergency) may be considered for screening one additional time. Only patients who were 
not enrolled due to these limited issues/circumstances may be screened a second time.
If the patient is screened again, a new informed consent form (ICF) will need to be signed and a 
new screening number will be assigned.
For Coronavirus Disease 2019 updates, see Appendix O.
4.6.
Screen Failure
Screening failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomized. Data for screen failure reason and minimal information 
including but not limited to demography, adverse events from the time of informed consent, and 
subject disposition, will be entered into the eCRF.


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5.
TREATMENTS
5.1.
Investigational Medicinal Products Used in the Study
Investigational medicinal product is defined as the test IMPs and matching placebo IMP to the 
test IMP. Patients will receive the IMP at Visits 3, 4, 5, and 6. Patients randomized to the 225 mg 
dose level will receive 1 injection of 225 mg fremanezumab and 2 injections of placebo; patients 
randomized to the 675 mg dose level will receive 3 injections of 225 mg fremanezumab; and 
patients randomized to placebo will receive 3 injections of placebo at each visit.
5.1.1.
Test Investigational Medicinal Product
Fremanezumab is a humanized IgG2Δa/kappa monoclonal antibody derived from a murine 
precursor. Additional details are provided in Table 2 and in the current IB.
5.1.1.1.
Starting Dose and Dose Levels
A high and low dose level will be studied: 675 mg sc monthly and 225 mg sc monthly. For each 
dose regimen, the starting dose will be the same as the subsequent dose. Patients will receive 
either placebo or 1 of 2 IMP dose levels for a total of 3 sc injections at each dosing visit.
The recommended sc injection sites follow the National Institutes of Health (NIH) Clinical 
Center Patient Education Materials (NIH Clinical Center Patient Education Materials 2016). The 
suggested injection site locations for sc administration are the following: back of upper arms, 
lower abdomen/belly/waistline, and front of thighs. The sc injection and location will be 
recorded for each administration visit (Visits 3, 4, 5, and 6). 
5.1.1.2.
Dosing Visits and Dose Modification
Visits 1, 2, 3, and 6 must occur at the study site. For Visits 4 and/or 5 (when at-home dosing is 
available), home visits are permitted for patients who are not able to go to the investigational 
center or if the investigational center staff are not able to see patients at the investigational center 
for any extenuating circumstances (see Section 3.5). After such extenuating circumstances 
resolve, home visits may be permitted to continue.
Doses will be administered at the study site or at home, as applicable, at the time of visits via a 
fixed dose pre-filled syringe; no dose modifications will be allowed. There will be a time 
window for doses that do not occur on the scheduled days. If a scheduled visit cannot occur 
within the ±7-day time window due to extenuating circumstances, the Medical Monitor should 
be contacted to determine if the window can be lengthened. Medical Monitor notification and 
consultation for all missed scheduled visits and related rescheduling and necessary plans of 
action is required.
For COVID-19 updates, see Appendix O.
5.1.2.
Placebo Investigational Medicinal Product
Fremanezumab placebo is the same vehicle as the test IMP formulation but does not contain 
active fremanezumab.


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Table 2:
Investigational Medicinal Products Used in the Study
IMP Name
Test IMP
Placebo IMP
Reference IMP 
Trade name and INN, if applicable, 
or company-assigned number
Fremanezumab; recombinant 
humanized IgG2Δa/kappa mAb 
against CGRP
Fremanezumab placebo
None
Formulation
Solution for injection is a sterile, 
unpreserved, and colorless to slightly 
yellow aqueous solution for sc 
injection for single-use administration. 
The drug product contains 
fremanezumab at 150 mg/mL nominal 
concentration in 16 mM histidine, 
6.6% w/v sucrose, 0.136 mg/mL 
disodium EDTA, 0.02% w/v 
polysorbate 80 at pH 5.5.
Fremanezumab will be provided in 
pre-filled syringes
Fremanezumab placebo is the same 
vehicle as the test IMP formulation but 
does not contain active fremanezumab
Placebo will be provided in uniquely 
numbered kits and stored (refrigerated 
at 2°C to 8°C) on site. Pre-filled 
syringes will contain the same vehicle 
and excipients as those for active 
injection.
Fremanezumab placebo will be 
provided in pre-filled syringes.
Unit dose strength(s)/Dosage level(s)
225 mg/1.5 mL
1.5 mL
Route of Administration
sc administration
sc administration
Packaging
IMP will be provided in a pre-filled 
syringe.
Pre-filled syringe
 
 
Dosing instructions/Dosing 
schedule/Treatment periods
sc fremanezumab or placebo on Visits 3, 4, 5, and 6 (days 1, 29, 57, and 85)
CGRP = calcitonin gene related peptide; EDTA = ethylenediaminetetraacetic acid; IgG = immunoglobulin G; IMP = investigational medicinal product; 
INN = international nonproprietary name; mAb = monoclonal antibody; sc = subcutaneous; w/v = weight/volume.


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5.2.
Preparation, Handling, Labeling, Storage, and Accountability for 
IMPs
5.2.1.
Storage and Security
The investigator or designee must confirm appropriate temperature conditions have been 
maintained for all IMPs received and any discrepancies are reported and resolved before use of 
the IMPs.
The test IMP (fremanezumab) and placebo IMP must be stored refrigerated at 2°C to 8°C 
(36°F to 46°F) and protected from light; the investigational center should have a process for 
monitoring the IMP storage temperature.
Diversion is considered to have occurred when the legal supply chain of prescription medicinal 
products is broken, and medicinal products are transferred from a licit to an illicit channel of 
distribution or use.
5.2.2.
Labeling
Supplies of IMPs will be labeled according to the current International Council for 
Harmonisation (ICH) guidelines on Good Clinical Practice (GCP) and Good Manufacturing 
Practice and will include any locally required statements. If necessary, labels will be translated 
into the local language.
5.2.3.
Accountability
Each IMP shipment will include a packing slip listing the contents of the shipment and any 
applicable forms.
The investigator is responsible for ensuring that deliveries of IMPs and other study materials 
from the sponsor are correctly received, recorded, handled, and stored safely and properly in 
accordance with the Code of Federal Regulations (CFR) or national and local regulations, and 
used in accordance with this protocol.
Only patients enrolled in the study may receive IMPs and only authorized staff at the 
investigational center may supply or administer IMPs. All IMPs must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labeled storage conditions or appropriate instructions with access limited to the investigator and 
authorized staff at the investigational center.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for IMP accountability, reconciliation, and record maintenance (ie, receipt, 
reconciliation, and final disposition records).
A record of IMP accountability (ie, IMP and other study materials received, used, retained, 
returned, or destroyed) must be prepared and signed by the principal investigator or designee, 
with an account given for any discrepancies. Empty syringes must be destroyed at the 
investigational center in accordance with the investigational center’s Standard Operating 
Procedures (SOPs) following sponsor approval. In the event that the investigational center is 
unable to destroy the empty units of IMP, the IMP must be returned to the sponsor or its 


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designee per sponsor instructions. Unused syringes and/or kits are to be returned to the depot for 
destruction.
For visits conducted at the patient’s home, it is the responsibility of the site to ensure the correct 
IMP is provided. If a sharps container is to be supplied to the patient, the site is responsible for 
arranging the container and ensuring it is available to be provided along with the IMP.
Detailed procedures are provided in Appendix H.
5.3.
Justification for Investigational Medicinal Products
5.3.1.
Justification for Dose of Test Investigational Medicinal Product
The fremanezumab doses and dosing regimens to be evaluated in this double-blind study were 
selected on the basis of animal pharmacodynamic and pharmacokinetic data, 
8 pharmacokinetic/safety studies in healthy volunteers, 5 safety/efficacy studies in patients with 
migraine, and population pharmacokinetic and pharmacokinetic/pharmacodynamic modeling and 
simulations.
The pharmacodynamics of fremanezumab were examined in animal models by characterization 
of the ability of fremanezumab to block CGRP functions in vivo (see Section 1.2.1). 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 the 
study, fremanezumab (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 fremanezumab 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 mg sc and 
2000 mg iv, respectively, in patients with migraine. Therefore, the 225 mg sc 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 fremanezumab from Phase 1 studies in healthy 
volunteers, 2 dose regimens were selected for sc administration in the Phase 2b study in patients 
with episodic migraine (EM) for a treatment period of 3 months. The 2 active arms were 225 mg
and 675 mg sc administered monthly. The results of the Phase 2b study demonstrated that both 
dose regimens were effective, safe, and well tolerated by patients with EM. The mean changes in 
number of migraine days relative to baseline for both fremanezumab 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 single doses up to 2000 mg iv 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 fremanezumab 
administered monthly, was preserved for the Phase 3 study in patients with EM. A second active 
treatment group will receive fremanezumab at 675 mg quarterly to determine efficacy using a 
higher dose in case the lower dose of 225 mg sc monthly is not effective or is minimally 
effective. The 225-mg monthly and 675-mg quarterly dose regimens demonstrated similar 
exposure over a 3-month period in clinical studies of patients with EM.


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For the current proof of concept study, 2 active dose regimens will be administered: a lower 
dosing regimen of 225 mg monthly and a higher dosing regimen of 675 mg monthly. The 
675-mg monthly dose will provide a discerningly higher exposure separation from the lower 
dose of 225 mg monthly. The calculated safety margin is 54-fold higher than the expected 
clinical exposure following 675 mg sc monthly. As indicated above, the 675-mg monthly dosing 
regimen was also found to be safe and well tolerated in patients with EM.
5.3.2.
Justification for Use of Placebo Investigational Medicinal Product
A placebo-controlled design is appropriate given the purpose and objectives of this clinical 
study. A placebo-controlled design allows for negative control, which facilitates measure of the 
actual effect of the treatment being tested in the clinical study.
5.4.
Other Medicinal Products/Non-Investigational Medicinal Products
Information regarding acetaminophen as a rescue medicinal product is provided in Table 3.
Table 3:
Other Medicinal Products Used in the Study
Medicinal Product Name
Rescue Medication
Trade name and INN, if applicable, or 
company-assigned number
Acetaminophen
Formulation
To be sourced by the site 
Unit dose strength(s)/Dosage level(s)
500 mg
Route of administration
Oral 
Dosing instructions
1 to 2 caplets with dose up to 1000 mg per dose;
maximum of 3000 mg/day
Packaging
To be sourced by the site
Manufacturer
To be sourced by the site
INN = International Nonproprietary Name.
5.5.
Treatment after the End of the Study
Patients will not have access to sc fremanezumab as provided in this study after the EOT/EOS or 
ET Visit (Visit 7). After Visit 7, all subsequent clinical care will be determined by or at the 
discretion of the treating physician.
5.6.
Restrictions
Patients will be required to comply with the following restrictions:
1. Agree not to initiate or modify any non-pharmacologic or pharmacologic interventions 
for FM during the study.
2. Agree to maintain usual level of activity during the study.


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5.6.1.
Activity
Patients must remain at the investigational center for safety observation for at least 30 minutes
after IMP administration. Patients may be asked to remain at the investigational center longer if 
it is judged to be medically necessary by the investigator.
5.6.2.
Blood Donation
Patients may not donate blood while taking the IMP and for 6 months after their last dose.
5.7.
Prior and Concomitant Medication or Therapy
5.7.1.
Permitted Concomitant Medication or Therapy
Selective serotonin reuptake inhibitors or OTC medications are permitted if started at least 
90 days prior to screening, have been on a stable dose for at least 90 days, and are expected to 
remain on a stable dose throughout the study, except for ≥60 mg/day of fluoxetine. 
Over-the-counter medications used to treat depression or anxiety are permitted provided the dose 
has been stable for at least 90 days prior to screening and is not changed during the study.
For rescue treatment of FM-related pain, only acetaminophen up to 1000 mg per dose and not to 
exceed 3000 mg/day (for any indication) may be used, if needed, after recording the PI-NRS 
score in the e-diary. Use of nasal, inhaled, and topical steroids is permitted.
Nonsteroidal anti-inflammatory drugs are permitted provided the use has been stable (ie, per 
patient’s usual dosing regimen) for at least 1 month prior to screening and will remain 
unchanged throughout the study.
Antihistamines are permitted for sleep. In addition, tricyclic antidepressants at low doses 
(amitriptyline [≤25 mg] or trazodone [≤150 mg]) or cyclobenzaprine (up to 10 mg), zolpidem 
(up to 10 mg), and melatonin may be used for sleep per the patient’s usual dosing regimen, with 
no dose change 1 month prior to screening and throughout the study.
Concomitant medications permitted during the study include the following: 1) SSRIs (stable 
use), 2) the use of acetaminophen as a rescue medication up to 1000 mg per dose and not to 
exceed 3000 mg/day as a rescue medication for pain, 3) medications required for the treatment of 
any adverse events, 4) aspirin (maximum daily dose 325 mg) for cardiovascular prophylaxis, 
5) nonsteroidal anti-inflammatory drugs (stable use), and 6) selected sleep medications. 
If using marijuana (cannabis), cannabidiol, or other cannabinoids, regardless of route of 
administration, subjects should be instructed to keep their use at approximately the same 
dose/amount, route of administration, and frequency throughout the study.
No other FM medications (prescription, OTC, behind-the-counter, IMPs other than those 
permitted in this study, or vaccine) will be allowed during the study. For details of allowed 
medications, see Appendix N.
5.7.2.
Prohibited Medication or Therapy
A list of prohibited medications is provided in Appendix I. At each visit at the investigational 
center after the Screening Visit, the investigator will ask patients whether they have taken any 


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medications (other than IMP[s]), including OTC medications, vitamins, or herbal or nutritional 
supplements, since the previous visit.
Concomitant medication and treatment will be recorded until the EOT/EOS or ET Visit 
(Visit 7/week 16).
5.7.3.
Recommended Washout Periods
The washout periods for common drugs are detailed in Table 4. While it is not mandatory to 
wash out of all concomitant medications, it is desirable to reduce the number of concomitant 
medications to a minimum, if possible. Note: Not all of these medications will require washout; 
see Section 5.7.1, Section 5.7.2, Appendix I, and Appendix N for further information about 
permitted concomitant medications. 
Washout periods are recommendations; actual washout periods must be determined by the 
investigator based on his/her clinical practice/judgement, the medication, and the dose of the 
respective medication. If there are any questions, contact the medical monitor.
Table 4:
List of Recommended Washout Periods for Common Medications
Name of Drug
Recommended Washout
Analgesic/antipyretic
Acetaminophen
1 week
Anticonvulsants
Gabapentin
1 week
Pregabalin
1 week
Antidepressants
Duloxetine
2 weeks
Venlafaxine
2 weeks
Amitriptyline
2 weeks
Nortriptyline
2 weeks
Cox-2 inhibitor
Celecoxib
1 week
Nonsteroidal anti-inflammatory drugs
Aspirin (high dose)
2 weeks
Aspirin (low dose) 
1 week
Choline magnesium trisalicylate
1 week
Diclofenac (gel)
1 week
Diclofenac (oral)
1 week
Diclofenac (patch)
1 week
Diflunisal
1 week
Etodolac
1 week


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Name of Drug
Recommended Washout
Fenoprofen
1 week
Ibuprofen
1 week
Indomethacin
1 week
Meclofenamate
1 week
Meloxicam
1 week
Methyl salicylate (high dose)
2 weeks
Methyl salicylate (low dose)
1 week
Nabumetone
1 week
Naproxen
1 week
Oxaprozin
2 weeks
Piroxicam
2 weeks
Salsalate
1 week
Tolmetin
1 week
Opioids
Codeine
1 week
Dihydrocodeine
1 week
Fentanyl
1 week
Hydrocodone
1 week
Methadone
2 weeks
Morphine
1 week
Oxycodone
1 week
Oxymorphone
1 week
Tramadol
1 week
Patches
Lidocaine
1 week
Serotonin and norepinephrine reuptake inhibitors
Desvenlafaxine 
2 weeks
Duloxetine
2 weeks
Levomilnacipran
2 weeks
Milnacipran 
2 weeks
Venlafaxine 
2 weeks


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5.8.
Procedures for Monitoring Patient Compliance
The investigator will be responsible for monitoring patient compliance. If the investigator or the 
sponsor determines that the patient does not comply with the study protocol, the investigator and 
the sponsor should determine whether the patient should be terminated from the study 
(Section 4.3). The Independent Ethics Committee (IEC)/Institutional Review Board (IRB) should 
be notified.
5.8.1.
Fibromyalgia Eligibility Review Committee
The Fibromyalgia Eligibility Review Committee is a sponsor- and site-independent review 
committee comprised of one or more external experts with experience in fibromyalgia study 
design and execution. The review committee has been charged with determining if patients 
proposed for study enrollment are appropriate candidates. Such determination will be based upon 
assessment of clinical information obtained during the screening period relevant to the diagnosis 
and treatment of fibromyalgia, as well as potential confounds to diagnosis, treatment, and/or 
study participation.
5.9.
Randomization and Blinding
This is a randomized, double-blind, placebo-controlled study. All IMPs will be identical and 
indistinguishable. Patients, investigators, and all clinical study center staff will remain blinded to 
treatment assignment during the study. Eligible patients will be randomly assigned via a 
qualified Randomization and Trial Supply Management (RTSM) system in a 1:1:1 ratio to 
fremanezumab at 225 mg sc or fremanezumab 675 mg sc, or placebo sc. Randomization will be 
stratified by sex (male/female) and age at FM onset (<40 years old and ≥40 years old).
Patients will be randomly assigned to treatment groups by means of a computer-generated 
randomization list. The generation of the randomization list and management of the RTSM 
system will be done by a qualified service provider. The specifications for randomization will be 
under the responsibility and oversight of Teva Global Statistics.
The sponsor’s clinical personnel (and delegates) involved in the study will be blinded to the 
identity of the IMPs until the database is locked for analysis and the IMP assignment is released. 
However, if a prioritized sample analysis is needed, bioanalytical and clinical pharmacology 
personnel may be unblinded.
In the event of an emergency, it will be possible to determine to which treatment group and dose 
a patient has been allocated by accessing the RTSM system. All investigational centers will be 
provided with details of how to access the system for code breaking at the start of the study. The 
Medical Monitor or equivalent should be notified, if possible, prior to unblinding or following 
unblinding. Any unblinding of the IMP performed by the investigator must be recorded in the 
source documents.
5.10.
Maintenance of Randomization and Blinding
5.10.1.
Maintenance of Randomization
Patient randomization codes will be maintained in a secure location at the service provider 
contracted to generate the codes. At the time of analysis (after the EOS), after receiving the 


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patient randomization list, without indication of IMP assignment, from the Teva statistician, the 
service provider will provide the unblinded IMP assignment according to the processes defined 
in the relevant SOP. The unblinded IMP assignment will be requested by Data Management 
from the clinical study center.
Packaging vendor(s) will package test IMP and placebo IMP according to Good Manufacturing 
Practice procedures. Kits will be identical in appearance. Adequate kit supply for upcoming 
study visits will be managed by RTSM and kept (refrigerated at 2°C to 8°C) at the 
investigational centers.
At Visits 3 through 6, the RTSM will be queried, and investigational center personnel will 
retrieve and administer each pre-filled syringe contained in the appropriately numbered kit(s). 
Kit numbers will be entered into the eCRF.
5.10.2.
Blinding and Unblinding
Blinded pharmacokinetic data may be assessed during the study. Personnel responsible for 
bioanalysis will be provided with the randomization code to facilitate the analysis. However, the 
personnel responsible for bioanalysis and pharmacokinetic data analysis will not have access to 
clinical safety and efficacy data and will provide concentration data to other personnel who are 
not part of the study team in a manner that will not identify individual patients (ie, a dummy 
patient identifier will be linked to the concentration data of an individual patient), if needed.
In case of a serious adverse event, pregnancy, or in cases when knowledge of the IMP 
assignment is needed to make treatment decisions, the investigator may unblind the patient’s 
IMP assignment as deemed necessary, mainly in emergency situations. Individual randomization 
codes, indicating the IMP assignment for each randomized patient, will be available to the 
investigator(s) or pharmacist(s) at the investigational center via the RTSM, both via telephone 
and internet. Breaking of the treatment code can always be performed by the investigator without 
prior approval by the sponsor; however, the sponsor should be notified following the breaking of 
the treatment code. The patient’s IMP assignment should not be revealed to the sponsor.
When a blind is broken, the patient will be terminated early from the study and the event will be 
recorded on the eCRF. The circumstances leading to the breaking of the code should be fully 
documented in the investigator’s study files and in the patient’s source documentation. 
Assignment of IMP should not be recorded in any study documents or source document.
In blinded studies, for an adverse event defined as a SUSAR (ie, reasonable possibility; see 
Section 7.1.4), Global Patient Safety and Pharmacovigilance (GPSP) may independently request 
that the blind code be broken (on a case-by-case basis) to comply with regulatory requirements. 
The report will be provided in an unblinded manner for regulatory submission. If this occurs, 
blinding will be maintained for the investigator and for other personnel involved in the conduct 
of the study, and analysis and reporting of the data.
5.10.3.
Independent Data Monitoring Committee
There will be no Independent Data Monitoring Committee (IDMC) for this study.


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5.11.
Total Blood Volume
The total blood volume that will be collected for each patient enrolling in this study for 
scheduled evaluation of ADAs, fremanezumab concentrations, clinical laboratory tests, and 
biomarkers is approximately 150.8 mL. Details are provided in Appendix J.
The total blood volume that will be collected over the duration of the study conforms to 
established blood volume collection for clinical research.


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6.
ASSESSMENT OF EFFICACY
6.1.
Assessments of Efficacy
6.1.1.
Pain Intensity-Numerical Rating Scale
The PI-NRS is an 11-point pain intensity numerical rating scale where 0=no pain and 10=worst 
possible pain. The PI-NRS is a widely used and validated pain scale in studies of approved 
therapies in FM (Arnold et al 2015, Farrar et al 2010). The PI-NRS will be used to rate average 
FM pain intensity over the past week at screening. This will be entered via the site tablet at 
screening. The remainder of the assessments are daily assessments from Visit 2 to Visit 7 and are 
recorded in the patient’s e-diary. The average daily FM pain intensity over the past 24 hours, the 
worst FM pain intensity over the past 24 hours, and at-the-moment pain intensity just prior to the 
use of rescue medication.
6.1.2.
Fibromyalgia Impact Questionnaire Revised
The FIQR is a commonly used instrument in the evaluation of FM patients. It contains 
21 questions in 3 domains: function (9 questions), overall impact (2 questions), and symptoms 
(10 questions). Questions are graded on a 0 to 10 numeric scale with 10 being the worst. All 
questions are framed in the context of the last 7 days. The weighting of these 3 domains is that 
30% of the total score is ascribed to “function,” 50% is ascribed to “symptoms,” and 20% is 
ascribed to “overall impact.” The total maximal score of the FIQR is 100 (Bennet et al 2009). 
6.1.3.
EuroQol-5 Dimension Questionnaire
The EQ-5D-5L is a standardized measure of health status developed by the EuroQol Group in 
order to provide a simple, generic measure of health for clinical and economic appraisal. The 
EQ-5D-5L consists of the descriptive system EQ Visual Analogue Scale (EQ VAS). The 
descriptive system comprises 5 dimensions (mobility, self-care, usual activities, pain/discomfort, 
anxiety/depression). Each dimension now has 5 levels: no problems, slight problems, moderate 
problems, severe problems, and extreme problems. The respondent is asked to indicate his/her 
health state by ticking (or placing a cross) in the box against the most appropriate statement in 
each of the 5 dimensions. The EQ VAS records the respondent’s self-rated health on a 
20 cm vertical, visual analogue scale (0 to 100) with endpoints labelled “the best health you can 
imagine” and “the worst health you can imagine” (EQ-5D-5L User Guide 2018).
6.1.4.
Patient Global Impression of Change
The PGIC scale evaluates all aspects of patients’ health and assesses if there has been an 
improvement or decline in clinical status since the start of the study. Improvement is recorded on 
a 7-point scale, with 1 indicating very much improved and 7 indicating very much worse (Arnold 
et al 2015).


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6.1.5.
Patient-Reported Outcomes Measurement Information System
6.1.5.1.
PROMIS Sleep Disturbance Short Form 8a
The PROMIS Sleep Disturbance SF8 Scale contains 8 items with a score range of 8 to 40 and 
measures quality of sleep and sleep-related impairment. The PROMIS Sleep Disturbance 
instrument assesses self-reported perceptions of sleep quality, sleep depth, and restoration 
associated with sleep. This includes perceived difficulties and concerns with getting to sleep or 
staying asleep, as well as perceptions of the adequacy of and satisfaction with sleep. Sleep 
Disturbance does not focus on symptoms of specific sleep disorders, nor does it provide 
subjective estimates of sleep quantities (total amount of sleep, time to fall asleep, amount of 
wakefulness during sleep). The Sleep Disturbance SF8 assesses sleep disturbance over the past 
7 days (PROMIS-Sleep Disturbance Scoring Manual). Collection of the PROMIS Sleep 
Disturbance SF8a will start the day of the BAPS Visit (Visit 2) and will be administered weekly 
via the e-diary Morning Report to assess the previous week’s sleep.
6.1.5.2.
PROMIS Physical Function Short Form 12a
The PROMIS Physical Function SF12a Scale contains 12 items with a score ranging from 12 to 
60. The PROMIS Physical Function Scale measures self-reported capability rather than actual 
performance of physical activities. This includes the functioning of one’s upper extremities 
(dexterity), lower extremities (walking or mobility), and central regions (neck, back), as well as 
instrumental activities of daily living, such as running errands over the past over the past 7 days. 
A single Physical Function capability score is obtained from a SF. A lower score indicates more 
limited physical disability (PROMIS-Physical Function Scoring Manual).
6.1.5.3.
PROMIS Fatigue Short Form 8a
The PROMIS Fatigue SF8a contains 8 items with a score range from 8 to 40. Each question has 
5 response options ranging in value from 1 to 5 over the past 7 days. To find the total raw score 
for an SF with all questions answered, sum the values of the response to each question. For the 
adult 8-item form, the lowest possible raw score is 8; the highest possible raw score is 40, 
indicating worst sleep (PROMIS-Fatigue Scoring Manual).
6.1.6.
Hospital Anxiety and Depression Scale
The HADS is a 14-item questionnaire that measures anxiety and depression in both hospital and 
community settings for a recall period of 7 days. It assesses the SS of anxiety disorders and 
depression in patients with illness and the general population. Scores of 0 to 7 in respective 
subscales are considered normal, with 8 to 10 borderline and 11 or over indicating clinical 
“caseness.” The HADS has been used in the study of patients with FM (Nam et al 2014).
6.1.7.
Inventory of Medical Diagnoses
The IMD is a 9-item, non-validated inventory that evaluates in patients (1) medical conditions 
diagnosed and present for at least 3 months at the Screening Visit and (2) improvement or 
non-improvement of these medical conditions at the end of the study.
Questions will be completed by the investigator at the Screening Visit (Visit 1) and at Visits 6 
and 7. For those medical conditions that a patient identifies as present at screening, the 


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investigator will query at Visits 6 and 7 whether those conditions are improved or not improved 
compared with when the patient entered the study.


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7.
ASSESSMENT OF SAFETY
In this study, safety will be assessed by qualified study personnel by evaluating reported adverse 
events, clinical laboratory test results, vital signs measurements, 12-lead ECG findings, physical 
examination findings (including body weight measurements), C-SSRS scores, local injection site 
assessments, use of concomitant medication, and laboratory test results. Study procedures and 
assessments are described in Table 1.
7.1.
Adverse Events
7.1.1.
Definition of an Adverse Event
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have to have a causal relationship with 
this treatment.
An adverse event can, therefore, be any unfavorable and unintended physical sign, symptom, or 
laboratory parameter that develops or worsens in severity during the course of this study, or 
significant worsening of the disease under study, or of any concurrent disease, whether or not 
considered related to the IMP. A new condition or the worsening of a pre-existing condition will 
be considered an adverse event. Stable chronic conditions (such as arthritis) that are present 
before study entry and do not worsen during this study will not be considered adverse events.
Accordingly, an adverse event can include any of the following:

intercurrent illnesses

physical injuries

events possibly related to concomitant medication

significant worsening (change in nature, severity, or frequency) of the disease under 
study or other pre-existing conditions

drug interactions

events occurring during diagnostic procedures or during any washout phase of this
study

laboratory or diagnostic test abnormalities that result in the early termination of the 
patient from the study, are associated with clinical signs and symptoms or a serious 
adverse event, require medical treatment or further diagnostic work-up, or are 
considered by the investigator to be clinically significant
(Note: Abnormal laboratory or diagnostic test results at the Screening Visit that 
preclude a patient from entering the study or receiving study treatment are not 
considered adverse events.)
Worsening of the disease under study will be assessed by the principal investigator and should be 
recorded as an adverse event only if the presentation or outcome is deemed more severe than 
would normally be expected from the normal course of the disease in a particular patient.


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7.1.2.
Recording and Reporting of Adverse Events
For recording of adverse events, the study period is defined for each patient as the time period 
from signature of the ICF to the end of the study or the ET visit for patients who discontinue 
from the study for any reason. Symptoms or signs of medication withdrawal during the weaning 
period should be recorded as a medication withdrawal adverse event. The period for reporting 
treatment-emergent adverse events is defined as the period after the first dose of IMP is 
administered.
All adverse events that occur during the defined study period must be recorded both on the 
source documentation and the eCRF, regardless of the severity of the event or judged 
relationship to the IMP. For serious adverse events, the serious adverse event form must be 
completed, and the serious adverse event must be reported immediately (Section 7.1.5.3.1). The 
investigator does not need to actively monitor patients for adverse events after the defined 
period.
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 eCRF and, if it is a serious adverse event, on 
the serious adverse event form.
The clinical course of each adverse event will be monitored at suitable intervals until resolved, 
stabilized, or returned to baseline; or until the patient is referred for continued care to a health 
care professional; or until a determination of a cause unrelated to the IMP or study procedure is 
made.
The onset and end dates, duration (in case of adverse event duration of less than 24 hours), action 
taken regarding IMP, treatment administered, and outcome for each adverse event must be 
recorded both on the source documentation and the eCRF.
The relationship of each adverse event to IMP and study procedures, and the severity and 
seriousness of each adverse event, as judged by the investigator, must be recorded as described 
below.
Further details are given in the Safety Monitoring Plan.
7.1.3.
Severity of an Adverse Event
The severity of each adverse event must be recorded as one of the following:
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 Investigational Medicinal Product
The relationship of an adverse event to the IMP is characterized as follows:


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Table 5:
The Relationship of an Adverse Event to the IMP
Term
Definition
Clarification
No reasonable 
possibility
(not related)
This category applies to adverse 
events that, after careful 
consideration, are clearly due to 
extraneous causes (disease, 
environment, etc) or to adverse 
events that, after careful medical 
consideration at the time they are 
evaluated, are judged to be unrelated 
to the IMP.
The relationship of an adverse event may be considered 
“no reasonable possibility” if it is clearly due to 
extraneous causes or if at least 2 of the following apply:

It does not follow a reasonable temporal sequence 
from the administration of the IMP.

It could readily have been produced by the patient’s 
clinical state, environmental or toxic factors, or other 
modes of therapy administered to the patient.

It does not follow a known pattern of response to the 
IMP.

It does not reappear or worsen when the IMP is 
re-administered.
Reasonable 
possibility
(related)
This category applies to adverse 
events for which, after careful 
medical consideration at the time 
they are evaluated, a connection with 
the administration of IMP cannot be 
ruled out with certainty.
The relationship of an adverse event may be considered 
“reasonable possibility” if at least 2 of the following 
apply:

It follows a reasonable temporal sequence from 
administration of the IMP.

It cannot be reasonably explained by the known 
characteristics of the patient’s clinical state, 
environmental or toxic factors, or other modes of 
therapy administered to the patient.

It disappears or decreases on cessation or reduction in 
dose. There are important exceptions when an 
adverse event does not disappear after 
discontinuation of the IMP, yet an IMP relationship 
clearly exists.

It follows a known pattern of response to the IMP.
7.1.5.
Serious Adverse Events
For recording of serious adverse events, the study period is defined for each patient as that time 
period from signature of the ICF to the end of the study or the ET visit for patients who 
discontinue from the study for any reason. Serious adverse events occurring in a patient after the 
end of the study should be reported to the sponsor if the investigator becomes aware of them, 
following the procedures described in Section 7.1.5.3.1.
7.1.5.1.
Definition of a Serious Adverse Event
A serious adverse event is an adverse event occurring at any dose that results in any of the 
following outcomes or actions:

results in death

is life-threatening adverse event (ie, the patient was at risk of death at the time of the 
event); it does not refer to an event which hypothetically might have caused death if it 
were more severe


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
requires inpatient hospitalization or prolongation of existing hospitalization, which 
means that hospital inpatient admission or prolongation of hospital stay were required 
for treatment of an adverse event, or that they occurred as a consequence of the event
Hospitalizations scheduled before the patient signed the ICF will not be considered 
serious adverse events unless there was worsening of the preexisting condition during 
the patient’s participation in this study.

results in persistent or significant disability/incapacity (refers to a substantial 
disruption of one’s ability to conduct normal life functions)

is a congenital anomaly/birth defect

an important medical event that may not result in death, be life-threatening, or require 
hospitalization, but may jeopardize the patient and may require medical intervention 
to prevent one of the outcomes listed in this definition
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization; or the development of drug dependency or drug abuse. Note: Any 
suspected transmission of an infectious agent via a medicinal product is considered an 
important medical event.
All occurrences of possible drug-induced liver injury that meet Hy’s law criteria, defined as all 
of the below, must be reported by the investigator to the sponsor as a serious adverse event:

ALT or AST increase of >3× the ULN

total bilirubin increase of >2× the ULN

absence of initial findings of cholestasis (ie, no substantial increase of alkaline 
phosphatase)
An adverse event that does not meet any of the criteria for seriousness listed above will be 
regarded as a nonserious adverse event.
7.1.5.2.
Expectedness
A serious adverse event that is not included in the Adverse Reaction section of the relevant 
reference safety information (RSI) by its specificity, severity, outcome, or frequency is 
considered an unexpected adverse event. The RSI for this study is the IB.
The sponsor’s GPSP will determine the expectedness for all serious adverse events.
For the purpose of SUSAR reporting, the version of the IB at the time of occurrence of the 
SUSAR applies.
7.1.5.3.
Reporting a Serious Adverse Event
7.1.5.3.1. Investigator Responsibility
To satisfy regulatory requirements, all serious adverse events that occur during the study, 
regardless of judged relationship to administration of the IMP, must be reported to the sponsor 
by the investigator. The event must be reported within 24 hours of when the investigator learns 


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about it. Completing the serious adverse event form and reporting the event must not be delayed, 
even if not all the information is available. The investigator does not need to actively monitor 
patients for adverse events once this study has ended.
Serious adverse events occurring to a patient after the last administration of IMP of that patient 
has ended should be reported to the sponsor if the investigator becomes aware of them.
The serious adverse event form should be sent to the local safety officer (LSO) or designee (a 
CRO in a country without a sponsor LSO) (contact information is in the Clinical Study Personnel 
Contact Information, Appendix A); the LSO will forward the report to the sponsor’s GPSP.
The following information should be provided to record the event accurately and completely:

study number

investigator and investigational center identification

patient number

onset date and detailed description of adverse event

investigator’s assessment of the relationship of the adverse event to the IMP (no 
reasonable possibility, reasonable possibility)
Additional information includes the following:

age and sex of patient

date of first dose of IMP

date and amount of last administered dose of IMP

action taken

outcome, if known

severity

explanation of assessment of relatedness

concomitant medication (including doses, routes of administration, and regimens) and 
treatment of the event

pertinent laboratory or other diagnostic test data

medical history

results of dechallenge/rechallenge, if known

for an adverse event resulting in death

cause of death (whether or not the death was related to IMP)

autopsy findings (if available)
Each report of a serious adverse event will be reviewed and evaluated by the investigator and the 
sponsor to assess the nature of the event and the relationship of the event to the IMP, study 
procedures, and to underlying disease.


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Additional information (follow-up) about any serious adverse event unavailable at the initial 
reporting should be forwarded by the investigator within 24 hours of when it becomes known to 
the same address as the initial report.
For all countries, the sponsor’s GPSP will distribute the Council for International Organizations 
of Medical Sciences form/Extensible Markup Language file to the LSO/CRO for submission to 
the competent authorities, IEC/IRBs, and investigators, according to regulations. The 
investigator must ensure that the IEC/IRB is also informed of the event, in accordance with 
national and local regulations.
For double-blind studies, blinding will be maintained for all study personnel. Therefore, in case 
of a SUSAR, only the LSO/CRO will receive the unblinded report for regulatory submission; the 
others will receive a blinded report.
7.1.5.3.2. Sponsor Responsibility
If a serious unexpected adverse event is believed to be related to the IMP or study procedures, 
the sponsor will take appropriate steps to notify all investigators participating in sponsored 
clinical studies of fremanezumab and the appropriate competent authorities (and IEC/IRB, as 
appropriate).
In addition to notifying the investigators and competent authorities (and IEC/IRB, as 
appropriate), other action may be required, including the following:

altering existing research by modifying the protocol

discontinuing or suspending the study

modifying the existing consent form and informing all study participants of new 
findings

modifying listings of expected toxicities to include adverse events newly identified as 
related to fremanezumab
7.1.6.
Protocol-Defined Adverse Events of Special Interest
For purposes of this protocol, the following are considered protocol-defined adverse events of 
special interest to be sent to the sponsor’s GPSP Department for evaluation:

ophthalmic-related adverse events of at least moderate severity, as determined by the 
investigator

severe hypersensitivity reactions or anaphylaxis (see Appendix C)
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). The clinical 
criteria for diagnosing anaphylaxis are provided in Appendix C. In the event of suspected 
anaphylaxis, vital signs (including oxygen saturation and respiration rate) will be measured.
The process for reporting a protocol-defined adverse event of special interest will be the same as 
that for reporting a serious adverse event (Section 7.1.5.3). Protocol-defined adverse events of 


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special interest to be reported to GPSP can either be serious or nonserious, according to the 
criteria outlined in Section 7.1.5.1.
7.1.7.
Protocol Deviations Because of an Adverse Event
If a patient experiences an adverse event or medical emergency, deviations from the protocol 
may be allowed on a case-by-case basis. To ensure patient safety, after the event has stabilized or 
treatment has been administered (or both), the investigator or other physician in attendance must 
contact the physician identified in the Clinical Study Personnel Contact Information section of 
this protocol (Appendix A) as soon as possible to discuss the situation. The investigator, in 
consultation with the sponsor, will decide whether the patient should continue to participate in 
the study.
7.2.
Pregnancy
Any female patient becoming pregnant during the study will discontinue IMP.
All pregnancies of women participating in the study and female partners of men participating in 
the study that occur during the study, or within at least 6 months after administration of IMP, 
will be reported immediately to the individual identified in the Clinical Study Personnel Contact 
Information section (Appendix A) of this protocol; the investigator must provide the sponsor 
(LSO/CRO) with the completed pregnancy form. The process for reporting a pregnancy is the 
same as that for reporting a serious adverse event but using the pregnancy form (Section 7.1.5.3).
The investigator is not required to report patients who are found to be pregnant between 
screening and baseline, provided no protocol-related procedures were applied.
All female patients (or female partners of men participating in the study) who become pregnant 
will be monitored for the outcome of the pregnancy (including spontaneous, elective, or 
voluntary abortion). 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 early termination from the study will be reported as an 
adverse event or serious adverse event, as appropriate.
If the pregnancy in the woman participating in the study and/or the female partners of men 
participating in the study does not continue to term, one of the following actions will be taken:

For a spontaneous abortion, report as a serious adverse event.

For an elective abortion due to developmental anomalies, report as a serious adverse 
event.

For an elective abortion not due to developmental anomalies, report on the pregnancy 
form; do not report as an adverse event.
7.3.
Medication Error and Special Situations Related to the 
Investigational Medicinal Products
The Medical Monitor should be contacted in any of the following events: 


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1. All 3 syringes from the assigned kit are unable to be administered during the visit.
2. Any dose has been administered and a syringe is damaged.
If a syringe is damaged prior to dose administration, a new kit should be requested. Additional 
information is provided in the Study Manual.
Any administration of IMP that is not in accordance with the study protocol should be reported 
on the eCRF either as a violation, if it meets the violation criteria specified in the protocol 
(Appendix D), or as a deviation, in the patients source documents, regardless of whether or not 
an adverse event occurs as a result.
The following are types of medication errors and special situations:
1. Medication error: Any unintentional error in the prescribing, dispensing, or 
administration of a medicinal product while in the control of the healthcare professional, 
patient, or consumer.
2. Overdose: Administration of a quantity of a medicinal product given per administration 
or cumulatively which is above the maximum recommended dose according to the 
authorized product information. Clinical judgment should always be applied. Any dose of 
IMP (whether the test IMP or placebo IMP), whether taken intentionally or 
unintentionally, in excess of that prescribed must be immediately reported to the sponsor.
3. Misuse: Situations where the IMP is intentionally and inappropriately used not in 
accordance with the authorized product information.
4. Abuse: Persistent or sporadic, intentional excessive use of IMP which is accompanied by 
harmful physical or psychological effects.
5. Off-label use: Situations where an IMP is intentionally used for a medical purpose not in 
accordance with the authorized product information.
6. Occupational exposure: Exposure to an IMP, as a result of one’s professional or 
non-professional occupation.
7. Breastfeeding: Suspected adverse reactions that occur in infants following exposure to a 
medicinal product from breast milk.
7.4.
Clinical Laboratory Tests
All clinical laboratory test results outside of the reference range will be judged by the 
investigator as belonging to one of the following categories:

abnormal and not clinically significant

abnormal and clinically significant
A laboratory test result that is judged by the investigator as clinically significant will be recorded 
both on the source documentation and on the eCRF as an adverse event and monitored as 
described in Section 7.1.2. An event may include a laboratory or diagnostic test abnormality 
(once confirmed by repeated testing) that results in the early termination of the patient from the 
study, the temporary or permanent discontinuation of IMP or medical treatment, or further 
diagnostic work-up. (Note: Abnormal laboratory or diagnostic test results at the Screening Visit 


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that preclude a patient from entering the study or receiving IMP are not considered adverse 
events.)
Table 6:
Clinical Laboratory Tests
Serum Chemistry
Hematology and Coagulation
Urinalysis
Calcium
Phosphate
Sodium
Potassium
Chloride
Creatinine
Glucose
Blood urea nitrogen (BUN)
Urate
Alanine aminotransferase (ALT)
Aspartate aminotransferase (AST)
Lactate dehydrogenase (LDH)
Gamma-glutamyl transpeptidase (GGT)
Alkaline phosphatase
Bicarbonate
Carbon dioxide
Protein
Albumin
Bilirubin
Direct bilirubin
Hepatitis B
Hemoglobin
Hematocrit
Erythrocytes
Platelets
Leukocytes
Neutrophils
Lymphocytes
Eosinophils
Monocytes
Basophils
Lymphocytes atypical
Prothrombin International 
Normalized Ratio (INR)
Protein
Glucose
Ketones
Hemoglobin
pH
Specific gravity
Microscopic tests
Bacteria
Erythrocytes
Leucocytes
Crystals
Casts
Tests to be performed at screening only
Tests to be performed as 
indicated in Table 1
Human immunodeficiency virus (HIV)
Hepatitis B surface antigen (HBsAg)
Hepatitis C antibody
Thyroid stimulating hormone (TSH)
Beta-human chorionic gonadotropin (β-HCG; 
women of childbearing potential only)
Drug screening
β-HCG (women of 
childbearing potential only)
7.4.1.
Serum Chemistry, Hematology, and Urinalysis
Clinical laboratory tests (serum chemistry, hematology and coagulation, urinalysis) will be 
performed at the time points detailed in Table 1. Clinical laboratory tests will be performed using 
a central laboratory; details will be specified in the Laboratory Manual. Specific laboratory tests 
to be performed are provided in Table 6.
7.4.2.
Other Clinical Laboratory Tests
At screening, patients will be tested for human immunodeficiency virus, hepatitis B surface 
antigen (HBsAg), hepatitis C antibody, and thyroid stimulating hormone (Table 6).


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7.4.2.1.
Beta-human Chorionic Gonadotropin Tests
Beta-human chorionic gonadotropin tests in serum will be performed for all women of 
childbearing potential at screening (Visit 1). Urine will be used for all subsequent visits and will 
be tested on site via β-HCG dipstick. Serum may be tested if clinically indicated, or as a 
confirmatory test for a positive dipstick result.
7.4.2.2.
Urine Drug Screen
A urine drug screen will be performed at the time points specified in Table 1, but patients should 
not be told at which visits the urine drug screen will be performed. The urine drug screen detects 
the presence of drugs of abuse, including opioids, and marijuana/cannabis (see details in the 
Laboratory Manual).
A positive result for any of the above drugs or their metabolites, except marijuana/cannabis, 
without medical explanation, will preclude the patient from randomization/enrollment or 
continued participation in the study.
7.5.
Physical Examinations
Physical examinations, including height and weight (to be obtained at the Screening Visit; and 
weight during each physical examination), will be performed at the time points detailed in
Table 1. Any physical examination finding that is judged by the investigator as clinically 
significant (except at the Screening Visit) will be considered an adverse event, recorded on the
eCRF, and monitored as described in Section 7.1.2.
A full physical examination will include at a minimum skin, lungs, cardiovascular, respiratory, 
gastrointestinal, and neurologic assessments.
An abbreviated physical examination will include at a minimum skin, lungs, cardiovascular 
system, and abdomen (liver and spleen).
Investigators should pay special attention to clinical signs related to previous serious diseases 
and record in the eCRF.
7.6.
Vital Signs
Vital signs (blood pressure [systolic/diastolic], respiratory rate, oral body temperature, and pulse)
will be measured at the time points detailed in Table 1. All vital signs results outside of the 
reference ranges will be judged by the investigator as belonging to one of the following 
categories:

abnormal and not clinically significant

abnormal and clinically significant
Before blood pressure and pulse are measured, the patient must rest in a supine or seated position 
for at least 5 minutes. (The same position and arm should be used each time vital signs are 
measured for a given patient.) For any abnormal vital sign value, the measurement should be 
repeated as soon as possible. Any vital sign value that is judged by the investigator as clinically 
significant will be recorded both on the source documentation and the eCRF as an adverse event 
and monitored as described in Section 7.1.2.


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7.7.
Electrocardiography
A 12-lead ECG will be recorded at the time points detailed in Table 1. A qualified physician at a 
central diagnostic center will be interpreting the ECG.
All ECG results outside of the reference ranges will be judged by the investigator as belonging to 
one of the following categories:

abnormal and not clinically significant

abnormal and clinically significant
Any ECG finding that is judged by the investigator as clinically significant (except at the 
Screening Visit) will be considered an adverse event, recorded on the source documentation and 
in the eCRF, and monitored as described in Section 7.1.2.
7.8.
Immunogenicity
Blood samples for ADA assessment will be collected prior to dosing at the designated visits, as 
well as upon observation of any severe hypersensitivity reaction or anaphylaxis.
7.9.
Assessment of Local Tolerability and Pain
Spontaneous reports of injection site reactions will be recorded as adverse events according to 
the following severity assessment criteria:

Spontaneous reports of injection site erythema, induration, and ecchymosis will be 
assessed and recorded by site personnel and categorized according to the following 
measurements: 5 to ≤50 mm (mild), >50 to ≤100 mm (moderate), and >100 mm 
(severe).

Spontaneous reports of local pain after the injection will be recorded as mild, 
moderate, or severe according to patient’s self-report.

Appropriate treatment may be provided if necessary, in which case it must be 
recorded as concomitant medication.
7.10.
Assessment of Suicidality
The sponsor considers it important to monitor for events of suicidal ideation or behavior during 
this clinical study.
The C-SSRS will be used to assess the patient’s suicidal ideation (severity and intensity) and 
behavior (Posner et al 2011). The C-SSRS Baseline/Screening version will be administered by 
certified site staff at Visit 1, and the C-SSRS Since Last Visit version will be completed by 
certified site staff at all other time points, as described in Table 1. Appropriate study staff should 
review the results. Any significant findings on the C-SSRS require evaluation by the site 
investigator.


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8.
ASSESSMENT OF PHARMACOKINETICS / BIOMARKERS / 
IMMUNOGENICITY / ANCILLARY STUDIES
8.1.
Pharmacokinetic Assessment
Sampling for pharmacokinetics will be sparse. The fremanezumab pharmacokinetic 
concentrations will be analyzed using a population pharmacokinetic model approach and will be 
reported separately from the CSR; individual pharmacokinetic concentration data will be 
summarized and listed in the CSR.
Blood samples (4 mL) will be collected via venipuncture or indwelling catheter (for details, see 
the Laboratory Manual) at the time points detailed in Table 1 for plasma concentration 
measurements of fremanezumab. The dates and times of IMP administration and the date and 
time of each pharmacokinetic sample collection will be recorded in the source documentation 
and entered into the eCRF.
Samples from patients who received active IMP will be analyzed for the concentration of 
fremanezumab using a validated method. Samples from patients who were randomized to receive 
placebo will not be analyzed. Details on sample handling, storage, shipment, and analysis will be 
included in the Laboratory Manual.
8.2.
Pharmacodynamics Assessment
Pharmacodynamic parameters will not be evaluated in this study.
8.3.
Immunogenicity Testing
Samples from patients who receive active IMP will be analyzed for ADA using a validated 
method. Samples from patients who receive placebo will not be analyzed.
Blood samples (6 mL) will be collected via venipuncture or indwelling catheter (for details, see 
the Laboratory Manual) at the time points detailed in Table 1 for immunogenicity testing. The 
dates and times of IMP administration and the date and time of each ADA sample collection will 
be recorded in the source documentation and entered into the eCRF.
8.4.
 
 
 
 
 
 
 


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9.
STATISTICS
This section describes the statistical analysis as foreseen at the time of planning the study. 
Changes, additions, and further details about the analyses will be described in the statistical 
analysis plan. After finalization of the statistical analysis plan, any additional analyses or 
changes to analyses that may be required will be fully disclosed in the CSR.
9.1.
Study Design and Randomization
This is a multicenter, double-blind, randomized, placebo-controlled, parallel-group study to 
evaluate the efficacy and safety of fremanezumab treatment in patients with FM. Patients will be 
randomly assigned to receive treatment with fremanezumab 225 mg sc, fremanezumab
675 mg sc, or matching placebo sc in a 1:1:1 ratio. Randomization and blinding will be as 
described in Section 5.9.
9.2.
Sample Size and Power Considerations
The sample size of 80 subjects per treatment group was selected based on expert consensus 
agreement at a scientific advisory board meeting; this sample size is expected to provide 
sufficient precision to estimate the treatment effect of fremanezumab versus placebo. Moreover, 
assuming a standard deviation of 2.2 for change from baseline in the weekly average of the daily 
average PI-NRS score, 80 patients per treatment group will provide at least 90% probability to 
observe the half length of the 95% confidence interval of the treatment difference between 
fremanezumab 225 mg sc or fremanezumab 675 mg sc and placebo less than 0.74. In total, 
240 patients will be enrolled in this study in a 1:1:1 randomization ratio.
9.3.
Analysis Sets
9.3.1.
Intent-to-Treat Analysis Set
The intent-to-treat (ITT) analysis set will include all randomized patients.
In the ITT analysis set, treatment will be assigned based on the treatment to which patients were 
randomized, regardless of which treatment they actually received.
Patient disposition, demographics, and baseline characteristics will use the ITT analysis set, as 
appropriate.
9.3.2.
Modified Intent-to-Treat Analysis Set
The modified intent-to-treat (mITT) analysis set is a subset of the ITT analysis set including only 
patients who received at least 1 dose of study medication and at least 1 post-baseline entry of 
daily average pain intensity using the PI-NRS.
In the mITT analysis set, treatment will be assigned based on the treatment to which patients 
were randomized, regardless of which treatment they actually received.
All efficacy analyses will use the mITT analysis set unless noted otherwise.


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9.3.3.
Safety Analysis Set
The safety analysis set will include all randomized patients who received at least 1 dose of study 
medication. In the safety analysis set, treatment will be assigned based on the treatment patients 
actually received, regardless of the treatment to which they were randomized.
All safety analyses will use the safety analysis set unless noted otherwise.
9.3.4.
Per-Protocol Analysis Set
The per-protocol (PP) analysis set is a subset of the mITT analysis set including only patients 
without major protocol violations defined in the statistical analysis plan before study unblinding. 
The PP analysis set will serve as support for the efficacy analyses.
In the PP analysis set, treatment will be assigned based on the treatment patients actually 
received, regardless of the treatment to which they were randomized.
The primary efficacy endpoint and selected secondary efficacy endpoints will be analyzed using 
PP analysis set; details will be specified in the statistical analysis plan.
9.3.5.
Pharmacokinetic Analysis Set
The pharmacokinetic analysis set will include those patients from the safety analysis set who 
have at least 1 plasma concentration value for fremanezumab.
9.4.
Data Handling Conventions
For all variables, only the observed data from the patients will be used in the by-visit descriptive
summaries. Data imputation rule(s) will be described in relevant sections and detailed in the 
statistical analysis plan.
9.4.1.
Handling Early Terminations and Missing Data
Details for handling early terminations and missing data will be provided in the statistical 
analysis plan; observed data will be analyzed and presented without data imputation unless 
specified otherwise in the statistical analysis plan.
9.5.
Study Population
Male and female patients, ≥18 to 75 years old, inclusive, with FM.
The ITT analysis set (Section 9.3) will be used for all study population summaries unless 
otherwise specified. Summaries will be presented by treatment group and for all patients.
9.5.1.
Patient Disposition
Descriptive statistics will be used to summarize data from the following groups: patients 
screened; patients screened but not randomized and reason not randomized; patients who are 
randomized; patients randomized but not treated (and reason); patients in the ITT, mITT, safety, 
PP, and pharmacokinetic analysis sets; patients who complete the treatment and the study; and 
patients who discontinue from the treatment and the study. Data from patients who discontinue 
from treatment and the study will also be summarized by reason for discontinuation using 
descriptive statistics.


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9.5.2.
Demographic and Baseline Characteristics
Patient demographic characteristics (age, sex, ethnicity, and race) and baseline characteristics 
(medical history, prior medications, and ECG findings) will be examined to assess the 
comparability of the treatment groups and will be summarized using descriptive statistics. For 
continuous variables, descriptive statistics (number [n], mean, standard deviation, standard error, 
median, minimum, and maximum) will be provided. For categorical variables, patient counts and 
percentages will be provided. Categories for missing data will be presented, if necessary.
9.6.
Efficacy Analysis
9.6.1.
Primary Endpoint
The primary efficacy endpoint is the change from baseline up to week 16 in the weekly average 
of the daily average PI-NRS score over the past 24 hours.
9.6.2.
Secondary Endpoints

change from baseline up to week 16 in the individual components of the FIQR: 
symptom subscore, impact subscore, and functional subscore score

responder rate of the PGIC rating (percentage of patients much improved or very 
much improved) up to week 16

percentage of patients who experience a ≥30% reduction in the weekly average of the 
daily average PI-NRS score up to week 16

percentage of patients who experience a ≥50% reduction in the weekly average of the 
daily average PI-NRS score up to week 16

change from baseline up to week 16 in the weekly average of the daily worst PI-NRS 
score over the past 24 hours

change from baseline up to week 16 in the PROMIS Sleep Disturbance SF8a score

change from baseline up to week 16 in the PROMIS Physical Function SF12a score

change from baseline up to week 16 in the PROMIS Fatigue SF8a score

number (%) of patients who did not complete the treatment (Kaplan-Meier Survival 
Analysis) due to lack of efficacy
9.6.3.


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
 
 
 
9.6.4.
Planned Method of Analysis
9.6.4.1.
Primary Efficacy Analysis
The primary efficacy variable will be analyzed using an MMRM model with the change from 
baseline up to week 16 in the weekly average of the daily average over the past 24 hours PI-NRS 
scores as the dependent variable; sex, age group at FM onset, week, treatment, and treatment by 
week interaction as fixed factors; and baseline PI-NRS scores as a covariate. The heterogeneous 
autoregressive correlation structure for repeated observations within patients will be used, and 
the denominator degrees of freedom will be estimated using Kenward-Roger’s approximation. 
An adjustment for missing data due to lack of efficacy or adverse event assumes the PI-NRS 
scores will, on average, return to baseline values. Missing data will be imputed 500 times to 
generate 500 complete data sets by using the SAS procedure PROC MI following the 3 steps 
below:

Step 1: The monotone missing pattern will be induced by the Markov Chain Monte 
Carlo method in the PROC MI procedure using seed number 4751523.

Step 2: The remaining missing data at subsequent weeks will be imputed using the 
regression method for the monotone pattern with seed number 4751523 and 
adjustment for covariates including treatment groups, randomization strata, relevant 
baseline and all values at preceding visits.

Step 3: The initially missing and now imputed data for patients discontinued from the 
study treatment due to lack of efficacy or adverse event will be center adjusted at the 
mean baseline value for that treatment group, ie, the final imputed score will be equal 
to the imputed score under missing at random minus (mean change from baseline 
score at the post-baseline time point for the treatment group).
Each imputed data set will be analyzed using the MMRM described above. The results from the 
500 analyses will be combined using Rubin’s formulae (PROC MIANALYZE). The least 
squares means estimates for the mean change from baseline to each time point, as well as the 
difference of the estimates between the fremanezumab and placebo groups, with the 
corresponding standard error, p-value and associated 95% confidence interval will be provided.
9.6.4.2.
Sensitivity Analysis
Sensitivity analyses will be included to address the assumptions in the primary model. The 
primary analysis will be repeated; however, the daily average pain scores measured on the days 
where the patient took rescue medication will be replaced with his or her PI-NRS score at the 
time of rescue medication use before the weekly average PI-NRS scores are derived. On days 
where a patient uses rescue medication more than once, the mean PI-NRS score at the time of 


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rescue mediation use will be used as the pain score in place of the average pain intensity score 
for that day.
Three subgroup analyses will be conducted as part of the planned second interim analysis for the 
primary endpoint using descriptive statistics.

analysis by baseline pain level (PI-NRS ≥4, PI-NRS ≥5, and PI-NRS ≥6)

analysis by normalizing data for use of analgesia at baseline by adding 1 to the 
baseline pain score for those using analgesia

analysis by use of analgesia during baseline
Details of the subgroup analyses will be specified in the interim analysis statistical analysis plan.
9.6.4.3.
Secondary Efficacy Analysis
The change from baseline in weekly average of the daily worst PI-NRS over the past 24 hours up 
to week 16 and the baseline FIQR score will be analyzed in the same manner as the primary 
efficacy endpoint; however, the baseline pain intensity over the past 24 hours and the baseline 
FIQR score, respectively, will be used as a covariate in the MMRM model instead of the baseline 
PI-NRS score.
The PGIC asks patients to rate their status on the following scale:
Since the start of the study, my overall status is:
1.
Very Much Improved
2.
Much Improved
3.
Minimally Improved
4.
No Change
5.
Minimally Worse
6.
Much Worse
7.
Very Much Worse
The PGIC data will be dichotomized, where a patient who responds as either “much improved” 
or “very much improved” will be considered improved, and all other responses will be 
considered not improved. The response variable will be analyzed using a logistic regression 
model with the treatment, age group at FM onset, and sex as explanatory factors. In addition, the 
PGIC data will be summarized as categorical variable by week and treatment group using 
descriptive statistics. 
The percentage of patients who experience ≥30% reduction and ≥50% reduction in the weekly 
average of the daily average PI-NRS score up to week 16 will be analyzed using a generalized 
estimating equation method, where the dependent variable experience ≥30% reduction and ≥50% 
reduction (Yes/No) will be modeled through the binomial link function, with treatment, sex, age 
group at FM onset, week, and treatment by week interaction as explanatory factors. In addition, a 
plot of percentage of improvement versus percentage of patients meeting the improvement level 
throughout the study will be presented by treatment group.


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Change from baseline up to week 16 in the PROMIS Sleep Disturbance SF8a score, change from 
baseline up to week 16 in the PROMIS Physical Function SF12a score, change from baseline up 
to week 16 in PROMIS Fatigue SF8a score, and change from baseline up to week 16 in the 
HADS will be analyzed using an MMRM model with treatment, sex, age group at FM onset, 
week, treatment-by-week interaction, and baseline value of the corresponding variable as 
explanatory factors.
The number and percentage of patients who did not complete the treatment due to lack of 
efficacy or adverse event will be summarized using descriptive statistics, and the time to 
treatment discontinuation due to lack of efficacy or adverse event will be analyzed using the 
Kaplan-Meier Survival Analysis method.
9.6.4.4.
Other Efficacy Analysis
Statistical modeling to be used for other efficacy endpoints will be described and detailed in the 
statistical analysis plan as appropriate.
9.6.4.5.
 
 
 
 
 
 
.
9.7.
Multiple Comparisons and Multiplicity
No multiplicity adjustment is planned for this study.
9.8.
Safety Analysis
Safety analyses will be performed on the safety analysis set. The safety analysis set will include 
all randomized patients who receive at least 1 dose of IMP.
9.8.1.
Safety Variables
The overall safety and tolerability of sc fremanezumab treatment will be assessed by evaluating 
adverse events and the following additional safety variables at the time points specified in 
Section 3.5:

clinical laboratory tests 

vital signs

physical examination 


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
12-lead ECGs

concomitant therapy or medication usage

C-SSRS
9.8.2.
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 test IMP (ie, reasonable 
possibility) (defined as related or with missing relationship) (overall and by severity), serious 
adverse events, and adverse events causing early termination from the study. Summaries will be 
presented by treatment group and for all patients. Patient listings of serious adverse events and 
adverse events leading to early termination will be presented.
The number and percentage of patients who did not complete the treatment due to lack of 
efficacy or adverse event will be summarized using descriptive statistics, and the time to 
treatment discontinuation due to lack of efficacy or adverse event will be analyzed using the 
Kaplan-Meier Survival Analysis method.
Changes in laboratory, ECG, vital signs measurements, and C-SSRS data will be summarized 
descriptively. All values will be compared with predefined criteria to identify potentially 
clinically significant values or changes, and such values will be listed.
The use of concomitant medications will be summarized by therapeutic class using descriptive 
statistics.
For continuous variables, descriptive statistics (n, mean, standard deviation, 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 early terminations due to adverse events, and 
potentially clinically significant abnormal values (clinical laboratory or vital signs) based on 
predefined criteria will be provided as well.
If any patient dies during the study, a listing of deaths will be provided, and all relevant 
information will be discussed in the patient narrative included in the CSR.
9.8.3.
Tolerability Analysis
Local tolerability findings (eg, erythema, induration, ecchymosis, and occurrence of injection 
site pain) will be listed and summarized descriptively.
9.9.
Pharmacokinetic Analysis
Plasma concentrations will be tabulated at each planned sampling time point by treatment group.
In addition, the most appropriate population pharmacokinetic model will be developed, and 
covariates that may affect pharmacokinetic parameters will be tested for inclusion in the model. 
This analysis will be reported separately from the CSR; individual pharmacokinetic 
concentration data will be summarized and listed in the CSR.


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9.10.
Pharmacodynamic Analysis
Efficacy will be the only pharmacodynamic parameter evaluated in this study.
9.11.
Pharmacokinetic/Pharmacodynamic Analysis
Plasma concentration of fremanezumab will be summarized by visit using descriptive summary 
statistics.
If appropriate, further pharmacokinetic/pharmacodynamic relationship may be estimated using 
the most appropriate model after comparing different candidate models for their quality of fit. 
Covariates that may affect the pharmacokinetic/pharmacodynamic relationship will be tested for 
inclusion in the model. If performed, this analysis will be reported separately from the CSR.
9.12.
Biomarker Analysis
Blood samples (approximately 19.0 mL) will be collected on day 1, prior to randomization and at 
the times specified in Table 1, 
 
 
 
9.13.
Immunogenicity Analysis
The summary of immunogenicity results will be provided, and the incidence of immunogenicity 
and the antibody titers will be calculated.
9.14.
Ancillary Studies Analysis
There are no ancillary studies planned for this study.
9.15.
Planned Interim Analysis
A formal interim analysis for futility in this proof-of-concept study is planned after 68 patients 
have been enrolled; the interim analysis will be performed by an independent third party. A 
second interim analysis, for futility or continuation of the study, is planned after approximately 
150 patients have completed the study; the interim analysis will be performed by a team, which 
is independent and isolated from the study team, who will be kept blinded. Details of the interim 
analyses will be specified in the interim analysis statistical analysis plan.
 
 
 
 
 
9.16.
Reporting Deviations from the Statistical Plan
Deviations from the statistical plan, along with the reasons for the deviations, will be described 
in subsequent protocol amendments, if any, the statistical analysis plan, the CSR, or any 


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combination of these, as appropriate, and in accordance with applicable national, local, and 
regional requirements and regulations.


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


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


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


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


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


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15.
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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.
Sann H, Pierau F-K. Efferent functions of C-fiber nociceptors. Z Rheumatol 1998;57(Suppl 
2):8-13.
SAVELLA® [package insert]. Irvine, CA: Allergan Pharmaceuticals International Limited; 
initial US approval 2009.
Serra J, Collado A, Solà R, Antonelli F, Torres X, Salguerio M, et al. Hyperexcitable C 
nociceptors in fibromyalgia. Ann Neurol 2014;75:196-208.
Staud R, Rodriguez ME. Mechanisms of disease: Pain in fibromyalgia syndrome. Nature Clin 
Prac Rheumatol 2006;2(2):90-8.


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Staud R, Smitherman ML. Peripheral and central sensitization in fibromyalgia: Pathogenetic 
role. Curr Pain Headache Reports 2002;6:259-66.
The Patient-Reported Outcomes Measurement Information System. Fatigue Scoring Manual. 
Available at 
http://www.healthmeasures.net/images/PROMIS/manuals/PROMIS_Fatigue_Scoring_Manual.p
df. Retrieved 15 May 2018.
The Patient-Reported Outcomes Measurement Information System. Physical Function Scoring 
Manual. Available at 
http://www.healthmeasures.net/images/PROMIS/manuals/PROMIS_Physical_Function_Scoring
_Manual.pdf. Retrieved 15 May 2018.
The Patient-Reported Outcomes Measurement Information System. Sleep Disturbance Scoring 
Manual. Available at 
http://www.healthmeasures.net/images/promis/manuals/PROMIS_Sleep_Disturbance_Scoring_
Manual.pdf. Retrieved 15 May 2018.
Üçeyler N, Zeller D, Kahn A-K, Kewenig S, Kittel-Schneider S, Schmid A, et al. Small fibre 
pathology in patients with fibromyalgia syndrome. Brain 2013;136(Pt 6):1857-67.
Wilbarger JL, Cook DB. Multisensory hypersensitivity in women with fibromyalgia: 
Implications for well-being and intervention. Arch Phys Med Rehabil 2011;92:653-6.
Willis WD Jr. Dorsal root potentials and dorsal root reflexes: A double-edged sword. Exp Brain 
Res 1999;124:395-421.
Wolfe F, Clauw DJ, Fitzcharles MA, Goldenberg DL, Hauser W, Katz RL, et al. 2016 Revisions 
to the 2010/2011 fibromyalgia diagnostic criteria. Semin Arthritis Rheum 2016;46(3):319-29.
Wolfe F, Clauw DJ, Fitzcharles M-A, Goldenberg DL, Katz RS, Mease PL, et al. The American 
College of Rheumatology preliminary diagnostic criteria for fibromyalgia and measurement of 
symptom severity. Arthritis Care and Research 2010;62(5):600-10.
Wolfe F, Ross K, Anderson J, Russell IJ, Hebert L. The prevalence and characteristics of 
fibromyalgia in the general population. Arthritis Rheum 1995;38:19-28.
Woolf CJ. Central sensitization: Implications for the diagnosis and treatment of pain. Pain 
2011;152(Suppl 3):S2-15.
ZANAFLEX® [package insert]. Ardsley, NY: Acorda Therapeutics Inc; initial US approval 
1996.


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16.
SUMMARY OF CHANGES TO PROTOCOL
16.1.
Amendment 05 Dated 09 August 2021
The primary reason for this amendment is to update relevant sections of the protocol to include patients using marijuana (cannabis), 
cannabidiol, or other cannabinoids into the study. Another primary reason for this amendment is the addition of a planned second 
interim analysis. In addition, the removal of an appendix on liver function tests monitoring will also be implemented in alignment with 
other recent fremanezumab studies; the total blood volume to be collected from each patient will be updated as a result of the change 
in the blood collection tube for the INR and the removal of the second FSH assessment during Visit 2; and CGRP pathway targeting 
treatment or compound drug class will be added to the list of prohibited medications and its use added to the exclusion criteria. Table 
1 (Schedule of Study Procedures and Assessments) has been revised to reflect changes described below. All major changes to the 
protocol body are listed below in the table and are reflected in the synopsis, as applicable. Minor editorial changes (typos, punctuation, 
etc.) have been made to the protocol (and protocol synopsis, as appropriate).
Original text with changes shown
New wording
Reason/justification for change
PREFACE
The protocol amendment 04 was approved on 16 June 2020. 
However, it was not submitted to a health authority or 
Institutional Review Board/Independent Ethics Committee 
(IRB/IEC). Subsequently, an interim analysis was added to the 
study. These circumstances led to a revised protocol 
amendment (Protocol Amendment 04 Revision 01).
The preface was removed to 
follow the protocol template; 
explanation for Protocol 
Amendment 04 Revision 01 was 
added to the amendment history
SPONSOR PROTOCOL APPROVAL and APPENDIX A. CLINICAL LABORATORIES AND OTHER DEPARTMENTS AND INSTITUTIONS
Sponsor’s Authorized Representative
 
Sponsor’s Authorized Representative
 
Administrative update
Section 3.5 Schedule of Study Procedures and Assessments


Placebo-Controlled Study–Fibromyalgia
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Original text with changes shown
New wording
Reason/justification for change
See new wording column
Table 1. (Study Procedures and Assessments) has been 
modified as follows:
•
Marijuana (cannabis), cannabidiol, or other 
cannabinoids (medicinal and social history) assessment 
was added to Screening Visit (Visit 1)
•
FSH test was removed from Visit 2
Editorial changes and updates reflecting the revisions 
made to the table were applied to Table 1 footnotes.
Updated the table to reflect the 
collection of marijuana
(cannabis), cannabidiol, or other 
cannabinoids medicinal and social 
history and the removal of the 
second FSH assessment during 
Visit 2
Section 4.1 Patient Inclusion Criteria
m. [Revision 1] must meet the following pregnancy-related 
criteria:
women surgically sterile by documented complete 
hysterectomy, bilateral oophorectomy, or
bitubal ligations or confirmed to be postmenopausal 
(at least 1 year since last menstrual period) and
menopausal women confirmed by a follicle
stimulating hormone >35 U/L
men surgically sterile by documented vasectomy OR
If of childbearing potential, patients must meet any of the 
following criteria:
must use highly effective contraception method 
(Appendix F) with their partners during the entire 
study period and for 6 months after the last dose of 
the IMP

sexual abstinence is only considered a highly 
effective method if defined as refraining from 
heterosexual intercourse in the defined period. The 
reliability of sexual abstinence needs to be evaluated 
in relation to the duration of the clinical study and the 
preferred and usual lifestyle of the patient. Periodic 
abstinence (eg, calendar, ovulation, symptothermal, 
post ovulation methods), declaration of abstinence 
for the duration of a study, and withdrawal are not 
acceptable methods of contraception.
m. [Revision 1] must meet the following 
pregnancy-related criteria:

females must have a negative serum beta-human 
chorionic gonadotropin (β-HCG) test at screening 
or be sterile or postmenopausal; definitions of 
sterile and postmenopausal are provided in 
Appendix F

females of childbearing potential whose male 
partners are potentially fertile (ie, no vasectomy) 
must use highly effective birth control methods 
for the duration of the study (ie, starting at 
screening) and for 6 months after the last dose of 
the IMP; further details are provided in 
Appendix F

males who are potentially fertile/reproductively 
competent (not surgically [eg, vasectomy] or 
congenitally sterile), and their female partners are 
of childbearing potential, should use highly 
effective birth control methods for the duration of 
the study (ie, starting at screening); further details 
are provided in Appendix F
Updated the criterion with more 
concise descriptions


Placebo-Controlled Study–Fibromyalgia
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Original text with changes shown
New wording
Reason/justification for change

females patients of childbearing potential must have 
a negative serum beta-human chorionic gonadotropin 
(β-HCG) pregnancy test at screening (confirmed by 
urine dipstick β HCG pregnancy test at baseline)or 
be sterile or postmenopausal; definitions of sterile 
and postmenopausal are provided in Appendix F

females of childbearing potential whose male 
partners are potentially fertile (ie, no vasectomy) 
must use highly effective birth control methods for 
the duration of the study (ie, starting at screening) 
and for 6 months after the last dose of the IMP; 
further details are provided in Appendix F

males who are potentially fertile/reproductively 
competent (not surgically [eg, vasectomy] or 
congenitally sterile), and their female partners are of 
childbearing potential, should use highly effective 
birth control methods for the duration of the study 
(ie, starting at screening); further details are provided 
in Appendix F
Section 4.2 Patient Exclusion Criteria
x.
[Revision 1]any marijuana use within 2 months prior to 
screeningif using marijuana (cannabis), meets the MINI 
(v.7.0.2) criteria for greater than mild substance use disorder 
for marijuana (cannabis), cannabidiol, or other cannabinoids 
during the preceding 12 months; and/or the investigator is 
concerned that the use of marijuana (cannabis), cannabidiol, 
or other cannabinoids could interfere with a subject’s ability 
to provide reliable data or comply with the protocol
x.
[Revision 1] if using marijuana (cannabis), meets the 
MINI (v.7.0.2) criteria for greater than mild substance use 
disorder for marijuana (cannabis), cannabidiol, or other 
cannabinoids during the preceding 12 months; and/or the
investigator is concerned that the use of marijuana 
(cannabis), cannabidiol, or other cannabinoids could 
interfere with a subject’s ability to provide reliable data or 
comply with the protocol
The criterion was updated to 
include patients using marijuana 
(cannabis), cannabidiol, or other 
cannabinoids into the study
dd. [New criterion] has received any CGRP pathway 
targeting treatment or compound (anti-CGRP antibodies, anti-
CGRP receptor antibodies, or CGRP receptor antagonists/oral 
gepants) for migraine
dd. [New criterion] has received any CGRP pathway 
targeting treatment or compound (anti-CGRP antibodies, 
anti-CGRP receptor antibodies, or CGRP receptor 
antagonists/oral gepants) for migraine
Added the use of CGRP pathway 
targeting treatment or compound 
to the exclusion criteria
ee. [New criterion] the patient is a pregnant or nursing female 
or plans to become pregnant during the study, including the 6-
month period after the administration of the IMP
ee. [New criterion] the patient is a pregnant or nursing 
female or plans to become pregnant during the study, 
including the 6-month period after the administration of 
Added pregnant or nursing 
females, or those with plans to 
become pregnant within a 
specified time period to the 


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Clinical Study Protocol with Amendment 05
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Original text with changes shown
New wording
Reason/justification for change
the IMP
exclusion criteria
Section 5.7.1 Permitted Concomitant Medication or Therapy
If using marijuana (cannabis), cannabidiol, or other 
cannabinoids, regardless of route of administration, subjects 
should be instructed to keep their use at approximately the 
same dose/amount, route of administration, and frequency 
throughout the study.
If using marijuana (cannabis), cannabidiol, or other 
cannabinoids, regardless of route of administration, 
subjects should be instructed to keep their use at 
approximately the same dose/amount, route of 
administration, and frequency throughout the study.
Added to include patients using 
marijuana (cannabis) and other 
cannabinoids into the study
Section 5.11 Total Blood Volume
The total blood volume that will be collected for each patient 
enrolling in this study for scheduled evaluation of ADAs, 
fremanezumab concentrations, clinical laboratory tests, and 
biomarkers is approximately 161.5150.8 mL.
An additional 30 mL of blood may be collected in the event of 
follow up for liver enzymes. Details are provided in 
Appendix J.
The total blood volume that will be collected for each 
patient enrolling in this study for scheduled evaluation of 
ADAs, fremanezumab concentrations, clinical laboratory 
tests, and biomarkers is approximately 150.8 mL. Details 
are provided in Appendix J.
Updated to reflect the change in 
the blood volume to be collected 
as a result of the change in the 
blood collection tube for the INR 
requiring a decrease of 1.8 mL 
from the volume of blood to be 
collected from each patient during 
Visits 1, 3, 6, and 7, and the 
removal of the second FSH 
assessment during Visit 2
Section 7.4.2.2 Urine Drug Screen
A urine drug screen will be performed at the time points 
specified in Table 1, but patients should not be told at which 
visits the urine drug screen will be performed. The urine drug 
screen detects the presence of drugs of abuse, including 
opioids, and marijuana/cannabis (see details in the Laboratory 
Manual).
A positive result for any of the above drugs or their 
metabolites, except marijuana/cannabis, without medical 
explanation, will preclude the patient from 
randomization/enrollment or continued participation in the 
study.
A urine drug screen will be performed at the time points 
specified in Table 1, but patients should not be told at 
which visits the urine drug screen will be performed. The 
urine drug screen detects the presence of drugs of abuse, 
including opioids, and marijuana/cannabis (see details in 
the Laboratory Manual).
A positive result for any of the above drugs or their 
metabolites, except marijuana/cannabis, without medical 
explanation, will preclude the patient from 
randomization/enrollment or continued participation in the 
study.
Updated to remove the alert flag 
for marijuana/cannabis or other 
cannabinoids at study sites to 
include patients using 
cannabis/marijuana or other 
cannabinoids, as specified in 
Section 5.7.1, into the study
Section 9.6.4.2 Sensitivity Analysis
Three subgroup analyses will be conducted as part of the 
planned second interim analysis for the primary endpoint 
using descriptive statistics.
Three subgroup analyses will be conducted as part of the 
planned second interim analysis for the primary endpoint 
using descriptive statistics.
Added a general description 
pertaining to the 3 subgroup
analyses to be conducted as part 


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Original text with changes shown
New wording
Reason/justification for change

analysis by baseline pain level (PI-NRS ≥4, PI-NRS ≥5, 
and PI-NRS ≥6)

analysis by normalizing data for use of analgesia at 
baseline by adding 1 to the baseline pain score for those 
using analgesia

analysis by use of analgesia during baseline
Details of the subgroup analyses will be specified in the 
interim analysis statistical analysis plan.

analysis by baseline pain level (PI-NRS ≥4, PI-NRS 
≥5, and PI-NRS ≥6)

analysis by normalizing data for use of analgesia at 
baseline by adding 1 to the baseline pain score for 
those using analgesia

analysis by use of analgesia during baseline
Details of the subgroup analyses will be specified in the 
interim analysis statistical analysis plan.
of the planned second interim 
analysis
Section 9.15 Planned Interim Analysis
There will be 1A formal interim analysis for futility in this 
proof-of-concept study is planned after 68 patients arehave 
been enrolled; the interim analysis will be performed by an 
independent third party. A second interim analysis, for futility 
or continuation of the study, is planned after approximately
150 patients have completed the study; the interim analysis 
will be performed by a team, which is independent and 
isolated from the study team, who will be kept blinded. The 
dDetails of the interim analysisanalyses will be specified in 
anthe interim analysis statistical analysis plan. If the study 
continues after the first interim analysis, a second interim 
analysis may be performed; the nature and timing of the 
second interim analysis will be prespecified in a subsequent 
protocol amendment. To ensure study integrity, all of the 
interim analyses will be performed by an independent third 
party; the study team will be kept blinded.
 
 
 
 
A formal interim analysis for futility in this proof-of-
concept study is planned after 68 patients have been 
enrolled; the interim analysis will be performed by an 
independent third party. A second interim analysis, for 
futility or continuation of the study, is planned after 
approximately 150 patients have completed the study; the 
interim analysis will be performed by a team, which is 
independent and isolated from the study team, who will be 
kept blinded. Details of the interim analyses will be 
specified in the interim analysis statistical analysis plan.
 
 
 
 
 
 
.
Updated to include details of a 
planned second interim analysis 
APPENDIX B.
STUDY PROCEDURES AND ASSESSMENTS BY VISIT


Placebo-Controlled Study–Fibromyalgia
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Original text with changes shown
New wording
Reason/justification for change
1.
Procedures for screening (Visit 1, day -35 [week -5])
The Screening Visit (Visit 1) will take place not more than 3 
weeks before the Baseline Assessment Period Start (BAPS) 
Visit (Visit 2). The following procedures will be performed at 
Visit 1: 
…
•
marijuana (cannabis), cannabidiol, or other cannabinoids
(medicinal and social history)
…
1.
Procedures for screening (Visit 1, day -35 [week -5])
The Screening Visit (Visit 1) will take place not more than 
3 weeks before the Baseline Assessment Period Start 
(BAPS) Visit (Visit 2). The following procedures will be 
performed at Visit 1: 
…
•
marijuana (cannabis), cannabidiol, or other 
cannabinoids (medicinal and social history)
…
Added the collection of marijuana 
(cannabis), cannabidiol, or other 
cannabinoids medicinal and social 
history as patients using 
marijuana (cannabis), cannabidiol, 
or other cannabinoids will be 
included into the study
3.
Procedures Before Administration of Investigational 
Medicinal Product(s) (BAPS Visit [Visit 2, day -14 (week -3) 
(±2 days)])
Patients who meet the inclusion and exclusion criteria at Visit 
1 will continue to Visit 2, when initial baseline assessments 
will be conducted.
The following procedures will be performed at Visit 2:
•
review inclusion and exclusion criteria
•
study assessments/pain reporting training
•
e-diary data review training
•
dispense/account rescue medication
•
provide e-diary
•
PI-NRS (recorded daily)
•
prior medication and treatment history
•
urine drug screen
•
abbreviated physical examination
•
vital signs measurements
•
serum FSH test (for postmenopausal women only)
…
3.
Procedures Before Administration of Investigational 
Medicinal Product(s) (BAPS Visit [Visit 2, day -14 (week 
-3) (±2 days)])
Patients who meet the inclusion and exclusion criteria at 
Visit 1 will continue to Visit 2, when initial baseline 
assessments will be conducted.
The following procedures will be performed at Visit 2:
•
review inclusion and exclusion criteria
•
study assessments/pain reporting training
•
e-diary data review training
•
dispense/account rescue medication
•
provide e-diary
•
PI-NRS (recorded daily)
•
prior medication and treatment history
•
urine drug screen
•
abbreviated physical examination
•
vital signs measurements
…
Updated to reflect the removal of 
serum FSH test during Visit 2
APPENDIX F.
BIRTH CONTROL METHODS AND PREGNANCY TESTING
Women/Girls of nonchildbearing potential are defined as:
•
surgically (documented hysterectomy, bilateral 
oophorectomy, or bilateral salpingectomy) or congenitally 
Women/Girls of nonchildbearing potential are defined 
as:
•
surgically (documented hysterectomy, bilateral 
Added the definition of 
women/girls of non-childbearing 
potential to Appendix F for clarity


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Original text with changes shown
New wording
Reason/justification for change
sterile
•
postmenopausal
oophorectomy, or bilateral salpingectomy) or congenitally 
sterile
•
postmenopausal
APPENDIX I.
LIST OF PROHIBITED MEDICATIONS AND THERAPEUTIC INTERVENTIONS
CALCITONIN GENE-RELATED PEPTIDE PATHWAY 
TARGETING TREATMENT OR COMPOUND
Anti-CGRP Antibodies
Eptinezumab-jjmr (Vyepti)
Galcanezumab-gnlm (Emgality)
Anti-CGRP Receptor Antibodies
Erenumab-aooe (Aimovig)
CGRP Receptor Antagonists/Oral Gepants
Ubrogepant (Ubrelvy)
Rimegepant (Nurtec ODT)
CALCITONIN GENE-RELATED PEPTIDE 
RECEPTOR PATHWAY TARGETING 
TREATMENT OR COMPOUND
Anti-CGRP Antibodies
Eptinezumab-jjmr (Vyepti)
Galcanezumab-gnlm (Emgality)
Anti-CGRP Receptor Antibodies
Erenumab-aooe (Aimovig)
CGRP Receptor Antagonists/Oral Gepants
Ubrogepant (Ubrelvy)
Rimegepant (Nurtec ODT)
Added CGRP pathway targeting 
treatment or compound to 
Appendix I
OTHER THERAPEUTIC INTERVENTIONS
Herbal agents (eg, St. John’s Wort)
Topical lidocaine within 1 month prior to screening
Capsaicin within 6 months prior to screening
Cannabinoids
Oral corticosteroids
OTHER THERAPEUTIC INTERVENTIONS
Herbal agents (eg, St. John’s Wort)
Topical lidocaine within 1 month prior to screening
Capsaicin within 6 months prior to screening
Oral corticosteroids
Cannabinoids was removed to 
include patients using marijuana 
(cannabis), cannabidiol, or other 
cannabinoids into the study
APPENDIX J.
TOTAL BLOOD VOLUME


Placebo-Controlled Study–Fibromyalgia
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Original text with changes shown
New wording
Reason/justification for change
Total blood volume to be collected for each patient in this 
study is approximately 161.5150.8 mL for scheduled tests. An 
additional 30 mL of blood may be collected in the event of 
follow up for liver enzymes. Refer to the Laboratory Manual 
for details on blood sampling.
Total Blood Volumes
Visit 
number
Visit 1
Visit 2
Visit 3
Visit 6
Visit 7
Total
Visit 
type
Screening 
visit
BAPS 
visit
Double-blind 
treatment
EOT/ 
EOS 
or ET 
visit
Number 
of 
samples
6
1 0
9
9
9
3433
Volume 
(mL)
33.5 31.7
3.50
41.5 
39.7
41.5 
39.7
41.5 
39.7
161.5 
150.8
a  This sample is for FSH assessment and will be drawn from 
postmenopausal women only.
See FDA Guidance (Guidance for Industry 2007) for acceptable 
blood volume loss per collection procedure.
BAPS = Baseline Assessment Period Start; EOS = end-of-study; 
EOT = end-of-treatment; ET = early termination; FDA = Food and 
Drug Administration; FSH = follicle stimulating hormone..
Total blood volume to be collected for each patient in this 
study is approximately 150.8 mL for scheduled tests. Refer 
to the Laboratory Manual for details on blood sampling.
Total Blood Volumes
Visit 
number
Visit 1
Visit 
2
Visit 
3
Visit 
6
Visit 
7
Total
Visit 
type
Screening 
visit
BAPS 
visit
Double-blind 
treatment
EOT/ 
EOS 
or 
ET 
visit
Number 
of 
samples
6
0
9
9
9
33
Volume 
(mL)
31.7
0
39.7
39.7
39.7
150.8
See FDA Guidance (Guidance for Industry 2007) for acceptable 
blood volume loss per collection procedure.
BAPS = Baseline Assessment Period Start; EOS = end-of-study; 
EOT = end-of-treatment; ET = early termination; FDA = Food 
and Drug Administration.
Updated to reflect the change in 
the blood volume to be collected 
as a result of the change in the 
blood collection tube for the INR 
requiring a decrease of 1.8 mL 
from the volume of blood to be 
collected from each patient during 
Visits 1, 3, 6, and 7, and the 
removal of the second FSH 
assessment during Visit 2
APPENDIX O. MANAGEMENT OF STUDY ACTIVITIES DURING COVID-19
APPENDIX O. GUIDANCE ON SAFETY 
MONITORING
APPENDIX N. MANAGEMENT OF STUDY 
ACTIVITIES DURING COVID-19
APPENDIX O. MANAGEMENT OF STUDY 
ACTIVITIES DURING COVID-19
An entire appendix containing the 
guidance on monitoring patients 
with elevated liver function tests 
was removed, because the level of 
monitoring of liver function tests 
described in it is no longer 
required, as liver function is no 
longer a protocol-defined adverse 
event of special interest in 
fremanezumab studies; the 


Placebo-Controlled Study–Fibromyalgia
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Original text with changes shown
New wording
Reason/justification for change
deletion resulted to an update to 
the lettering of subsequent 
appendices and their in-text cross 
references
16.2.
Amendment 04 with Revision 01 Dated 25 June 2020
The primary reason for this revision is to include interim analyses. All major changes to the protocol body are listed below in the table 
and are reflected in the synopsis, as applicable. Minor editorial changes (typos, punctuation, etc) have been made to the protocol (and 
protocol synopsis, as appropriate).
Original text with changes shown
New wording
Reason/justification for change
PREFACE
The protocol amendment 04 was approved on 16 June 2020. 
However, it was not submitted to a health authority or 
Institutional Review Board/Independent Ethics Committee 
(IRB/IEC). Subsequently, an interim analysis was added to the 
study. These circumstances led to a revised protocol 
amendment (Protocol Amendment 04 Revision 01).
The protocol amendment 04 was approved on 16 June 
2020. However, it was not submitted to a health authority 
or Institutional Review Board/Independent Ethics 
Committee (IRB/IEC). Subsequently, an interim analysis 
was added to the study. These circumstances led to a 
revised protocol amendment (Protocol Amendment 04 
Revision 01).
A preface was added to explain 
why Protocol Amendment 04 was 
updated with Revision 01, and the 
date of approval of Amendment 
04, which was previously listed as 
12 June 2020, was corrected to 16 
June 2020 (when the approval 
signature was obtained)
Section 9.15 Planned Interim Analysis
There will be no1 formal interim analysis for futility in this 
study after 68 patients are enrolled. The details of the interim 
analysis will be specified in an interim analysis statistical 
analysis plan. If the study continues after the first interim 
analysis, a second interim analysis may be performed; the 
nature and timing of the second interim analysis will be 
prespecified in a subsequent protocol amendment. To ensure 
study integrity, all of the interim analyses will be performed 
by an independent third party; the study team will be kept 
blinded.
There will be 1 formal interim analysis for futility in this 
study after 68 patients are enrolled. The details of the 
interim analysis will be specified in an interim analysis 
statistical analysis plan. If the study continues after the 
first interim analysis, a second interim analysis may be 
performed; the nature and timing of the second interim 
analysis will be prespecified in a subsequent protocol 
amendment. To ensure study integrity, all of the interim 
analyses will be performed by an independent third party; 
the study team will be kept blinded.
Updated to include futility and 
interim analyses


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16.3.
Amendment 04 Dated 16 June 2020
The primary reasons for this amendment are to add to the exclusion criterion related to prior hypersensitivity reactions in patients with 
a history of Stevens-Johnson Syndrome or toxic epidermal necrolysis syndrome. A second primary reason for this amendment is to 
provide flexibility and reduce patient burden. In addition, rescreening will be available to patients who could not be randomized due to 
technical issues, or who were in screening and not randomized because of the Coronavirus Disease 2019 (COVID-19) pandemic. All 
major changes to the protocol body are listed below in the table, and are reflected in the synopsis, as applicable. Minor editorial 
changes (typos, punctuation, etc) have been made to the protocol (and protocol synopsis, as appropriate). 
Additionally, COVID-19 pandemic-related operational updates were added to the study as a new appendix (Appendix P).
The Clinical Study Protocol Synopsis, Table 1 (Study Procedures and Assessments), and Figure 1 (Overall Study Schematic Diagram) 
have been revised to reflect changes described below.
Original text with changes shown
New wording
Reason/justification for change
TITLE PAGE
Teva Branded Pharmaceutical
Products R&D, Inc.
41 Moores Road145 Brandywine Parkway
FrazerWest Chester, Pennsylvania 1938055
United States of America
Teva Branded Pharmaceutical
Products R&D, Inc.
145 Brandywine Parkway
West Chester, Pennsylvania 19380
United States of America
Administrative update
SPONSOR PROTOCOL APPROVAL
Sponsor’s Authorized Representative
 
Sponsor’s Authorized Representative
Provided additional information 
on title/credentials for Sponsor’s 
Authorized Representative


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COORDINATING INVESTIGATOR AGREEMENT
Executed signature pages are maintained within the 
Investigator Site File and the Trial Master File
Executed signature pages are maintained within the 
Investigator Site File and the Trial Master File
Clarified that the coordinating 
investigator signature will be on 
file in the official repository
Section 1.1 Introduction (Other sections affected by this change: Section 5.1.1 and Section 5.1.2 [Table 2]) 
Fremanezumab (also known as TEV-48125 [formerly PF-
04427429, RN307, and LBR-101, TEV 48125, or Ajovy]), a 
humanized immunoglobulin G (IgG) 2Δa/kappa monoclonal 
antibody (mAb) derived from a murine precursor, is currently 
approved in the United States (US) for the preventive
treatment of migraine in adults (episodic and chronic) and 
marketed under the trade name AJOVY®. Fremanezumab is 
under development for cluster headache (CH), persistent post 
traumatic headache, and chronic pain indications.
Refer to the current Investigator’s Brochure (IB) for detailed 
information on the background, pharmaceutical particulars, 
nonclinical experience, and clinical experience with 
fremanezumab.
Fremanezumab (TEV-48125 [formerly PF-04427429, 
RN307, and LBR-101]), a humanized immunoglobulin G 
(IgG) 2Δa/kappa monoclonal antibody (mAb) derived 
from a murine precursor, is currently approved in the 
United States (US) for the preventive treatment of 
migraine in adults and marketed under the trade name 
AJOVY®. Fremanezumab is under development for 
chronic pain indications.
Refer to the current Investigator’s Brochure (IB) for 
detailed information on the background, pharmaceutical 
particulars, nonclinical experience, and clinical experience 
with fremanezumab.
The history of the names 
representing fremanezumab was 
clarified. Delta symbol added for 
accuracy in describing the 
antibody
Added a sentence referring the 
reader where information on 
fremanezumab is located
Section 1.2.2 Clinical Studies
As of 30 August 20182019, approximately 40804972
subjects/patients (33334062 adult patients with migraine, 15 
pediatric patients with migraine, 250380 patients with cluster 
headache [CH], 2337 patients with persistent post-traumatic 
headache, an estimated 4 patients with FM, and 474 healthy 
subjects) have been exposed to fremanezumab. The 
fremanezumab clinical program comprises 2324 clinical 
studies (10 Phase 1; 54 Phase 2, 2b, or 2b/3; and 810 Phase 3 
studies), of which 1219 have been completed.
The safety and tolerability of fremanezumab was studied in all 
of the 12 completed 24 studies in the migraine clinical 
program (ie, 8 Phase 1 studies in healthy subjects, and 2 Phase 
2b studies and 2 Phase 3 studies in patients with migraine10 
Phase 1, 2 Phase 2, 2 Phase 2b, 2 Phase 2b/3, and 8 Phase 3 
studies). Based on the safety results of the completed studies, 
the safety profile was assessed to include the following events 
As of 30 August 2019, approximately 4972 
subjects/patients (4062 adult patients with migraine, 15 
pediatric patients with migraine, 380 patients with cluster 
headache [CH], 37 patients with persistent post-traumatic 
headache, an estimated 4 patients with FM, and 474 
healthy subjects) have been exposed to fremanezumab. 
The fremanezumab clinical program comprises 24 clinical 
studies (10 Phase 1; 4 Phase 2, 2b, or 2b/3; and 10 Phase 3 
studies), of which 19 have been completed.
The safety and tolerability of fremanezumab was studied 
in all of the 24 studies in the clinical program (ie, 10 Phase 
1, 2 Phase 2, 2 Phase 2b, 2 Phase 2b/3, and 8 Phase 3 
studies). Based on the safety results of the completed 
studies, the safety profile was assessed to include the 
following events as identified risks qualifying as adverse 
drug reactions: injection site induration, injection site 
Updated text with current 
information


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as identified risks qualifying as adverse drug reactions: 
injection site induration, injection site erythema, injection site 
pruritus, injection site pain, and injection site rash.
erythema, injection site pruritus, injection site pain, and 
injection site rash.
Section 1.3.1 Known and Potential Benefits and Risks of the Test Investigational Medicinal Product(s)
Risks
Fremanezumab (sc) has generally been well tolerated over the 
range of doses evaluated (single doses of 0.02 to 2000 mg in 
healthy subjects, multiple doses of 30 to 300 mg in healthy 
volunteers, and multiple doses of 225 to 900 mg sc in patients 
with migraine). The most common treatment-emergent 
adverse events in patients with migraine were mild to 
moderate transient general administration site 
disorders/reactions. Other commonly reported treatment-
emergent adverse events were upper respiratory tract 
infection, back pain, nausea, and dizziness. Based on the 
exposure and body of evidence from Teva’s studies of 
fremanezumab in other indications, the benefit and risk 
assessment for fremanezumab is expected to be favorable.
Known risks that do not impact the risk-benefit profile are as 
follows:
•
injection site induration
•
injection site erythema
•
injection site pruritus
•
injection site pain
•
injection site rash
None of these risks are considered clinically meaningful.
Severe hypersensitivity reactions are regarded as a potential 
risk for fremanezumab based on the following considerations: 
mild and moderate drug hypersensitivity events were observed 
infrequently albeit with similar incidence in placebo and 
fremanezumab in the clinical development program for 
migraine, but no anaphylaxis or severe hypersensitivity 
reactions related to the investigational medicinal product 
(IMP) were seen. However, it cannot be excluded that severe 
events may occur in the futureWhile no severe 
Risks
Fremanezumab (sc) has generally been well tolerated over 
the range of doses evaluated (single doses of 0.02 to 2000 
mg in healthy subjects, multiple doses of 30 to 300 mg in 
healthy volunteers, and multiple doses of 225 to 900 mg sc 
in patients with migraine). The most common treatment-
emergent adverse events in patients with migraine were 
mild to moderate transient general administration site 
disorders/reactions. Other commonly reported treatment-
emergent adverse events were upper respiratory tract 
infection, back pain, nausea, and dizziness. Based on the 
exposure and body of evidence from Teva’s studies of 
fremanezumab in other indications, the benefit and risk 
assessment for fremanezumab is expected to be favorable.
Known risks that do not impact the risk-benefit profile are 
as follows:
•
injection site induration
•
injection site erythema
•
injection site pruritus
•
injection site pain
•
injection site rash
None of these risks are considered clinically meaningful.
Severe hypersensitivity reactions are regarded as a 
potential risk for fremanezumab based on the following 
considerations: mild and moderate drug hypersensitivity 
events were observed infrequently albeit with similar 
incidence in placebo and fremanezumab in the clinical 
development program for migraine, but no anaphylaxis or 
severe hypersensitivity reactions related to the 
investigational medicinal product (IMP) were seen. While 
no severe hypersensitivity or anaphylactic reactions 
Updated text to include new 
information on injection site 
reactions, one case of Stevens-
Johnson Syndrome, clarification 
for anaphylaxis reactions, and 
theoretical risks of unfavorable 
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hypersensitivity or anaphylactic reactions occurred as a result 
of fremanezumab administration in the clinical development 
program for migraine, a small number of severe 
hypersensitivity reactions, including anaphylaxis, have been 
reported in the postmarketing period. One patient, who was 
taking multiple concomitant medications including 
lamotrigine and treated with fremanezumab, was reported to 
have Stevens-Johnson Syndrome. This reaction has also been 
rarely reported to occur in patients taking other anti-CGRP 
pathway monoclonal antibodies, along with concomitant 
medications including lamotrigine.
Because CGRP is a vasodilator, there is a theoretical risk of 
unfavorable cardiovascular effects with CGRP inhibition. 
Extensive research conducted with the CGRP ligand 
antagonists has not identified relevant safety cardiovascular 
concerns in humans. Dedicated studies conducted in monkey 
and humans using fremanezumab have not identified 
clinically relevant changes in heart rate, blood pressure, or 
other cardiovascular parameters. No relevant cardiovascular 
event has been seen in the completed studies.
Refer to the current IB for aAdditional information regarding 
benefits and risks to patients may be found in the IB.
occurred as a result of fremanezumab administration in the 
clinical development program for migraine, a small 
number of severe hypersensitivity reactions, including 
anaphylaxis, have been reported in the postmarketing 
period. One patient, who was taking multiple concomitant 
medications including lamotrigine and treated with 
fremanezumab, was reported to have Stevens-Johnson 
Syndrome. This reaction has also been rarely reported to 
occur in patients taking other anti-CGRP pathway 
monoclonal antibodies, along with concomitant 
medications including lamotrigine.
Because CGRP is a vasodilator, there is a theoretical risk 
of unfavorable cardiovascular effects with CGRP 
inhibition. Extensive research conducted with the CGRP 
ligand antagonists has not identified relevant safety 
cardiovascular concerns in humans. Dedicated studies 
conducted in monkey and humans using fremanezumab 
have not identified clinically relevant changes in heart 
rate, blood pressure, or other cardiovascular parameters. 
No relevant cardiovascular event has been seen in the
completed studies.
Refer to the current IB for additional information 
regarding benefits and risks to patients.
 
 
 
 
 
 
 
 
 


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Section 3.1 General Study Design and Study Schematic Diagram (Other sections affected by this change: Section 3.5, Section 4.1, Section 7.1.2, 
Section 7.1.5, Appendix B, and Appendix J)
This is a 2135-week, multicenter, randomized, double-blind, 
placebo-controlled, parallel-group study to evaluate the 
efficacy and safety of fremanezumab in adult patients with 
FM. Fremanezumab 225 mg, fremanezumab 675 mg, or 
placebo will be administered sc for 4 monthly doses. The 
study will consist of a 17- to 35-day screening period (Visit 1, 
phone contact, and Baseline Assessment Period Start [BAPS] 
Visit [Visit 2]), and a 16-week double-blind treatment period 
(Visits 3, 4, 5, 6, and 7), and a 14 week follow up period with 
1 follow up visit (Visit 8). Patients enrolled in the study will 
be male or female patients with FM. Patients will be required 
to wash out of all prohibited concomitant medication(s) prior 
to the BAPS Visit (Visit 2).
Therefore, the total duration of patient participation in the 
study is planned to be 3521 weeks, consisting of the screening 
period of up to 5 weeks (ranging from 17 to 35 days), and the 
double-blind treatment period of 16 weeks, and the 14 week 
follow up period; details are given in Section 5.
The end-of-study (EOS) is defined as completion of the last 
follow up visit of the last patient.
The study duration will be from May 2019 until 
approximately May 2021July 2022.
This is a 21-week, multicenter, randomized, double blind,
placebo controlled, parallel group study to evaluate the 
efficacy and safety of fremanezumab in adult patients with 
FM. Fremanezumab 225 mg, fremanezumab 675 mg, or 
placebo will be administered sc for 4 monthly doses. The 
study will consist of a 17- to 35-day screening period 
(Visit 1, phone contact, and Baseline Assessment Period 
Start [BAPS] Visit [Visit 2]), and a 16-week double blind 
treatment period (Visits 3, 4, 5, 6, and 7). Patients enrolled 
in the study will be male or female patients with FM. 
Patients will be required to wash out of all prohibited 
concomitant medication(s) prior to the BAPS Visit 
(Visit 2).
Therefore, the total duration of patient participation in the 
study is planned to be 21 weeks, consisting of the 
screening period of up to 5 weeks (ranging from 17 to 
35 days) and the double blind treatment period of 
16 weeks; details are given in Section 5.
The end-of-study (EOS) is defined as completion of the 
visit of the last patient.
The study duration will be from May 2019 until 
approximately July 2022.
Removed Visit 8 to shorten the 
duration of patient participation 
and reduce patient burden
In addition, the estimated overall 
study duration was updated based 
on study activities to date
Section 3.1 General Study Design and Study Schematic Diagram, Figure 1 (Other sections affected by this change: Section 3.5 [Table 1, new footnote c, 
revised footnote i], Section 5.1.1.2, Section 5.3, Appendix B, and Appendix O)
Note: For Visits 4 and 5 (when at-home dosing is available), 
home visits are permitted for patients who are not able to go to 
the investigational center or if the investigational center staff 
are not able to see patients at the investigational center (see 
Section 3.5).
Note: For Visits 4 and 5 (when at-home dosing is 
available), home visits are permitted for patients who are 
not able to go to the investigational center or if the 
investigational center staff are not able to see patients at 
the investigational center (see Section 3.5).
Added note in Study Schematic 
Diagram to reflect home dosing at 
Visits 4 and 5
Section 3.2 Planned Number of Patients and Countries
Approximately 369 patients will be screened to achieve 240 
patients will be randomized.
Approximately 240 patients will be randomized.
The study is planned to be conducted in the United States 
Increased planned number of 
investigational centers based on 


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The study is planned to be conducted in the United States of 
America in approximately 3040 investigational centers.
of America in approximately 40 investigational centers.
study activities to date
Section 3.5 Schedule of Study Procedures and Assessments (Table 1) (Other sections affected by one or more of these changes: Section 3.6.2, 
Section 5.1.1.2, Section 6.1.5, Appendix B, and Appendix J)
For Visits 4 and 5 (when at-home dosing is available), home 
visits are permitted for patients who are not able to go to the 
investigational center or if the investigational center staff are 
not able to see patients at the investigational center. Home 
visits may be completed by a Home Care Visiting Service 
Provider (ie, home care, visiting nurse, or other medical 
professional) under supervision by the investigational center 
staff, as required, to complete assessments/procedures. The 
Home Care Visiting Service Provider will be a centralized 
provider identified by the sponsor. The investigational center 
must contact the sponsor before any home visits are initiated. 
Home visits will be documented.
Visits should be conducted in accordance with the timelines 
specified in the protocol (see Table 1), whenever feasible. 
Averting a missed visit is considered a high priority. 
Therefore, if additional time is required beyond the specified 
visit window to complete the visit, the Medical Monitor 
should be contacted, and the visit window may be extended 
for appropriate reasons. In such instances, the reasons for 
deviation in the date of the visit will be clearly documented.
For Visits 4 and 5 (when at-home dosing is available), 
home visits are permitted for patients who are not able to 
go to the investigational center or if the investigational 
center staff are not able to see patients at the 
investigational center. Home visits may be completed by a 
Home Care Visiting Service Provider (ie, home care, 
visiting nurse, or other medical professional) under 
supervision by the investigational center staff, as required, 
to complete assessments/procedures. The Home Care 
Visiting Service Provider will be a centralized provider 
identified by the sponsor. The investigational center must 
contact the sponsor before any home visits are initiated. 
Home visits will be documented.
Visits should be conducted in accordance with the 
timelines specified in the protocol (see Table 1), whenever 
feasible. Averting a missed visit is considered a high 
priority. Therefore, if additional time is required beyond 
the specified visit window to complete the visit, the 
Medical Monitor should be contacted, and the visit 
window may be extended for appropriate reasons. In such 
instances, the reasons for deviation in the date of the visit 
will be clearly documented.
To provide information on home 
visits
Visit 8 (EOS) was removed. Accordingly, the following 
assessments were added at Visit 7 (EOT/EOS or ET):

Blood sample for serum ADA concentration

Visit 7 (EOT/EOS or ET)
Removed Visit 8 to shorten the 
duration of patient participation 
and reduce patient burden. Given 
this removal, added more 
assessments (eg, ADA blood 
sample collection) to Visit 7 to 
serve the purpose of Visit 8.
Day and allowed time window for Days 29, 57, 85, and 113 
±37 days
Day and allowed time window for Days 29, 57, 85, and 
113 ±7 days
To provide flexibility and reduce 
patient burden


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At Visits 4 and 5, the following assessments were removed:

Clinical laboratory tests (serum chemistry, 
hematology, and urinalysis)

Blood samples for plasma concentration of IMP

Blood sample for serum ADA concentration

To reduce patient burden
At Visits 4 and 6, the following procedure was added: Inform 
patients of study restrictions and compliance
To improve patient compliance
Alcohol screen (social history)m
Alcohol (social history)m
Clarification
The injection site reactions assessment was deleted
Injections site reactions will be 
spontaneously reported and 
included in adverse event 
assessment
A footnote c was added to Visits 4 and 5.
c
For Visits 4 and 5 (when at-home dosing is available), 
home visits are permitted for patients who are not able to go to 
the investigational center or if the investigational center staff 
are not able to see patients at the investigational center (see 
Section 3.5).
c
For Visits 4 and 5 (when at-home dosing is available), 
home visits are permitted for patients who are not able to 
go to the investigational center or if the investigational 
center staff are not able to see patients at the 
investigational center (see Section 3.5).
Clarified that visits can also occur 
at home
he
Assessment will be completed at any unscheduled 
visit.For unscheduled visits, procedures and assessments will 
be completed as needed, at the investigator’s discretion. For 
further details, see Appendix B.
e
For unscheduled visits, procedures and assessments 
will be completed as needed, at the investigator’s 
discretion. For further details, see Appendix B.
Clarified footnote on unscheduled 
visits and moved its location to 
indicate that investigator has 
discretion on all assessments and 
procedures at such visits
jk
The 2016 ACR diagnostic criteria for fibromyalgia 
(Wolfe et al 2016) must be met at the Screening Visit and at 
the Randomization Visit.
k
The 2016 ACR diagnostic criteria for fibromyalgia 
(Wolfe et al 2016) must be met at the Screening Visit.
Removed extraneous detail
aabb The C-SSRS Baseline/Screening version will be 
completed at Visit 1, and the C-SSRS Since Last Visit version 
will be completed at all other time points except for Visit 7.
bb
The C-SSRS Baseline/Screening version will be 
completed at Visit 1, and the C-SSRS Since Last Visit 
version will be completed at all other time points.
Correction


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Section 3.6.1 e-Diary (Other sections affected by this change: Section 3.5 [Table 1, footnote h] and Appendix B)
Patients will be trained by the site staff on the use of the 
e-diary at Visits 1 and 2, and as necessary at needed for
subsequent visits retraining throughout the study.
Patients will be trained by the site staff on the use of the e-
diary at Visits 1 and 2, and as needed for subsequent 
retraining throughout the study.
Clarified that training can also 
occur in between the visits and 
not just at specified visits
Section 3.6.2 Tablet (Other sections affected by this change: Section 3.5 [Table 1, footnote g] and Appendix B)
Patients will be trained by the site staff via the tablet on 
accurate pain reporting and placebo response reduction at 
Visits 1 and 2, and as necessary at needed for subsequent 
visits retraining throughout the study.
Patients will be trained by the site staff via the tablet on 
accurate pain reporting and placebo response reduction at 
Visits 1 and 2, and as needed for subsequent retraining 
throughout the study.
Clarified that training can also 
occur in between the visits and 
not just at specified visits
Section 4.1 Patient Inclusion Criteria (Other section affected by this change: Section 3.5 [Table 1], for second change only)
c.
agree to comply with the requirements and restrictions 
listed in this protocol, including remaining at the clinic for the 
duration of each required visit during the study period to 
complete all scheduled procedures and assessments, and 
returning to the clinic for the follow up procedures and 
assessments as specified in this protocol
c.
agree to comply with the requirements and restrictions 
listed in this protocol, including remaining at the clinic for 
the duration of each required visit during the study period 
to complete all scheduled procedures and assessments
Removed follow-up visit to 
shorten the duration of patient 
participation and reduce patient 
burden
e.
willing to comply with recording of once daily scores 
using the PI-NRS, completed every evening (approximately 
the same time each day) starting at the BAPS Visit (Visit 2) 
and continuing to the end-of-treatment (EOT)/EOS or early 
termination (ET) Visit (Visit 7). A minimum of 12 of 14 daily 
average pain intensity ratings AND daily worst pain intensity
ratings are required to be recorded in an e-diary during the 
baseline assessment period (Section 
1.6.3
).
e.
willing to comply with recording of once daily scores 
using the PI-NRS, completed every evening 
(approximately the same time each day) starting at the 
BAPS Visit (Visit 2) and continuing to the end-of-
treatment (EOT)/EOS or early termination (ET) Visit 
(Visit 7). A minimum of 12 of 14 daily average pain 
intensity ratings AND daily worst pain intensity ratings are 
required to be recorded in an e-diary during the baseline 
assessment period (Section 
1.6.3
).
Clarified that the minimal 
recording requirement for daily 
pain ratings during the baseline 
assessments period applies to both 
the daily average and the daily 
worst pain ratings
f.
all of the following diagnostic criteria for FM according 
to 2016 American College of Rheumatology (Wolfe et al 
2016) are met at the Screening Visit and at randomization:
f.
all of the following diagnostic criteria for FM 
according to 2016 American College of Rheumatology 
(Wolfe et al 2016) are met at the Screening Visit
A duplicate of the screening 
assessment was not needed
n.
must agree not to participate in another interventional 
study from the screening period through the EOT/EOS or ET
Visit
n.
must agree not to participate in another interventional 
study from the screening period through the EOT/EOS or 
ET Visit
Clarification 


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Section 4.2 Patient Exclusion Criteria
a.
unable or unwilling to discontinue/washout of prohibited 
medications (Appendix JI); selective serotonin reuptake 
inhibitors (SSRIs; with the exception of <60 mg/day of 
fluoxetine) or over the counter (OTC) medications used to 
treat depression or anxiety (Appendix J) are permitted if 
started at least 90 days prior to screening, have been on a 
stable dose for at least 90 days, and are expected to remain on 
a stable dose throughout the study Note: Medications used to 
treat depression or anxiety are permitted provided they were 
started at least 90 days prior to screening, have been used at a 
stable dose for at least 90 days, and will be maintained at that 
dose for the duration of the study. Therefore, both over-the-
counter (OTC) medications used to treat depression or anxiety 
and selective serotonin reuptake inhibitors (SSRIs; with the 
exception of ≥60 mg/day of fluoxetine) are permitted.
a.
unable or unwilling to discontinue/washout of 
prohibited medications (Appendix I); Note: Medications 
used to treat depression or anxiety are permitted provided 
they were started at least 90 days prior to screening, have 
been used at a stable dose for at least 90 days, and will be 
maintained at that dose for the duration of the study. 
Therefore, both over-the-counter (OTC) medications used 
to treat depression or anxiety and selective serotonin 
reuptake inhibitors (SSRIs; with the exception of ≥60 
mg/day of fluoxetine) are permitted.
Clarification of text
n.
known history of hypersensitivity reactions to injected 
proteins, including mAbs and animal venoms, or a history of 
Stevens-Johnson Syndrome/toxic epidermal necrolysis 
syndrome
n.
known history of hypersensitivity reactions to injected 
proteins, including mAbs and animal venoms, or a history 
of Stevens-Johnson Syndrome/toxic epidermal necrolysis 
syndrome
Updated to align with program-
wide safety update
s.
any prior exposure to mAbs targeting the CGRP pathway 
(including erenumab, ALD304eptinezumab, galcanezumab, or 
fremanezumab) at any time. If the patient has participated in a 
clinical study with any of these mAbs, it has to be confirmed 
that the patient received placebo in order to be eligible for this 
study.
s.
any prior exposure to mAbs targeting the CGRP 
pathway (including erenumab, eptinezumab, 
galcanezumab, or fremanezumab) at any time. If the 
patient has participated in a clinical study with any of 
these mAbs, it has to be confirmed that the patient 
received placebo in order to be eligible for this study.
Updated to use the approved 
generic name of ALD304
w.
known history of alcohol and/or drug abuse within the 
past 12 months per the MINI or have a positive urine drug 
screen for illegal drugs of abuse or alcohol test at the 
Screening Visit, BAPS Visit, or prior to randomization
w.
known history of alcohol and/or drug abuse within the 
past 12 months per the MINI or have a positive urine drug 
screen for illegal drugs of abuse at the Screening Visit, 
BAPS Visit, or prior to randomization
Updated to reflect that reference 
to urine alcohol testing is no 
longer required
Section 4.5 Rescreening (Other section affected by this change: Section 4.6)
There is no provision for rescreening. Rescreening will not be 
routinely allowed for patients who are screened but not 
enrolled (eg, because eligibility criteria were not met 
[inclusion criteria not met and/or exclusion criteria met]). 
Rescreening will not be routinely allowed for patients who 
are screened but not enrolled (eg, because eligibility 
criteria were not met [inclusion criteria not met and/or 
exclusion criteria met]). However, patients who were 
Updated rescreening criterion to 
account for extraordinary 
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However, patients who were screened but not enrolled due to 
technical issues (eg, diary malfunction) or are out of Visit 2 
window due to urgent extenuating circumstances (eg, public 
health emergency) may be considered for screening one 
additional time. Only patients who were not enrolled due to 
these limited issues/circumstances may be screened a second 
time.
If the patient is screened again, a new informed consent form 
(ICF) will need to be signed and a new screening number will 
be assigned.
screened but not enrolled due to technical issues (eg, diary 
malfunction) or are out of Visit 2 window due to urgent 
extenuating circumstances (eg, public health emergency) 
may be considered for screening one additional time. Only 
patients who were not enrolled due to these limited 
issues/circumstances may be screened a second time.
If the patient is screened again, a new informed consent 
form (ICF) will need to be signed and a new screening 
number will be assigned.
Section 4.6 Screen Failure
Patients who fail screening will not be allowed to 
rescreen.Screening failures are defined as participants who 
consent to participate in the clinical study but are not 
subsequently randomized. Data for screen failure reason and 
minimal information, including but not limited to 
demography, adverse events from the time of informed 
consent, and subject disposition, will be entered into the 
eCRF.
Screening failures are defined as participants who consent 
to participate in the clinical study but are not subsequently 
randomized. Data for screen failure reason and minimal 
information, including but not limited to demography, 
adverse events from the time of informed consent, and 
subject disposition, will be entered into the eCRF.
Provided additional details on 
screen failures
Section 5.1.1 Test Investigational Medicinal Product
Fremanezumab is a humanized IgG2Δa/kappa monoclonal 
antibody derived from a murine precursor. Additional details 
may be found are provided in Table 2 and in the current IB for 
fremanezumab.
Fremanezumab is a humanized IgG2Δa/kappa monoclonal 
antibody derived from a murine precursor. Additional 
details are provided in Table 2 and in the current IB.
Clarification
Section 5.1.1.2 Dosing Visits and Dose Modification
Section 5.1.1.2 Dosing Visits and Dose Modification and 
Dose Stratification
Visits 1, 2, 3, and 6 must occur at the study site. For Visits 4 
and 5 (when at-home dosing is available), home visits are 
permitted for patients who are not able to go to the 
investigational center or if the investigational center staff are 
not able to see patients at the investigational center for any 
extenuating circumstances (see Section 3.5). After such 
extenuating circumstances resolve, home visits may be 
Section 5.1.1.2 Dosing Visits and Dose Modification
Visits 1, 2, 3, and 6 must occur at the study site. For Visits 
4 and 5 (when at-home dosing is available), home visits 
are permitted for patients who are not able to go to the 
investigational center or if the investigational center staff 
are not able to see patients at the investigational center for 
any extenuating circumstances (see Section 3.5). After 
such extenuating circumstances resolve, home visits may 
be permitted to continue.
Clarification of the title of the 
section 
Clarification of the continuation 
of home visits
In conjunction with increasing the 
window length for scheduled 
visits, allowed for potential 
further extension of the window 


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permitted to continue.
Doses will be delivered administered at the study site or at 
home, as applicable, at the time of visits via a fixed dose 
pre-filled syringe; no dose modifications will be allowed. 
There will be a time window for doses that do not occur on 
the scheduled days. A visit ±3 days from a scheduled visit is 
acceptable, a visit between 4 and 7 days of a scheduled visit is 
allowed but will be considered a protocol deviation, and a 
visit >7 days after the scheduled visit is not permitted. If a 
scheduled visit cannot occur within the ±7-day time window 
due to extenuating circumstances, the Medical Monitor should 
be contacted to determine if the window can be lengthened. 
Medical Monitor notification and consultation for all missed 
scheduled visits and related rescheduling and necessary plans 
of action isare required.
Doses will be administered at the study site or at home, as 
applicable, at the time of visits via a fixed dose pre-filled 
syringe; no dose modifications will be allowed. There will 
be a time window for doses that do not occur on the 
scheduled days. If a scheduled visit cannot occur within 
the ±7-day time window due to extenuating circumstances, 
the Medical Monitor should be contacted to determine if 
the window can be lengthened. Medical Monitor 
notification and consultation for all missed scheduled 
visits and related rescheduling and necessary plans of 
action are required.
due to COVID-19 pandemic
Section 5.2.3 Accountability
For visits conducted at the patient’s home, it is the 
responsibility of the site to ensure the correct IMP is provided. 
If a sharps container is to be supplied to the patient, the site is 
responsible for arranging the container and ensuring it is 
available to be provided along with the IMP.
For visits conducted at the patient’s home, it is the 
responsibility of the site to ensure the correct IMP is 
provided. If a sharps container is to be supplied to the 
patient, the site is responsible for arranging the container 
and ensuring it is available to be provided along with the 
IMP.
Provided additional details on the 
newly allowed at-home visits as 
relates to IMP accountability
Section 5.5 Treatment after the End of the Study
Patients will not have access to sc fremanezumab as provided 
in this study after the EOT/EOS or ET Visit (Visit 7). After 
Visit 7, the study patients advised to return to their all 
subsequent clinical care will be determined by or at the 
discretion of the treating physician to resume their treatment 
for FM.
Patients will not have access to sc fremanezumab as 
provided in this study after the EOT/EOS or ET Visit 
(Visit 7). After Visit 7, all subsequent clinical care will be 
determined by or at the discretion of the treating physician.
Given the removal of Visit 8, 
clarified that study patients will 
not be directed or advised on care 
following Visit 7
Section 5.6.1 Activity
Patients must remain at the investigational center for safety 
observation for at least 60 30 minutes after IMP 
administration.
Patients must remain at the investigational center for 
safety observation for at least 30 minutes after IMP 
administration.
The vast majority of 
hypersensitivity reactions occur 
within 30 minutes of dosing


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Section 5.7 Prior and Concomitant Medication or Therapy (Other section affected by this change: Section 3.1 [Figure 1, footnote a], Section 3.5 
[Table 1, footnote b] and Appendix N)
Section 5.7.1 Permitted Concomitant Medication or Therapy
Nonsteroidal anti-inflammatory drugs are permitted provided 
the use has been stable (ie, per patient’s usual dosing regimen) 
for at least 1 month prior to screening and will remain 
unchanged throughout the study.
Antihistamines are permitted for sleep. In addition, tricyclic 
antidepressants at low doses (amitriptyline [≤25 mg] or 
trazodone [≤150 mg]) or cyclobenzaprine (5 up to 10 mg), 
zolpidem (up to 10 mg), and melatonin may be used for sleep 
per the patient’s usual dosing regimen, with no dose change 
1 month prior to screening and throughout the study.
Concomitant medications permitted during the study include 
the following: 1) SSRIs (stable use), 2) the use of 
acetaminophen as a rescue medication up to 1000 mg per dose 
and not to exceed 3000 mg/day as a rescue medication for 
pain, 3) medications required for the treatment of any adverse 
events, 4) aspirin (maximum daily dose 325 mg) for 
cardiovascular prophylaxis, and 5) some analgesics, such as 
nonsteroidal anti-inflammatory drugs may be permitted only 
to treat acute events (eg, injuries such as muscle sprains) for 
up to 3 days (stable use), and 6) selected sleep medications.
No other FM medications (prescription, OTC, behind-the-
counter, IMPs other than those permitted in this study, or 
vaccine) will be allowed during the study. Full For details of 
allowed medications, are provided in see Appendix ON.
Section 5.7.2 Prohibited Medication or Therapy
A list of prohibited medications is given provided in 
Appendix JI. At each visit at the investigational center after 
the Screening Visit, the investigator will ask patients whether 
they have taken any medications (other than IMP[s]), 
including OTC medications, vitamins, or herbal or nutritional 
supplements, since the previous visit.
Section 5.7.3 Recommended Washout Periods
The washout periods for common drugs are detailed in 
Section 5.7.1 Permitted Concomitant Medication or 
Therapy
Nonsteroidal anti-inflammatory drugs are permitted 
provided the use has been stable (ie, per patient’s usual 
dosing regimen) for at least 1 month prior to screening and 
will remain unchanged throughout the study.
Antihistamines are permitted for sleep. In addition, 
tricyclic antidepressants at low doses (amitriptyline 
[≤25 mg] or trazodone [≤150 mg]) or cyclobenzaprine (up 
to 10 mg), zolpidem (up to 10 mg), and melatonin may be 
used for sleep per the patient’s usual dosing regimen, with 
no dose change 1 month prior to screening and throughout 
the study.
Concomitant medications permitted during the study 
include the following: 1) SSRIs (stable use), 2) the use of 
acetaminophen as a rescue medication up to 1000 mg per 
dose and not to exceed 3000 mg/day as a rescue 
medication for pain, 3) medications required for the 
treatment of any adverse events, 4) aspirin (maximum 
daily dose 325 mg) for cardiovascular prophylaxis, 5) 
nonsteroidal anti-inflammatory drugs (stable use), and 6) 
selected sleep medications.
No other FM medications (prescription, OTC, behind-the-
counter, IMPs other than those permitted in this study, or 
vaccine) will be allowed during the study. For details of 
allowed medications, see Appendix N.
Section 5.7.2 Prohibited Medication or Therapy
A list of prohibited medications is provided in Appendix I. 
At each visit at the investigational center after the 
Screening Visit, the investigator will ask patients whether 
they have taken any medications (other than IMP[s]), 
including OTC medications, vitamins, or herbal or 
nutritional supplements, since the previous visit.
Section 5.7.3 Recommended Washout Periods
Section headers 5.7.1 and 5.7.2 
added for clarity
Allowed additional concomitant 
medications (with limitations) 
based on patient population
In addition, the order of the text 
within this section was changed, 
and edits were made for 
consistency both within the 
section and with Appendix O 
(only additions, but not moves of 
unchanged text, are indicated)
Section 5.7.3 was created for 
clarity. The information including 
Table 4 are from the original 
Appendix D, which was deleted.


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Table 4. While it is not mandatory to wash out of all 
concomitant medications, it is desirable to reduce the number 
of concomitant medications to a minimum, if possible. Note: 
Not all of these medications will require washout; see Section 
5.7.1, Section 5.7.2, Appendix I, and Appendix N for further 
information about permitted concomitant medications. 
Washout periods are recommendations; actual washout 
periods must be determined by the investigator based on 
his/her clinical practice/judgement, the medication, and the 
dose of the respective medication. If there are any questions, 
contact the medical monitor.
Table 4, which lists the recommended washout periods for 
common medications was created.
The washout periods for common drugs are detailed in 
Table 4. While it is not mandatory to wash out of all 
concomitant medications, it is desirable to reduce the 
number of concomitant medications to a minimum, if 
possible. Note: Not all of these medications will require 
washout; see Section 5.7.1, Section 5.7.2, Appendix I, and 
Appendix N for further information about permitted 
concomitant medications. 
Washout periods are recommendations; actual washout 
periods must be determined by the investigator based on 
his/her clinical practice/judgement, the medication, and the 
dose of the respective medication. If there are any 
questions, contact the medical monitor.
Section 5.10.1 Maintenance of Randomization
At Visits 3 through 76, the RTSM will be queried, and 
investigational center personnel will retrieve and administer 
each pre-filled syringe contained in the appropriately 
numbered kit(s). Kit numbers will be entered into the eCRF.
At Visits 3 through 6, the RTSM will be queried, and 
investigational center personnel will retrieve and 
administer each pre-filled syringe contained in the 
appropriately numbered kit(s). Kit numbers will be entered 
into the eCRF.
Clarification
Section 6.1.5.2 PROMIS Physical Function Short Form 12a
The PROMIS Physical Function SF12a Scale contains 12 
items with a score ranging from 12 to 3660.
The PROMIS Physical Function SF12a Scale contains 
12 items with a score ranging from 12 to 60.
Corrected description of 
assessment scale
Section 7.1.6 Protocol-Defined Adverse Events of Special Interest
•
severe hypersensitivity reactions or anaphylaxis (see 
Appendix C)
•
severe hypersensitivity reactions or anaphylaxis (see 
Appendix C)
Updated to include anaphylactic 
reactions
Section 15 References
Curran SL, Andrykowski MA, Studts JL. Short Form of the 
Profile of Mood States (POMS SF): Psychometric 
information. Psychol Assess 1995;7(1):80 3.
Lindgren KN, Mastren VL, Tiburzi MJ, Ford DP, Bleecker 
ML. The factor structure of the Profile of Mood States 
(POMS) and its relationship to occupational lead exposure. J 
National Institutes of Health. NIH Clinical Center Patient 
Education Materials Giving a Subcutaneous Injection. 
Bethesda, MD: National Institutes of Health Clinical 
Center; 2016.
Two references were deleted 
because they were no longer cited 
in the document and 1 reference 
was added


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Reason/justification for change
Occup Environ Med 1999;41(1):3 10.
National Institutes of Health. NIH Clinical Center Patient 
Education Materials Giving a Subcutaneous Injection. 
Bethesda, MD: National Institutes of Health Clinical Center;
2016.
Appendix A Clinical Laboratories and Other Departments and Institutions
 Teva 
Branded Pharmaceutical Products R&D, Inc.
Tel: 
, 
Teva Branded Pharmaceutical Products R&D, Inc.
Tel: 
Updated as outlined in 
Administrative Letter 01
Teva Branded Pharmaceutical Products R&D, Inc.
Tel: 
Cell: 
Teva Branded Pharmaceutical Products R&D, Inc.
Cell: 
Updated contact information
Appendix B. Study Procedures and Assessments by Visit (Other section affected by this change: Section 3.5 [Table 1])
IMD was removed from subsection 3 (Visit 2).
Corrected to align with 
Section 3.5 [Table 1]
•
alcohol screen (social history) (for Visit 1
•
alcohol (social history) (for Visit 1
Corrected to align with 
Section 3.5 [Table 1]
Appendix D. Washout Periods For Common Medications
Appendix D was deleted. The contents of this appendix were 
moved to the newly created Section 5.7.3.
Clarification
Appendix F. Birth Control Methods And Pregnancy Testing
Assessment of likelihood of possible interaction between IMP 
or concomitant medications and hormonal contraception 
should be conducted. While Hhormonal contraception may be 
susceptible to interaction with the an IMP, which may that
reduces the efficacy of the contraception contraceptive
While hormonal contraception may be susceptible to 
interaction with an IMP that reduces the efficacy of the 
contraceptive method, eg, CYP 4A inducers, no 
adjustment in dosing should be necessary. 
Language updated to align with 
other fremanezumab protocols.


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method, eg, CYP 4A inducers, no adjustments in dosing 
should be necessary. 
Although dDrug interaction studies have not been conducted 
with fremanezumab, like other therapeutic antibodies, 
fremanezumab is expected to be primarily metabolized via 
proteolytic catabolism. Therefore, interaction with and impact 
on drug metabolizing enzymes (eg, CYP isoforms) is 
considered unlikely in humans.
Furthermore, fremanezumab was tested for stimulation of pro-
inflammatory cytokine release in human whole blood (Study 
PF-04427429/24Aug09/111320) and did not elicit significant 
cytokine release (tumor necrosis factor α, interleukin-6, 
interferon-γ, or interleukin-1β) in any donor including at 
concentrations up to 100 μg/mL. As such, there is also no 
reason to suspect that fremanezumab may influence CYP 
activity via cytokine release.
In case of suspected interaction, hormonal contraceptive alone 
may not be sufficient. In the absence of clinical 
pharmacokinetic interaction study data in IMPs with 
demonstrated or suspected human teratogenicity/fetotoxicity,
recommendation for use of hormonal contraceptives should be 
thoroughly justified by the sponsor. Additional contraceptive 
methods, including supplementary barrier methods, may be 
considered.
Although drug interaction studies have not been conducted 
with fremanezumab. Like other therapeutic antibodies, 
fremanezumab is expected to be primarily metabolized via 
proteolytic catabolism. Therefore, interaction with and 
impact on drug metabolizing enzymes (eg, CYP isoforms) 
is considered unlikely in humans.
Furthermore, fremanezumab was tested for stimulation of 
pro-inflammatory cytokine release in human whole blood 
(
) and did not elicit 
significant cytokine release (tumor necrosis factor α, 
interleukin-6, interferon-γ, or interleukin-1β) in any donor 
including at concentrations up to 100 μg/mL. As such, 
there is also no reason to suspect that fremanezumab may 
influence CYP activity via cytokine release.
Postmenopausal women:
•
1 year postmenopausal (no menses for 12 months without 
an alternative medical cause plus an increased concentration 
of follicle stimulating hormone of more than 35 U/L) in 
women not using hormonal contraception or hormonal 
replacement therapy
Recommendations for application of birth control methods:
•
IMPs with Marketing Authorisation (MA)

In case of no contraception recommendations, the 
principles of IMPs without MA should be applied
•
IMPs without MA

In case of clinical trials with IMPs that have not yet 
Postmenopausal women:
•
1 year postmenopausal (no menses for 12 months 
without an alternative medical cause plus an increased 
concentration of follicle stimulating hormone of more than 
35 U/L) in women not using hormonal contraception or 
hormonal replacement therapy
Language updated to align with 
other fremanezumab protocols.


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received MA, there is usually limited or no information about 
the outcome of pregnancies in humans following in utero or 
gonadal exposure. Depending on the stage of clinical 
development there may also be limited or no information from 
non clinical reproduction toxicity studies.

The general recommendation in the ICH M3(R2) 
guideline is that “all female reproduction toxicity studies and 
standard battery of genotoxicity tests should be completed 
prior to the inclusion, in any clinical trial, of women of 
childbearing potential (WOCBP) not using highly effective 
birth control or whose pregnancy status is unknown”.

In case of insufficient or unavailable non clinical data, the 
impact on the risk categorization should be evaluated. 
Unavailable or insufficient nonclinical data should be 
considered as “effects detected” and the highest risk category 
assumed.
•
IMP with demonstrated or suspected human 
teratogenicity/fetotoxicity

Highly effective contraception using methods with low 
user dependency

Contraception during treatment and until the end of 
relevant systemic exposure. This period should be extended 
by 30 days in case of genotoxicity.
○
Monthly pregnancy testing
○
Pregnancy testing during treatment and until end of 
relevant systemic exposure. In case of genotoxicity, this 
period should be extended by 30 days. Shorter testing 
intervals are to be considered depending on drug dosing 
schedule.

In case of genotoxicity, methods of birth control for male 
participants must be used until end of relevant systemic 
exposure and in addition for further 90 days.
•
IMP with possible human teratogenicity/fetotoxicity

Highly effective method of contraception

Contraception during treatment and until the end of 


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Reason/justification for change
relevant systemic exposure

Additional pregnancy testing to be considered; as a 
minimum, at the end of relevant systemic exposure

In each case of delayed menstrual period (over 1 month 
between menstruations) confirmation of absence of pregnancy 
is strongly recommended. This recommendation also applies 
to WOCBP with infrequent or irregular menstrual cycles.
•
IMP with unlikely risk of human 
teratogenicity/fetotoxicity, for which assessment of the 
completed necessary nonclinical studies does not indicate 
teratogenicity/fetotoxicity, in early pregnancy and human data 
are not available or do not contradict these findings or there is 
already sufficient evidence for lack of risk based on human 
data

An acceptable effective method of contraception unless 
an absence of risk of human teratogenicity/fetotoxicity in 
early pregnancy can be justified

As a minimum, contraception until treatment 
discontinuation
Description of different birth control methods
Highly effective birth control methods:
Highly effective birth control methods are methods that can 
achieve a failure rate of less than 1% per year when used 
consistently and correctly are considered. Such methods 
include the following:
•
Combined estrogen and progestogen hormonal 
contraception (oral, intravaginal, transdermal) associated with 
inhibition of ovulation; these should be initiated at least 7 days 
(for IMPs without suspected teratogenicity/genotoxicity) and 
1 month (for IMPs potentially teratogenic/genotoxic) before 
the first dose of IMP
•
Progestogen-only hormonal contraception (oral, 
injectable, implantable) associated with inhibition of 
ovulation; these should be initiated at least 7 days (for IMPs 
without suspected teratogenicity/genotoxicity) and 1 month 
(for IMPs potentially teratogenic/genotoxic) before the first 
Description of different birth control methods
Highly effective birth control methods:
Highly effective birth control methods are methods that 
can achieve a failure rate of less than 1% per year when 
used consistently and correctly are considered. Such 
methods include the following:
•
Combined estrogen and progestogen hormonal 
contraception (oral, intravaginal, transdermal) associated 
with inhibition of ovulation; these should be initiated at 
least 7 days before the first dose of IMP
•
Progestogen-only hormonal contraception (oral, 
injectable, implantable) associated with inhibition of 
ovulation; these should be initiated at least 7 days before 
the first dose of IMP
•
Intrauterine device (IUD) and intrauterine hormone-
releasing system (IUS) need to be in place at least 2 
Language updated to align with 
other fremanezumab protocols.


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Reason/justification for change
dose of IMP
•
Intrauterine device (IUD) and intrauterine hormone-
releasing system (IUS) need to be in place at least 2 months 
before screening visit (V1)
•
Bilateral tubal occlusion
•
Vasectomized partner provided he is the sole sexual 
partner and has received medical assessment of the surgical 
process
•
Sexual abstinence is only considered a highly effective 
method if defined as refraining from heterosexual intercourse 
in the defined period. The reliability of sexual abstinence 
needs to be evaluated in relation to the duration of the clinical 
study and the preferred and usual lifestyle of the patient.
•
Periodic abstinence (eg, calendar, ovulation, 
symptothermal, post-ovulation methods), declaration of 
abstinence for the duration of a study, and withdrawal are not 
acceptable methods of contraception (according to Medicines 
and Healthcare Products Regulatory Agency).
Acceptable birth control methods:
Acceptable birth control methods that result in a failure rate of 
more than 1% per year include the following: progestogen
only oral hormonal contraception for which the inhibition of 
ovulation is not the primary mode of action; male or female 
condom with or without spermicide; cap, diaphragm, or 
sponge with spermicide. The combination of male condom 
with either cap, diaphragm, or sponge with spermicide (double 
barrier methods) are also considered acceptable but not highly 
effective methods of birth control.
Unacceptable birth control methods:
Periodic abstinence (calendar, symptothermal, post-ovulation 
methods), withdrawal (coitus interruptus), spermicides only, 
and lactational amenorrhoea method (LAM) are not 
acceptable methods of contraception. Female condom and 
male condom should not be used together.
Male contraception
Male patients must always use a condom including 
months before screening visit (V1)
•
Bilateral tubal occlusion
•
Sexual abstinence is only considered a highly 
effective method if defined as refraining from heterosexual 
intercourse in the defined period. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration 
of the clinical study and the preferred and usual lifestyle of 
the patient.
•
Periodic abstinence (eg, calendar, ovulation, 
symptothermal, post-ovulation methods), declaration of 
abstinence for the duration of a study, and withdrawal are 
not acceptable methods of contraception (according to 
Medicines and Healthcare Products Regulatory Agency).
Unacceptable birth control methods:
Periodic abstinence (calendar, symptothermal, post-
ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhoea method 
(LAM) are not acceptable methods of contraception. 
Female condom and male condom should not be used 
together.
Male contraception
Male patients must always use a condom including 
vasectomized men if their partners are of child-bearing 
potential.
Vasectomy:
Use of contraceptive methods applies also to vasectomized 
men.


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Reason/justification for change
vasectomized men if their partners are of child-bearing 
potential, except in cases of no genotoxicity; or no 
demonstrated or suspected human teratogenicity/fetotoxicity.
Vasectomy:
Use of contraceptive methods applies also to vasectomized 
men, because of the risk associated with transfer of a drug via 
seminal fluid.
Contraception for female partners of male study 
participants:
Female partners (who are not pregnant) of male study 
participants must use contraception for non pregnant WOCBP 
until the end of relevant systemic exposure in case of IMPs 
with genotoxicity or IMPs with no genotoxicity but 
demonstrated or suspected human teratogenicity/fetotoxicity.
Pregnancy tests in WOCBP:
1.
Conduct monthly pregnancy testing from first dose of 
IMP until last dose of IMP and additional 30 days in case the 
IMP does not have a marketing authorization and has 
suspected human teratogenicity/genotoxicity/fetotoxicity. 
Conduct monthly pregnancy testing and in case the IMP has a 
marketing authorization, if the IMP has a demonstrated or 
suspected human teratogenicity/genotoxicity/fetotoxicity 
according to Risk Safety Information. Shorter testing intervals 
are to be considered depending on drug dosing schedule.
2.
Consider additional pregnancy testing, but at least at the 
end of relevant systemic exposure, in case of possible human 
teratogenicity/fetotoxicity. This refers to IMPs, for which 
human data on pregnancies is limited or not available, there is 
no suspicion of human teratogenicity based on class effects or 
genotoxic potential, and nonclinical reproductive toxicity 
studies of relevance for early human pregnancy show positive 
findings that do not generate a strong suspicion of human 
teratogenicity/ fetotoxicity.
3.
For IMPs with unlikely risk of human 
teratogenicity/fetotoxicity, additional pregnancy testing is 
generally not necessary. This refers to IMPs for which 


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Reason/justification for change
assessment of the completed necessary nonclinical studies 
does not indicate teratogenicity/fetotoxicity in early pregnancy 
and human data are not available or do not contradict these 
findings or there is already sufficient evidence for lack of risk 
based on human data.
Appendix I. List of Prohibited Medications and Therapeutic Interventions
These medication lists are not exhaustive; the investigator 
should check with the Medical Monitor on about any drug not 
listed in this appendix. For those medications listed in Section 
5.7, the medications fluoxetine (Prozac) and naltrexone that 
are listed in the table below, only doses greater than the 
maximum listed dose are prohibited.
These medication lists are not exhaustive; the investigator 
should check with the Medical Monitor about any drug not 
listed in this appendix. For the medications fluoxetine 
(Prozac) and naltrexone that are listed in the table below, 
only doses greater than the maximum listed dose are 
prohibited.
Clarification
Vortioxetine (Brintellix Trintellix) (formerly called Brintellix)
Vortioxetine (Trintellix) (formerly called Brintellix)
Updated trade name
Naltrexone ≤≥4.5 mg
Naltrexone ≥4.5 mg
Updated to correct a 
typographical error
Appendix J. Total Blood Volume (Other section affected by this change: Section 5.11)
Total blood volume to be collected for each patient in this 
study is approximately 248161.5 mL for scheduled tests.
Number of samples: Visit 4 90; Visit 5 90; Visit 7 49; 
Visit 8 60
Volume (mL): Visit 4 41.50; Visit 5 41.50; Visit 7 16.541.5; 
Visit 8 29.00
Total blood volume to be collected for each patient in this 
study is approximately 161.5 mL for scheduled tests. 
Number of samples: Visit 4 0; Visit 5 0; Visit 7 9; 
Visit 8 0
Volume (mL): Visit 4 0; Visit 5 0; Visit 7 41.5; Visit 8 0
Updated the total blood volume 
because of the changes in blood 
collection occasions, namely, 
removal of blood collection at 
Visits 4 and 5, updated sample 
volume at Visit 7, and removal of 
Visit 8; updated the table of blood 
volumes, accordingly
Appendix P Management of Study Activities During COVID-19 (Other sections affected by this change: Title Page, Amendment History, Section 3.1, 
Section 4.5, Section 5.1.1.2, Appendix D, and Appendix E)
New appendix and text.
Additional text too numerous to include in this table; refer 
to Appendix P of this protocol.
Provided new appendix with 
details on how to manage study 
conduct during the COVID-19 
pandemic
In addition, cross-references to the 
new appendix were added to the 
indicated sections, as relevant


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16.4.
Administrative Letter 01 Dated 28 February 2020


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16.5.
Amendment 03 Dated 22 July 2019
The primary reason for this amendment is to update the protocol-defined adverse events of 
special interests. This amendment is considered to be substantial (ie, requires approval by CA, 
IEC, and/or IRB) by the sponsor’s Authorized Representative. Other nonsubstantial changes 
have been made to the protocol (and protocol synopsis, as appropriate). These changes are 
unlikely to affect the safety or rights (physical or mental integrity) of the patients in this clinical 
study or the scientific value of the clinical study.
Original text with changes shown
New wording
Reason/Justification for change
Section 1.2.1 Nonclinical Studies (Other sections affected by this change: Section 5.3.1)
The calculated safety margins 
ranged from is 54-fold higher to at 
least 158 fold higher than the 
expected clinical exposure following 
675 mg sc monthly, depending on 
the proposed indication and dosing 
regimen.
The calculated safety margin is 
54-fold higher than the expected 
clinical exposure following 675 mg 
sc monthly.
This correction was made to account 
for exposure at the single dose used 
in this study.
Section 2.1 Primary and Secondary Study Objectives and Endpoints (Other Sections affected by this change: 
Sections 2.2, 9.6.2, and 9.6.3)
number (%) of patients who did not 
complete the studytreatment
(Kaplan-Meier Survival Analysis) 
due to lack of efficacy
number (%) of patients who did not 
complete the treatment (Kaplan-
Meier Survival Analysis) due to lack 
of efficacy
This correction was made to identify 
patients identified for this endpoint.
Added “up to week 16” for relevant 
endpoints 
The primary efficacy endpoint is the 
change from baseline up to week 16 
in the weekly average of the daily 
average Pain Intensity-Numerical 
Rating Scale (PI NRS) score over 
the past 24 hours.
Changed to align with 
clinicaltrials.gov listing that clarifies 
the timeframe for endpoints
change from baseline up to week 16 
in the individual components of the 
Fibromyalgia Impact Questionnaire 
Revised (FIQR): symptom subscore, 
impact subscore, and functional 
subscore score
responder rate of the Patient Global 
Impression of Change (PGIC) rating 
(percentage of patients much 
improved or very much improved) 
up to week 16
the percentage of patients who 
experience a ≥30% reduction in the 
weekly average of the daily average 
PI NRS score up to week 16
the percentage of patients who 
experience a ≥50% reduction in the 
weekly average of the daily average 
PI NRS score up to week 16


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change from baseline up to week 16 
in the weekly average of the daily 
worst PI-NRS score over the past 24 
hours
change from baseline up to week 16 
in the Patient-Reported Outcomes 
Measurement Information System 
(PROMIS) Sleep Disturbance Short 
Form (SF) 8a score
change from baseline up to week 16 
in the PROMIS Physical Function 
SF12a score
change from baseline up to week 16 
in the PROMIS Fatigue SF8a score
change from randomization up to 
week 16 in the clinical laboratory 
tests (serum chemistry, hematology, 
and urinalysis)
change from baseline up to week 16 
in vital signs (pulse, respiratory rate, 
systolic and diastolic blood pressure, 
and oral body temperature 
measurements at each visit)
 
 
 
 
 
 
 
 
 
 
Section 3.5 Schedule of Study Procedures and Assessments (Other Sections affected by these changes: 
Section 5.1.2, Appendix B)
Several rows and footnotes in the 
table were rearranged and updated.
These minor changes were made to 
clarify and temporally align the 
assessments.
Addition of C-SSRS to Visit 7
C-SSRS was added to Visit 7 in the 
event a patient terminates from the 
study early.
Study days for visits 4, 5, 6, 7, and 8 
day 29, day 57, day 85, day 113, and 
This correction was made to ensure 


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were updated by 1 day (previously 
day 28, day 56, day 84, day 112, and 
day 210)
day 211
28 days between visits 3 and 4.
Separated footnote ‘e’ for tablet and 
e-diary
Training patients on accurate pain 
reporting and placebo response 
reduction to use the site’s tablet will 
occur at Screening (Visit 1), the 
BAPS Visit (Visit 2), and as needed 
for subsequent visits.
This footnote was added to 
distinguish the tablet training from 
the e-diary training.
Review of study compliance 
includes review of e-diary 
recordings, rescue medication use, 
and other factors.
Review of study compliance 
includes review of e-diary 
recordings, rescue medication use, 
concomitant medication use, and use 
of non-pharmacologic therapies 
(including normal daily exercise 
routines, chiropractic care, physical 
therapy, psychotherapy, and 
massage therapy).
This change was made to specify 
compliance factors.
Section 3.6.2
Tablet

WPI and SS scale

Mini International 
Neuropsychiatric Interview 
(MINI)

FIQR

PGI-C

PROMIS 12a Physical 
Function

PROMIS Fatigue SF8a

POMS-2A Short Form

EQ-5D-5L

C SSRS (Baseline and 
Since Last Visit)

HADS

IMD
The tablet assessments will be 
completed per the Study Procedures 
and Assessments (Table 1). 
Additional information collected on 
the tablet only at the Screening Visit 
includes the patient-reported average 
PI-NRS rating, worst PI NRS rating, 
and at the moment PI NRS rating
over the past 7 days…Patients will 
be trained by the site staff viaon the 
use of the tablet on accurate pain 
reporting and placebo response 
reduction at Visits 1 and 2, and as 
necessary at subsequent visits 

FIQR

PGI-C

PROMIS 12a Physical 
Function

PROMIS Fatigue SF8a

POMS-2A Short Form

EQ-5D-5L

HADS

IMD
The tablet assessments will be 
completed per the Study Procedures 
and Assessments (Table 1). 
Additional information collected on 
the tablet only at the Screening Visit 
includes the patient-reported average 
PI-NRS rating over the past 7 
days… Patients will be trained by 
the site staff via the tablet on 
accurate pain reporting and placebo 
response reduction at Visits 1 and 2 
and as necessary at subsequent visits 
throughout the study.
This text was modified to clarify the 
tablet assessments.


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throughout the study.
Section 4.1 Patient Inclusion Criteria (Other changes affected by these changes: Section 5.6.2 and 7.2)
e. willing to comply with recording 
of once daily scores using the PI-
NRS, completed every evening 
(approximately the same time each 
day) starting at the BAPS Visit 
(Visit 2) upand continuing to the 
Randomization EOT (Visit (Visit 
37). A minimum of 12 of 14 daily 
average pain ratings are required to 
be recorded in an e-diary during the 
baseline assessment period (Section 
3.6.1)
e. willing to comply with recording 
of once daily scores using the PI-
NRS, completed every evening 
(approximately the same time each 
day) starting at the BAPS Visit 
(Visit 2) and continuing to the EOT 
(Visit 7). A minimum of 12 of 
14 daily average pain ratings are 
required to be recorded in an e-diary 
during the baseline assessment 
period (Section 3.6.1)
This change was made to ensure
patient compliance in the study.
m. .. must use highly effective 
contraception method with their 
partners during the entire study 
period and for 56 months after the 
last dose of the IMP
m. ...must use highly effective 
contraception method with their 
partners during the entire study 
period and for 6 months after the last 
dose of the IMP
This correction was made to account 
for the half-life of fremanezumab.
Section 5.1.1.1 Starting Dose and Dose Levels
The recommended sc injection sites 
follow the National Institutes of 
Health (NIH) Clinical Center Patient 
Education Materials (NIH Clinical 
Center Patient Education Materials 
2016). The suggested injection site 
locations for sc administration are 
the following: back of upper arms, 
lower abdomen/belly/waistline, and 
front of thighs. The sc injection and 
location will be recorded for each 
administration visit (Visits 3, 4, 5, 
and 6).
The recommended sc injection sites 
follow the National Institutes of 
Health (NIH) Clinical Center Patient 
Education Materials (NIH Clinical 
Center Patient Education Materials 
2016). The suggested injection site 
locations for sc administration are 
the following: back of upper arms, 
lower abdomen/belly/waistline, and 
front of thighs. The sc injection and 
location will be recorded for each 
administration visit (Visits 3, 4, 5, 
and 6).
This change was made to clarify 
identification of sc injection sites.
Section 5.1.1.2 Dose Modification and Dose Stratification
Doses will be delivered at the study 
site at the time of visits via a fixed 
dose pre-filled syringe; no dose 
modifications will be allowed. There 
will be a time window for missed 
doses
these are visits that do not 
occur on the scheduled daysdoses 
that do not occur on the scheduled 
days. A visit ±3 days from a 
scheduled visit is acceptable, a visit 
between 4 and 7 days of a scheduled 
visit is allowed but will be 
considered a protocol deviation, and 
a visit >7 days after the scheduled 
visit is not permitted. Medical 
Monitor notification and 
Doses will be delivered at the study 
site at the time of visits via a fixed 
dose pre-filled syringe; no dose 
modifications will be allowed. There 
will be a time window for doses that 
do not occur on the scheduled days. 
A visit ±3 days from a scheduled 
visit is acceptable, a visit between 4 
and 7 days of a scheduled visit is 
allowed but will be considered a 
protocol deviation, and a visit >7 
days after the scheduled visit is not 
permitted. Medical Monitor 
notification and consultation for all 
missed scheduled visits and related 
rescheduling and necessary plans of 
This change was made to clarify the 
process in the event of dose 
modification.


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consultation for all missed scheduled
visits and related rescheduling and 
necessary plans of action is required.
action is required.
Section 5.2.3 Accountability
Changes in how unused syringes are 
accounted for.
Unused syringes and/or kits are to be 
returned to the depot for destruction.
These changes were made to account 
for difference in accounting for 
unused syringes vs empty syringes.
Section 6.1.5 Profile of Mood States 2 – Adult Short Form (Other Sections affected by this change: Sections 
2.2, 3.5, 3.6.2, 6.1.5, 9.6.3, and Appendix B)
The POMS-2A Short Form is a 
psychological rating scale for the 
assessment of patients’ specific 
mood states. 
The POMS-2A Short Form is a 
psychological rating scale for the 
assessment of patients’ specific 
mood states.
The 35-item POMS short form has a 
very high correlation with the full 
65-item POMS and is less time 
consuming and burdensome for 
patients.
Section 6.1.8 Inventory of Medical Diagnoses (Other sections affected by this change: Section 2.2 and 9.6.3)
For those medical conditions that a 
patient identifies as present at 
screening Visits 6 and 7, the 
investigator will query at Visits 6 
and 7 whether those conditions 
present at screening are improved or 
not improved compared with when 
the patient entered the study.
For those medical conditions that a 
patient identifies as present at 
screening, the investigator will query 
at Visits 6 and 7 whether those 
conditions are improved or not 
improved compared with when the 
patient entered the study.
This correction was made to ensure 
and include all conditions are 
determined at screening rather than 
only including conditions updated at 
later visits.
Section 7.1.3 Severity of an Adverse Event
The severity of each adverse event 
must be recorded as one of the 
following:
Mild:
No limitation of usual 
activities
Moderate:
Some limitation of 
usual activities
Severe: Inability to carry out usual 
activities
The severity of each adverse event 
will be graded according to the 
National Cancer Institute Common 
Terminology Criteria for Adverse 
Events (NCI CTCAE).
Adverse events that are not included 
in the NCI CTCAE lists will be 
graded according to the NCI 
CTCAE general guideline for 
grades:
Grade 1:
Mild; asymptomatic or 
mild symptoms; clinical or 
diagnostic observations only; 
intervention not indicated
Grade 2:
Moderate; minimal, 
The severity of each adverse event 
must be recorded as one of the 
following:
Mild:
No limitation of usual 
activities
Moderate:
Some limitation of 
usual activities
Severe: Inability to carry out usual 
activities
This change was made to reflect the 
decision that severity will not be 
graded by NCI CTCAE criteria.


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local intervention or noninvasive 
intervention indicated; limiting 
age appropriate instrumental 
activities of daily living (ADL) 
(eg, preparing meals, shopping for 
groceries or clothes, using the 
telephone, managing money)
Grade 3:
Severe or medically 
significant but not immediately life 
threatening; hospitalization or 
prolongation of hospitalization
indicated; disabling; limiting 
self care ADL (eg, bathing, dressing 
and undressing, feeding self, using 
the toilet, taking medications, and 
not bedridden)
Grade 4:
Life threatening 
consequences; urgent intervention 
indicated
Grade 5:
Death related to 
adverse event
Section 7.1.6 Protocol-Defined Adverse Events of Special Interest
Severe hypersensitivity reactions are 
considered protocol defined adverse 
events to be sent to the sponsor’s 
GPSP Department for evaluation. 
The process for reporting a protocol
defined adverse event of special 
interest will be the same as that for 
reporting a serious adverse event 
(see Section 7.1.5.3).
For purposes of this protocol, the 
following are considered protocol-
defined adverse events of special 
interest to be sent to the sponsor's 
GPSP Department for evaluation:

ophthalmic-related adverse 
events of at least moderate 
severity, as determined by 
the investigator

severe hypersensitivity 
reactions (see Section 7.9)
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). The clinical 
criteria for diagnosing anaphylaxis 
are provided in Appendix C. In the 
event of suspected anaphylaxis, vital 
signs (including oxygen saturation 
and respiration rate) will be 
measured.
The process for reporting a protocol-
defined adverse event of special 
interest will be the same as that for 
The new text was added to update 
protocol-defined adverse events of 
special interest, to clarify the 
investigator’s role in determining 
adverse event severity, and to align 
with recent fremanezumab 
protocols.


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reporting a serious adverse event 
(Section 7.1.5.3). Protocol-defined 
adverse events of special interest to 
be reported to GPSP can either be 
serious or nonserious, according to 
the criteria outlined in Section 
7.1.5.1.
Section 7.3 Medication Error and Special Situations Related to the Investigational Medicinal Products
Text added for additional scenarios 
in which Medical Monitor should be 
contacted.
The Medical Monitor should be 
contacted in any of the following 
events: 
1.
All 3 syringes from the 
assigned kit are unable to 
be administered during the 
visit.
2.
Any dose has been 
administered and a syringe 
is damaged.
If a syringe is damaged prior to dose 
administration, a new kit should be 
requested. Additional information is 
provided in the Study Manual.
This text was added to align with 
other recent protocols.
Section 7.4 Clinical Laboratory Tests
Added screening laboratory tests to 
Table 5
These assessments were added to 
ensure that a more comprehensive 
outline of clinical laboratory tests is 
provided.
Section 7.9 Assessment of Local Tolerability and Pain
Local tolerability at the injection site 
(eg, pain, erythema, ecchymosis, 
induration) will be evaluated 
immediately (ie, within 20 minutes) 
and at 1 hour postdose 
(ie, postinjection). The allowed time 
windows for these assessments are 
provided below. 
The table describing assessment 
time windows was removed.
Erythema, ecchymosis, and 
induration will be considered only if 
they reach a diameter of at least 5 
mm. The surface diameter in 
millimeters should be recorded, and 
erythema, induration, and 
ecchymosis at the injection site will 
be graded according to the diameter 
measurements: Absent, 5 mm to ≤50 
mm (mild), >50 to ≤100 mm 
(moderate), and >100 mm (severe). 
Induration must be assessed by
Spontaneous reports of injection site 
reactions will be recorded as adverse 
events according to the following 
severity assessment criteria:

Spontaneous reports of 
injection site erythema, 
induration, and 
ecchymosis will be 
assessed and recorded 
by site personnel and 
categorized according 
to the following 
measurements: 5 to 
≤50 mm (mild), >50 to 
≤100 mm (moderate), 
and >100 mm (severe).

Spontaneous reports of 
This change was made to highlight 
fremanezumab program changes in 
the assessment and reporting of 
injection site reactions.


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careful superficial palpation 
avoiding pressuring or squeezing the 
injection site.
Severity of local tolerability 
symptoms should be assessed as 
described below. Severe cases 
should be recorded as an adverse 
event. Appropriate treatment may be 
provided if necessary, in which case 
it must be recorded as concomitant 
medication.
The table describing Severity 
Assessment of Local Tolerability 
was removed.
local pain after the 
injection will be 
recorded as mild, 
moderate, or severe 
according to patient’s 
self-report.
Appropriate treatment may be 
provided if necessary, in which case 
it must be recorded as concomitant 
medication.
Section 9.6.4.3 Secondary Efficacy Analysis (Other sections affected by this change: Section 9.8.2)
The PGIC data will be 
dichotomized, where a patient who 
responds as either “much improved” 
or “very much improved” will be 
considered improved, and all other 
responses will be considered not 
improved. The response variable 
will be analyzed using a generalized 
estimating equation (GEE) 
methodlogistic regression model
with the logit link function, with 
treatment, sex, age group at FM 
onset, month, and treatment by 
month interactionsex as explanatory 
factors. In addition, the PGIC data 
will be summarized as categorical 
variable by monthweek and 
treatment group using descriptive 
statistics. Data collected from 
patients after discontinuing 
treatment will be excluded and 
considered missing for this analysis.
...
Change from baseline in the 
PROMIS Sleep Disturbance SF8a 
score will be analyzed using the 
same MMRM model as the primary 
efficacy endpoint with baseline 
Sleep Disturbance SF8a score as a 
covariate.
Change from baseline in the 
PROMIS Physical Function SF12a 
score, change from baseline in 
PROMIS Fatigue SF8a score, and 
change from baseline in the HADS 
will be analyzed using an MMRM 
model with treatment, sex, age group 
The PGIC data will be 
dichotomized, where a patient who 
responds as either “much improved” 
or “very much improved” will be 
considered improved, and all other 
responses will be considered not 
improved. The response variable 
will be analyzed using a logistic 
regression model with the treatment, 
age group at FM onset, and sex as 
explanatory factors. In addition, the 
PGIC data will be summarized as 
categorical variable by week and 
treatment group using descriptive 
statistics. 
...
Change from baseline in the 
PROMIS Sleep Disturbance SF8a 
score, change from baseline in the 
PROMIS Physical Function SF12a 
score, change from baseline in 
PROMIS Fatigue SF8a score, and 
change from baseline in the HADS 
will be analyzed using an MMRM 
model with treatment, sex, age group 
at FM onset, week, treatment-by-
week interaction, and baseline value 
of the corresponding variable as 
explanatory factors.
The number and percentage of 
patients who did not complete the 
treatment due to lack of efficacy or 
adverse event will be summarized 
using descriptive statistics, and the 
time to treatment discontinuation 
due to lack of efficacy or adverse 
event will be analyzed using the 
This change was made to correct the 
analysis for secondary efficacy 
endpoints.


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at FM onset, monthweek, treatment-
by- monthweek interaction, and 
baseline value of the corresponding 
variable as explanatory factors.
The number and percentage of 
patients who did not complete the 
treatment due to lack of efficacy or 
adverse event will be summarized 
using descriptive statistics, and the 
time to treatment discontinuation 
due to lack of efficacy or adverse 
event will be analyzed using the 
Kaplan-Meier Survival Analysis 
method.
Kaplan-Meier Survival Analysis 
method.


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16.6.
Amendment 02 Dated 16 April 2019
The primary reasons for this amendment are to describe the method and timing of the collection of e-diary assessments, to reflect the 
change in the assessment scale used to evaluate concurrent conditions, and to correct errors surrounding the timing of visits during the 
screening period. This amendment is considered to be substantial (ie, requires approval by a CA, IEC, and/or IRB) by the sponsor’s 
Authorized Representative. Other nonsubstantial changes have been made to the protocol (and protocol synopsis, as appropriate). 
These changes are unlikely to affect the safety or rights (physical or mental integrity) of the patients in this clinical study or the 
scientific value of the clinical study.
Table 1 (Study Procedures and Assessments) and Figure 1 (Overall Study Schematic Diagram) have been revised to reflect changes 
described below.
Original text with changes shown
New wording
Reason/Justification for 
change
Section 1.1 Introduction (Other sections affected by this change: Sections 3.3, 3.5, 4.1)
According to the 2010/2011 2016 American College of 
Rheumatology FM diagnostic criteria (Wolfe et al 2016), FM may be 
diagnosed when all of the following criteria are met:
1.
There is a widespread pain index (WPI) ≥7 and a symptom 
severity (SS) scale score ≥5 or WPI of 3 to 6 and SS score ≥9.
2.
Symptoms have been present at a similar level for at least 3 
months. 
3.
The patient does not have a disorder that would otherwise 
explain the pain.
1. Generalized pain, defined as pain in at least 4 of 5 regions, is 
present.
2. Symptoms have been present at a similar level for at least 3 
months.
3. Widespread pain index (WPI) ≥7 and symptom severity (SS) scale 
score ≥5 OR WPI of 4 to 6 and SS scale score ≥9.
4. A diagnosis of FM is valid irrespective of other diagnoses. A 
diagnosis of FM does not exclude the presence of other clinically 
According to the 2016 American College of 
Rheumatology FM diagnostic criteria (Wolfe et al 
2016), FM may be diagnosed when all of the 
following criteria are met:
1. Generalized pain, defined as pain in at least 4 of 5 
regions, is present.
2. Symptoms have been present at a similar level for 
at least 3 months.
3. Widespread pain index (WPI) ≥7 and symptom 
severity (SS) scale score ≥5 OR WPI of 4 to 6 and 
SS scale score ≥9.
4. A diagnosis of FM is valid irrespective of other 
diagnoses. A diagnosis of FM does not exclude the 
presence of other clinically important illnesses.
This change was made to 
ensure FM diagnosis is made 
using current diagnostic 
criteria.


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Reason/Justification for 
change
important illnesses.
 
 
 
Section 3.1 General Study Design and Study Schematic Diagram
The study duration will be from March May 2019 until approximately 
March May 2021.
The study duration will be from May 2019 until 
approximately May 2021.
This change was made to 
reflect the shift in study start 
and completion date.
Section 3.2 Planned Number of Patients and Countries
The study is planned to be conducted in the United States of America 
in approximately 25 30 investigational centers.
The study is planned to be conducted in the United 
States of America in approximately 30 investigational 
centers.
This change was made to 
accommodate shifts in the 
program timeline.
Section 3.6 e-Diary and Tablet Data Collection (Other sections affected by this change: Sections 3.5, 4.1, 4.3, Appendix A, Appendix B)
e-Diary and Tablet Data Collection
The primary data collection tools that will be used in this study are 
the e-diary and the tablet administered by Stefanini (Appendix A).
e-Diary
The e-diary will be dispensed to each patient at the BAPS Visit (Visit 
2). The e-diary will be used to record the following data:

Average PI-NRS rating

Worst PI-NRS rating

At-the-moment PI-NRS rating

Rescue medication use

Amount of rescue medication used for a specific 
breakthrough pain episode

Time of rescue medication used for a specific breakthrough 
pain episode

PROMIS Sleep Scale (Morning Report only)
e-Diary and Tablet Data Collection
The primary data collection tools that will be used in 
this study are the e-diary and the tablet administered 
by Stefanini (Appendix A).
e-Diary
The e-diary will be dispensed to each patient at the 
BAPS Visit (Visit 2). The e-diary will be used to 
record the following data:
•
Average PI-NRS rating
•
Worst PI-NRS rating
•
At-the-moment PI-NRS rating
•
Rescue medication use
•
Amount of rescue medication used for a specific 
breakthrough pain episode
•
Time of rescue medication used for a specific 
This change was made to 
specify the method and timing 
of collection of electronic 
assessments throughout the 
study.


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Reason/Justification for 
change
The e-diary will be completed per the Study Procedures and 
Assessments (Table 1). The e-diary will contain the following reports, 
which will guide the patient through completion of the necessary data 
collection on any respective day during the study: Evening Report, 
Make-up Evening Report, Morning Report, and Make-up Morning 
Report. The Evening Report will be available to patients each evening 
for completion between 1800h and 2200h. The Evening Report will 
have audible alarms that will sound at 3 different times before the 
entry window expires or upon completion of the report. If a patient 
cannot complete or forgets to complete the Evening Report, a 
Make-up Evening Report will become available for completion 
between 0300h and 1300h the next day. The Make-up Evening Report 
will also have audible alarms that will sound 3 times during this 
interval but will cease to sound upon completion of the report.
The Morning Report will be available to patients for completion 
between 0300h and 1300h on the respective day as scheduled in Table 
1. The Morning Report will have audible alarms that will sound at 
3 different times during this interval but will cease to sound upon 
completion of the report. If a patient cannot complete or forgets to 
complete the Morning Report, a Make-up Morning Report will 
become available for completion between 1800h and 2200h the same 
day. The Make-up Morning Report will not have separate audible 
alarms because it becomes available during the same time interval as 
the Evening Report for that day, which does have audible alarms.
The Rescue Medication tab will be available to patients 24 hours per 
day; tapping this tab will automatically display all required 
information for the patient to complete. The e-diary main menu will 
have tabs for each of the aforementioned reports, on which the patient 
will tap to access the respective report. In the case of a missed report, 
the respective report will have “Missed” as an indicator to the patient 
on the main menu. Patients will be trained by the site staff on the use 
of the e-diary at Visits 1 and 2, and at each visit throughout the study. 
Additional information on the e-diary can be found in the Study 
Manual.
Tablet
The tablet will be dispensed to each clinical site. Patients will use the 
tablet at their visits to complete the required assessments. The tablet 
breakthrough pain episode
•
PROMIS Sleep Scale (Morning Report only)
The e-diary will be completed per the Study 
Procedures and Assessments (Table 1). The e-diary 
will contain the following reports, which will guide 
the patient through completion of the necessary data 
collection on any respective day during the study: 
Evening Report, Make-up Evening Report, Morning 
Report, and Make-up Morning Report. The Evening 
Report will be available to patients each evening for 
completion between 1800h and 2200h. The Evening 
Report will have audible alarms that will sound at 
3 different times before the entry window expires or 
upon completion of the report. If a patient cannot 
complete or forgets to complete the Evening Report, a 
Make-up Evening Report will become available for 
completion between 0300h and 1300h the next day. 
The Make-up Evening Report will also have audible 
alarms that will sound 3 times during this interval but 
will cease to sound upon completion of the report.
The Morning Report will be available to patients for 
completion between 0300h and 1300h on the 
respective day as scheduled in Table 1. The Morning 
Report will have audible alarms that will sound at 3 
different times during this interval but will cease to 
sound upon completion of the report. If a patient 
cannot complete or forgets to complete the Morning 
Report, a Make-up Morning Report will become 
available for completion between 1800h and 2200h 
the same day. The Make-up Morning Report will not 
have separate audible alarms because it becomes 
available during the same time interval as the Evening 
Report for that day, which does have audible alarms.
The Rescue Medication tab will be available to 
patients 24 hours per day; tapping this tab will 
automatically display all required information for the 
patient to complete. The e-diary main menu will have 


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change
will be used to record the following information:

WPI and SS scale

Mini-International Neuropsychiatric Interview (MINI)

FIQR

PGI-C

PROMIS 12a Physical Function

PROMIS Fatigue 8a

POMS

EQ-5D-5L

C-SSRS (Baseline and Since Last Visit)

IMD
The tablet will be completed per the Study Procedures and 
Assessments (Table 1). The tablet main menu will contain individual 
tabs for each of the visits. Assessments will be completed by study 
site staff and/or the patient at the study site in the same order. Patients 
will be trained by the site staff on the use of the tablet at Visits 1 and 
2, and at each visit throughout the study. Additional information on 
the tablet can be found in the Study Manual.
tabs for each of the aforementioned reports, on which 
the patient will tap to access the respective report. In 
the case of a missed report, the respective report will 
have “Missed” as an indicator to the patient on the 
main menu. Patients will be trained by the site staff on 
the use of the e-diary at Visits 1 and 2, and at each 
visit throughout the study. Additional information on 
the e-diary can be found in the Study Manual.
Tablet
The tablet will be dispensed to each clinical site. 
Patients will use the tablet at their visits to complete 
the required assessments. The tablet will be used to 
record the following information:
•
WPI and SS scale
•
Mini-International Neuropsychiatric Interview 
(MINI)
•
FIQR
•
PGI-C
•
PROMIS 12a Physical Function
•
PROMIS Fatigue 8a
•
POMS
•
EQ-5D-5L
•
C-SSRS (Baseline and Since Last Visit)
•
IMD
The tablet will be completed per the Study Procedures 
and Assessments (Table 1). The tablet main menu will 
contain individual tabs for each of the visits. 
Assessments will be completed by study site staff 
and/or the patient at the study site in the same order. 
Patients will be trained by the site staff on the use of 
the tablet at Visits 1 and 2, and at each visit 
throughout the study. Additional information on the 
tablet can be found in the Study Manual.


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Reason/Justification for 
change
Section 4.1 Patient Inclusion Criteria (Other sections affected by this change: Section 5.8.1)
a. approved for study participation by the Fibromyalgia Eligibility 
Review Committee (Section 5.8.1)
a. approved for study participation by the 
Fibromyalgia Eligibility Review Committee (Section 
5.8.1)
This inclusion criterion was 
added to indicate there will be 
an independent review of 
patient enrollment eligibility.
Section 4.2 Patient Exclusion Criteria (Other sections affected by this change: Section 5.7, Appendix O)
a.
unable or unwilling to discontinue/washout of prohibited 
medications (Appendix J).; Sselective serotonin reuptake inhibitors 
(SSRIs; with the exception of <60 mg/day of fluoxetine) or over-the-
counter (OTC) medications used to treat depression or anxiety 
(Appendix J) are permitted if started at least 90 days prior to 
screening, have been on a stable dose for at least 690 days, and are 
expected to remain on a stable dose throughout the study, except for 
≥60 mg of fluoxetine
a.
unable or unwilling to discontinue/washout of 
prohibited medications (Appendix J); selective 
serotonin reuptake inhibitors (SSRIs; with the 
exception of <60 mg/day of fluoxetine) or over-the-
counter (OTC) medications used to treat depression or 
anxiety (Appendix J) are permitted if started at least 
90 days prior to screening, have been on a stable dose 
for at least 90 days, and are expected to remain on a 
stable dose throughout the study
This change was made to align 
the number of days since 
starting a depression/anxiety 
medication with the number of 
days for which the drug dose 
should be stable.
Section 5.1 Investigational Medicinal Products Used in the Study
Investigational medicinal product is defined as the test IMP and 
matching placebo IMP to the test IMP. Patients will receive the IMP 
at Visits 3, 4, 5, and 6. Patients randomized to the 225 mg dose level 
will receive 1 injection of 225 mg fremanezumab and 2 injections of 
placebo; patients randomized to the 675 mg dose level will receive 
3 injections of 225 mg fremanezumab; and patients randomized to 
placebo will receive 3 injections of placebo at each visit.
Investigational medicinal product is defined as the test 
IMP and matching placebo IMP to the test IMP. 
Patients will receive the IMP at Visits 3, 4, 5, and 6. 
Patients randomized to the 225 mg dose level will 
receive 1 injection of 225 mg fremanezumab and 
2 injections of placebo; patients randomized to the 
675 mg dose level will receive 3 injections of 225 mg 
fremanezumab; and patients randomized to placebo 
will receive 3 injections of placebo at each visit.
This change was made to 
specify the administration of 
IMP.
Section 5.11 Total Blood Volume (Other sections affected by this change: Appendix K)
The total blood volume that will be collected for each patient 
enrolling in this study for scheduled evaluation of ADAs, 
fremanezumab concentrations, clinical laboratory tests, and 
biomarkers is approximately 195248.5 mL for scheduled tests.
The total blood volume that will be collected for each 
patient enrolling in this study for scheduled evaluation 
of ADAs, fremanezumab concentrations, clinical 
laboratory tests, and biomarkers is approximately 
248.5 mL for scheduled tests.


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Reason/Justification for 
change
Section 6.1.1 Pain Intensity-Numerical Rating Scale
The PI-NRS will be used to collect average daily pain intensity over 
the past 24 hours, the worst pain intensity over the past 24 hours, and 
at-the-moment pain intensity just prior to the use of rescue 
medication.
The PI-NRS will be used to collect average daily pain 
intensity over the past 24 hours, the worst pain 
intensity over the past 24 hours, and at-the-moment 
pain intensity just prior to the use of rescue 
medication.
This change was made to 
clarify how pain scores will be 
collected.
Section 6.1.8 Inventory of Medical Diagnoses (Other sections affected by this change: Sections 2.2, 3.5, 3.6.2, 9.6.3, 9.6.4.5, and Appendix B)
Complex Inventory of Medical Inventory Diagnoses
The Complex Inventory of Medical Inventory (CMSI Diagnoses 
(IMD) is a 529-item, non-validated inventory that measures evaluates 
in patients the presence or absence of (1) medical conditions 
diagnosed and present physical symptoms (lasting for at least 
3 months) over the past year at the Screening Visit. and (2) their 
improvement or non-improvement at the end of the study.
Questions 1 to 51, with exception of question 15, will be completed 
by the investigator at the Screening Visit (Visit 1) and baseline at 
Visits 6 and 7. If the For those medical conditions that a patient 
answered “yes” at identifies as present at Visits 6 and 7 screening to 
any of the questions, the investigator will query the patient as to 
whether the pain is better those conditions present at screening are 
improved or not improved, or worse than compared with when the 
patient they entered the study.
Inventory of Medical Diagnoses
The Inventory of Medical Diagnoses (IMD) is a 9-
item, non-validated inventory that evaluates in 
patients (1) medical conditions diagnosed and present 
for at least 3 months at the Screening Visit and 
(2) their improvement or non-improvement at the end 
of the study.
Questions will be completed by the investigator at the 
Screening Visit (Visit 1) and at Visits 6 and 7. For 
those medical conditions that a patient identifies as 
present at Visits 6 and 7, the investigator will query 
whether those conditions present at screening are 
improved or not improved compared with when the 
patient entered the study.
This text was added to reflect 
the change in assessment scales
used. The Complex Medical 
Symptoms Inventory will be 
replaced with the IMD to 
collect data on concurrent 
medical conditions.
Section 7.1.6 Protocol-Defined Adverse Events of Special Interest
Severe hypersensitivity reactions For purposes of this protocol, the 
adverse events are considered protocol-defined adverse events of 
special interest for expedited reporting to pharmacovigilance and to 
be followed during the study to be sent to the sponsor’s GPSP 
Department for evaluation. ophthalmic related adverse events 
(nonserious of at least moderate severity, and and serious), or events 
of suspected anaphylaxis and Cardiovascular events are The process 
for reporting a protocol-defined defined as adverse events of special 
interest that will be periodically analyzed by the Product Safety 
Group. Adverse events adverse event of special interest will be the 
same as that for reporting a serious adverse event (see 
Severe hypersensitivity reactions are considered 
protocol-defined adverse events to be sent to the 
sponsor’s GPSP Department for evaluation. The 
process for reporting a protocol-defined adverse event 
of special interest will be the same as that for 
reporting a serious adverse event (see 
Section 7.1.5.3).
These changes were made to 
align the reporting of adverse 
events of special interest with 
other fremanezumab studies.


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change
Section 7.1.5.3). presented in the clinical study report (CSR), but 
there are no special requirements for expedited reporting
Section 7.4.2.1 Beta-human Chorionic Gonadotropin Tests (Other sections affected by this change: Section 3.5 and Appendix B)
Beta-human chorionic gonadotropin tests in serum or urine will be 
performed for all women of childbearing potential at screening 
(Visit 1)). Urine will be used for all subsequent visits and, will be 
tested on site via β-HCG dipstick. Serum may be tested if clinically 
indicated, thereafter or as a confirmatory test for a positive dipstick 
result.
Beta-human chorionic gonadotropin tests in serum 
will be performed for all women of childbearing 
potential at screening (Visit 1). Urine will be used for 
all subsequent visits and will be tested on site via β-
HCG dipstick. Serum may be tested if clinically 
indicated, or as a confirmatory test for a positive 
dipstick result.
This change was made to 
clarify that urine pregnancy 
tests will be used throughout 
the study and will be 
confirmed with serum testing if 
necessary.
 
 
 
 
 
 
 
 


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16.7.
Amendment 01 Dated 08 February 2019
The primary reason for this amendment is to correct errors surrounding the timing of visits during the screening period. This 
amendment is considered to be substantial (ie, requires approval by a Competent Authority (CA), IEC, and/or IRB) by the sponsor’s 
Authorized Representative. Other nonsubstantial changes have been made to the protocol (and protocol synopsis, as appropriate). 
These changes are unlikely to affect the safety or rights (physical or mental integrity) of the patients in this clinical study or the 
scientific value of the clinical study.
Table 1 (Study Procedures and Assessments) and Figure 1 (Overall Study Schematic Diagram) have been revised to reflect changes 
described below.
Original text with changes shown
New wording
Reason/Justification for change
Section 2.1 Primary and Secondary Objectives and Endpoints (Other sections affected by this change: Sections 9.6.2 and 9.6.4.)
•
the percentage of patients who experience a ≥30% reduction in the 
weekly average of the daily average PI-NRS score
•
the percentage of patients who experience 
a ≥30% reduction in the weekly average of the 
daily average PI-NRS score
This change was made throughout 
to clarify which score is being 
used as an endpoint.
 
 
 
 
 
 
 
 
 
 
 
 
 
.
Section 3.1 General Study Design and Study Schematic Diagram; Other sections affected by this change: Section 3.5 and Appendix B
Day 2101
Day 210
This change is a correction of the 
study day for the End-of-Study 
Visit (Visit 8).
Sections 3.1 General Study Design and Study Schematic Diagram; Other sections affected by this change: Sections 3.5, 4.1, 4.2, and Appendix B
174- to 35-day screening period (Visit 1, phone contact, a Baseline 
Assessment Period Start [BAPS] Visit [Visit 2])
17- to 35-day screening period (Visit 1, phone 
contact, a Baseline Assessment Period Start 
This change to the name of the 
visit was made throughout the 
protocol to reflect that the 


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[BAPS] Visit [Visit 2])
baseline assessments are started at 
Visit 2 and continue through 
Visit 3 (Randomization Visit).
Section 3.2 Planned Number of Patients and Countries
Number of Patients Planned (total): Approximately 369 patients will be 
screened to achieve 240 randomized patients. The number of evaluable 
patients is planned to be 180.
Number of Patients Planned (total):
Approximately 369 patients will be screened 
to achieve 240 randomized patients.
This change was made to 
eliminate redundant text.
Section 3.5 Schedule of Study Procedures and Assessments; Other sections affected by this change: Section 3.1 and Appendix B
Week 3
Day 21
±5 days
Washout
Day -33
through
Day -15
Scheduling
and
Instructionsd
Day -33
through
Day -15
Scheduling
and
Instructionsd
This change was made to reflect 
the change to the length of the 
longest washout period (from 
3 weeks to 2 weeks, maximum; 
see Appendix D).
Inclusion and
X
exclusion criteria
...
Assess concomitant 
X
medication 
Inclusion and
X
exclusion criteria
...
Assess concomitant 
X
medication
These changes were made to 
correct the Schedule of 
Assessments.
V8 (EOS)
...
Serum β-HCG 
X
test for women
Urine pregnancy 
X
test for WOCBPo
V8 (EOS)
...
Serum β-HCG 
test for women
Urine pregnancy 
X
test for WOCBPo
This change was made because 
this is the end of the study, and a 
serum pregnancy test for women 
is not necessary unless 
confirmation is required.
b Patients will be instructed to start the washout period during the 
screening period prior to phone contact. The duration of the washout 
period will be 7 to 3019 days; suggested washout periods for commonly 
used analgesics are listed in Appendix D. Laboratory values will be 
b Patients will be instructed to start the 
washout period during the screening period 
prior to phone contact. The duration of the 
washout period will be 7 to 19 days; suggested 
These changes were made to 
clarify timing of the phone call 
and to reflect the changes made to 
the recommended washout 


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checked prior to the phone call by the investigator. V2 will be scheduled 
and the monitoring plan for washout will be defined by the investigator. 
The washout period will need to be completed before the Baseline 
Assessment BAPS Visit (Visit 2). Training and Instructions will be 
provided to patients regarding the monitoring of withdrawal symptoms 
during the washout period.
washout periods for commonly used 
analgesics are listed in Appendix D. 
Laboratory values will be checked prior to the 
phone call by the investigator. V2 will be 
scheduled and the monitoring plan for 
washout will be defined by the investigator. 
The washout period will need to be completed 
before the BAPS Visit (Visit 2). Training and 
Instructions will be provided to patients 
regarding the monitoring of withdrawal 
symptoms during the washout period.
periods made in Appendix D.
c All baseline assessments will take place on day 1, except for the PI NRS 
scores, which will be recorded days 14 to 1 (±3 days), inclusive. 
cdPatients who do not require a washout may be scheduled for the BAPS 
Visit (Visit 2) following the availability of laboratory results.
d Training on each assessment and the e-diary will occur at all visits after 
the e-diary is provided, except for Visit 5.
c Patients who do not require a washout may 
be scheduled for the BAPS Visit (Visit 2) 
following the availability of laboratory 
results.
d Training on each assessment and the e-diary 
will occur at all visits after the e-diary is 
provided, except for Visit 5.
Footnote c was removed as it 
provided information already in 
the table. Footnote ‘c’ was added 
to clarify actions for those patients 
who are not on medications 
requiring a washout period as 
outlined in Appendix D.
f For the baseline assessment 14 day period before (ie, between the BAPS 
Visit [Visit 2] and the Baseline Randomization Visit [Visit 32]), patients 
will record their daily average pain intensity score and daily worst pain 
intensity score on the PI-NRS once daily and will continue to taper off 
of other prohibited medications. Patients will record their scores in the e-
diary every evening at approximately the same time between 1800 and 
2200 hours. Pain intensity scores prior to the use of rescue medication 
will also be entered in the e-diary daily if rescue medication is used.
g Record PI NRS average and worst pain intensity score daily in the e
diary every evening between 1800 and 2200 hours during the study.
f For the baseline assessment period (ie, 
between the BAPS Visit [Visit 2] and the 
Randomization Visit [Visit 3]), patients will 
record their daily average pain intensity 
score and daily worst pain intensity score 
using the PI-NRS in the e-diary every 
evening at approximately the same time
between 1800 and 2200 hours. Pain intensity
scores prior to the use of rescue medication 
will also be entered in the e-diary daily if 
rescue medication is used.
This change was made to refer to 
the correct study visit, to include 
timing information from the 
protocol synopsis that was not in 
the protocol body, and to clarify 
that the PI-NRS score must be 
documented before rescue meds 
are taken.
ih Clinical laboratory tests will include serum chemistry, hematology, and 
urinalysis. HIV, HBsAg, hepatitis C antibody, and TSH will also be 
completed only at the Screening Visit (Visit 1). 
h Clinical laboratory tests will include serum 
chemistry, hematology, and urinalysis. HIV, 
HBsAg, hepatitis C antibody, and TSH will 
also be completed only at the Screening 
Visit (Visit 1).
This change was made to include 
all clinical laboratory tests as 
outlined in Section 7.4
o A serum pregnancy test may be completed as a confirmatory test, if 
warranted.
o A serum pregnancy test may be completed 
as a confirmatory test, if warranted.
This change was made to clarify 
that a urine dipstick test may be 
confirmed with a serum 


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Reason/Justification for change
pregnancy test, if needed.
Section 3.5 Schedule of Study Procedures and Assessments; Other sections affected by this change: Section 6.1.6.1
q
The sleep e-diary or PROMIS Sleep Disturbance SF8a should be 
performed weekly on awakening. Collection of the PROMIS Sleep 
Disturbance SF8a will start at the BAPS Visit (Visit 2) at the study site to 
assess the previous week’s sleep.
q The sleep e-diary or PROMIS Sleep 
Disturbance SF8a should be performed 
weekly on awakening. Collection of the 
PROMIS Sleep Disturbance SF8a will start 
at the BAPS Visit (Visit 2) at the study site 
to assess the previous week’s sleep.
This footnote was modified to 
clearly state when the SF8a 
assessment will begin.
Section 4.1 Patient Inclusion Criteria
b. agree to comply with the requirements and restrictions listed in this 
protocol, including remaining at the clinic for the duration of each the
required visit duration during the study period to complete all scheduled 
procedures and assessments, and returning to the clinic for the follow-up 
evaluation procedures and assessments, as specified in this protocol.
...
m. must be willing and able to comply with study restrictions and to 
remain at the investigational center during visits to complete all scheduled 
procedures and assessments, and be willing to return to the investigational 
center for further visits, as applicable, and the follow up procedures and 
assessments as specified in this protocol
b. agree to comply with the requirements and 
restrictions listed in this protocol, including 
remaining at the clinic for each required visit 
duration during the study period to complete 
all scheduled procedures and assessments, and 
returning to the clinic for the follow-up 
procedures and assessments as specified in 
this protocol
This change was made to 
eliminate a redundant inclusion 
criterion.
d. willing to comply with recording of once-daily scores using the PI-
NRS, completed every evening (approximately the same time each day) 
starting 14 days before the Baseline Visit at the BAPS Visit (Visit 2) up to 
the Randomization Visit (Visit 3). A minimum of 12 of 14 daily average 
pain ratings are required to be recorded in an e-diary during the baseline 
assessment period.
d. willing to comply with recording of once-
daily scores using the PI-NRS, completed 
every evening (approximately the same time 
each day) starting at the BAPS Visit (Visit 2) 
up to the Randomization Visit (Visit 3). A 
minimum of 12 of 14 daily average pain 
ratings are required to be recorded in an e-
diary during the baseline assessment period
This change was made to clarify 
the time boundaries of the 
washout period and to clarify the 
baseline assessment period.
e. all of the following diagnostic criteria for FM according to 2010/2011 
American College of Rheumatology (Wolfe et al 2010) are met at the 
Screening Visit and at randomization:
e. all of the following diagnostic criteria for 
FM according to 2010/2011 American 
College of Rheumatology (Wolfe et al 2010) 
are met at the Screening Visit and at 
randomization:
This change was made to match 
criterion ‘e’ text from the synopsis 
and provide description of the 
resource.
Section 4.2 Patient Exclusion Criteria


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c. known history of noncompliance leading to unsuccessful completion 
after enrollment in 1 or more FM registrational trials
Deleted criteria
This change was made as it was 
non-specific.
d. known history of intolerability or allergy to 2 or more medications
Deleted criteria
This change was made as it was 
non-specific.
hf. known history of clinically significant or unstable hematologic, 
cardiac, or thromboembolic events (ie, arterial or venous thrombotic or 
embolic events, including cerebrovascular accident [including transient 
ischemic attacks], deep vein thrombosis, or pulmonary embolism); renal, 
endocrine, pulmonary, gastrointestinal, genitourinary, or neurologic 
disorders [exclusive of FM]; psychotic disorders, dementia, bipolar 
disorder, major depressive disorders, anxiety disorders, suicidality, and 
substance use disorders as diagnosed using the Mini International 
Neuropsychiatric Interview [MINI]; infectious, hepatic, or ocular disease, 
at the discretion of the investigator, as determined by a medical and 
psychiatric history; and physical examination, 12-lead ECG, serum 
chemistry, hematology, coagulation, and urinalysis). Abnormal test results 
may be repeated for confirmation
f. known history of clinically significant or 
unstable hematologic, cardiac, or 
thromboembolic events (ie, arterial or venous 
thrombotic or embolic events, including 
cerebrovascular accident [including transient 
ischemic attacks], deep vein thrombosis, or 
pulmonary embolism); renal, endocrine, 
pulmonary, gastrointestinal, genitourinary, or 
neurologic disorders [exclusive of FM]; 
infectious, hepatic, or ocular disease, at the 
discretion of the investigator, as determined 
by a medical and psychiatric history; and 
physical examination, 12-lead ECG, serum 
chemistry, hematology, coagulation, and 
urinalysis). Abnormal test results may be 
repeated for confirmation
This change was made to align 
with other exclusion criteria to 
clarify inclusion/exclusion of 
patients with mental disorders 
and/or who may be on prohibited 
medications.
vt. clinically significant elevations in hepatic enzymes (alanine 
aminotransferase [ALT] or aspartate aminotransferase [AST]) based on 
the upper limit of normal (ULN) or investigator judgment, which have 
been reconfirmed on a repeat test
t. clinically significant elevations in hepatic 
enzymes (alanine aminotransferase [ALT] or 
aspartate aminotransferase [AST]) based on 
the ULN or investigator judgement, which
have been reconfirmed on a repeat test
This change was made to define 
“clinically significant” for this 
criterion.
yw. known history of alcohol and/or drug abuse within the past 12 months
that in the investigator’s opinion could interfere with the study evaluations 
or the patient’s safety per the MINI or have a positive urine drug screen 
for illegal drugs of abuse or alcohol test at the Screening Visit, Baseline 
Assessment BAPS Visit, or prior to randomization
w. known history of alcohol and/or drug abuse 
within the past 12 months per the MINI or 
have a positive urine drug screen for illegal 
drugs of abuse or alcohol test at the Screening 
Visit, BAPS Visit, or prior to randomization
This change was made for 
clarification.
Section 4.3 Discontinuation from IMP/Early Termination from Study Criteria and Procedures for the Patient; Other sections affected by this change: 
Section 3.5
Efficacy endpoints (primary, secondary, 
) will be derived 
from subjective pain ratings collected daily using an e-diary. Eligible 
patients will receive comprehensive training from site personnel on the 
Efficacy endpoints (primary, secondary, 
 
will be derived from subjective 
pain ratings collected daily using an e-diary. 
This text was added to outline 
procedures for e-diary 
compliance.


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Reason/Justification for change
correct use of the e-diary. Site personnel will also instruct patients on the 
requirement for timely and daily completion of the e-diary. At least 75% 
compliance with e-diary recordings on a weekly basis is expected after the 
randomization period. Site personnel will monitor patients’ compliance 
that e-diary entry is at least 75% every week during the double-blind 
treatment period. If weekly 75% compliance is not maintained, a reminder 
and any other corrective actions, as deemed necessary, will be issued to 
the patient.
In the following circumstances, the IMP will be discontinued immediately:
Eligible patients will receive comprehensive 
training from site personnel on the correct use 
of the e-diary. Site personnel will also instruct 
patients on the requirement for timely and 
daily completion of the e-diary. At least 75% 
compliance with e-diary recordings on a 
weekly basis is expected after the 
randomization period. Site personnel will 
monitor patients’ compliance that e-diary 
entry is at least 75% every week during the 
double-blind treatment period. If weekly 75% 
compliance is not maintained, a reminder and 
any other corrective actions, as deemed 
necessary, will be issued to the patient.
In the following circumstances, the IMP will 
be discontinued immediately:
Section 5.2.3 Accountability
Partially used Empty and unused pre-filled syringes must be destroyed at 
the investigational center in accordance with the investigational center’s 
Standard Operating Procedures (SOPs) following sponsor approval. In the 
event that the investigational center is unable to destroy the empty and/or 
unused units of IMP, the IMP must be returned to the sponsor or its 
designee per sponsor instructions. and unused pre filled syringes of IMP 
will be returned to the sponsor or designee.
Empty and unused pre-filled syringes must be 
destroyed at the investigational center in 
accordance with the investigational center’s 
Standard Operating Procedures (SOPs) 
following sponsor approval. In the event that 
the investigational center is unable to destroy 
the empty and/or unused units of IMP, the 
IMP must be returned to the sponsor or its 
designee per sponsor instructions.
This change was made to correct 
procedures for disposal of used 
and unused IMP.
Section 5.4 Other Medicinal Products
Dosing Instructions: 1 to 2 caplets with dose up to 1000 mg/day per dose; 
maximum of 3000 mg per day
Dosing Instructions: 1 to 2 caplets with dose 
up to 1000 mg/day per dose; maximum of 
3000 mg per day
This change was made to correct 
the acetaminophen dose used as 
rescue medication.
Section 5.7 Prior and Concomitant Medication or Therapy
In addition, tricyclic antidepressants at low doses (amitriptyline 
[≤25 mg]), cyclobenzaprine [2.5 mg sublingual or 5 to 10 mg], or 
trazodone [≤150 mg]) may be used for sleep.
In addition, tricyclic antidepressants at low 
doses (amitriptyline [≤25 mg], 
cyclobenzaprine [2.5 mg sublingual or 5 to 
10 mg], or trazodone [≤150 mg]) may be used 
This change was made to clarify 
and organize which dosages 
applied to which medication.


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for sleep.
Section 5.11 Total Blood Volume
The total blood volume that will be collected for each patient enrolling in 
this study for scheduled evaluation of ADAs, fremanezumab 
concentrations, clinical laboratory tests, and biomarkers treatment with 
fremanezumab is approximately 195.5 mL for scheduled tests. An 
additional 30 mL of blood may be collected in the event of follow-up for 
liver enzymes.
The total blood volume that will be collected for each patient enrolling in 
this study for evaluation of ADAs, fremanezumab concentrations, and 
safety (adverse events and concomitant medications) is approximately 
195.5 mL. Details are provided in Appendix K.
The total blood volume that will be collected 
for each patient enrolling in this study for 
scheduled evaluation of ADAs, 
fremanezumab concentrations, clinical 
laboratory tests, and biomarkers is 
approximately 195.5 mL. An additional 
30 mL of blood may be collected in the event 
of follow-up for liver enzymes. Details are 
provided in Appendix K.
This change was made to clarify 
the total blood volume to be 
collected.
Section 6.1.6.1 PROMIS Sleep Disturbance Short Form 8a
The PROMIS Sleep Disturbance SF8 Scale contains 8 items with a score 
range of 8 to 40 and measures quality of sleep and sleep-related 
impairment within the previous 24 hours.
The PROMIS Sleep Disturbance SF8 Scale 
contains 8 items with a score range of 8 to 40 
and measures quality of sleep and sleep-
related impairment.
This change was made to correct 
an error in the text.
Section 7.4 Clinical Laboratory Tests
Albumin
Bilirubin
Direct bilirubin
Hepatitis B
Albumin
Bilirubin
Direct bilirubin
Hepatitis B
This change was made to clarify 
that assessment for Hepatitis B 
should be conducted as part of 
serum chemistry clinical 
laboratory testing.
Section 7.9 Assessment of Local Tolerability and Pain
±15 min
±15 min
This change was made to reflect 
the correction to the assessment 
window.
Section 9.2 Sample Size and Power Considerations; Other sections affected by this change: Section 9.6.4.2
Moreover, assuming a standard deviation of 2.2 for change from baseline 
in the weekly average of the daily average PI-NRS score, 80 patients per 
treatment group will provide at least 90% probability to observe the half 
length of the 95% confidence of the treatment difference between 
fremanezumab 225 mg sc or fremanezumab 675 mg sc and placebo of less 
Moreover, assuming a standard deviation of 
2.2 for change from baseline in the weekly 
average of the daily average PI-NRS score, 
80 patients per treatment group will provide at 
least 90% probability to observe the half 
This change was made to clarify 
how the score is being used as an 
endpoint.


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Original text with changes shown
New wording
Reason/Justification for change
than 0.74.
length of the 95% confidence of the treatment 
difference between fremanezumab 225 mg sc 
or fremanezumab 675 mg sc and placebo less 
than 0.74.
Section 9.6.2 Secondary Endpoints
•
change from baseline in the PI NRS score over the past 24 hours 
•
change from baseline in the individual components of the FIQR: 
symptom subscore, impact subscore, and functional subscore score
•
change from baseline in the individual 
components of the FIQR: symptom subscore, 
impact subscore, and functional subscore 
score
This change was made because 
this endpoint does not appear in 
either protocol.
Appendix A CLINICAL LABORATORIES AND OTHER DEPARTMENTS AND INSTITUTIONS
Tel: 
 
Tel: 
This change was made to include 
the Coordinating Investigator’s 
contact information in 
Appendix A.
Teva Pharmaceutical Industries Ltd.
Tel: 
Cell: 
 
Teva Pharmaceutical Industries Ltd.
Tel: 
Cell: 
Teva Pharmaceutical Industries Ltd.
Tel: 
Cell: 
This change was made to reflect a 
personnel change at the Sponsor.
TBD
This change was made to provide 
an information update.


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Original text with changes shown
New wording
Reason/Justification for change
TBD
This change was made to provide 
an information update
TBD
TBD
This change was made to provide 
an information update
TBD
This change was made to provide 
an information update
TBD
This change was made to provide 
an information update
Clinical Data 
Management System
Clinical Data 
Management 
System
This change was made to provide 
an information update
Appendix B STUDY PROCEDURES AND ASSESSMENTS BY VISIT
[Visit 2, day -14 (week -3) (±23 days)]
[Visit 2, day -14 (week -3) (±2 days)])
This change was made to correct 
the Visit 2 visit window respective
to inclusion criterion ‘d’.
•
serum FSH test (for postmenopausal women only) and β-HCG serum 
pregnancy test (women)
•
urine pregnancy test for women of childbearing potential
•
inform patients of study restrictions and compliance requirements
•
serum FSH test (for postmenopausal 
women only) and β-HCG serum pregnancy 
test (women)
•
urine pregnancy test for women of 
childbearing potential
•
inform patients of study restrictions and 
compliance requirements
This change was made to 
accurately reflect those 
assessments given at Visit 2.
•
assess for injection site reactions
•
assess for injection site reactions
This change was made to clarify 
that injection site reactions are not 
assumed to occur, rather injection 
site reactions will be assessed 
if/when they occur.
•
review of IMP accountability and rescue medication
•
collect IMP rescue medication
•
review of IMP accountability and rescue 
medication
•
collect rescue medication
This change was made to account 
for the review and collection of 
rescue medication at unscheduled 
visits.
Appendix D WASHOUT PERIODS FOR COMMON MEDICATIONS


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Reason/Justification for change
Duloxetine
12 weeks
...
Venlafaxine
12 weeks
Nortriptyline
32 weeks
...
Desvenlafaxine
32 weeks
Duloxetine
32 weeks
Levomilnacipran
32 weeks
Milnacipran
32 weeks
Venlafaxine
32 weeks
Duloxetine
2 weeks
...
Venlafaxine
2 weeks
Nortriptyline
2 weeks
...
Desvenlafaxine
2 weeks
Duloxetine
2 weeks
Levomilnacipran
2 weeks
Milnacipran
2 weeks
Venlafaxine
2 weeks
This change was made to clarify 
the washout periods.
Appendix J LIST OF PROHIBITED MEDICATIONS AND THERAPEUTIC INTERVENTIONS
These medication lists are not exhaustive; the investigator should check 
with the Medical Monitor on any drug not listed in this appendix. For 
those medications listed in Section 5.7, doses greater than the listed dose 
are prohibited.
These medication lists are not exhaustive; the 
investigator should check with the Medical 
Monitor on any drug not listed in this 
appendix. For those medications listed in 
Section 5.7, doses greater than the listed dose 
are prohibited.
This change was made to ensure 
the medications listed in 
Appendix J do not conflict with 
those listed in Section 5.7.
Any new therapy taken within 90 days of the Screening Visit (Visit 1) or 
planned therapy concurrent with the study that could affect pain or any 
other symptom associated with FM (eg, physical therapy, massage, 
chirotherapy, psychotherapy, and counseling).
Any new therapy taken within 90 days of the 
Screening Visit (Visit 1) or planned therapy 
concurrent with the study that could affect 
pain or any other symptom associated with 
FM (eg, physical therapy, massage, 
chirotherapy, psychotherapy, counseling).
This change was made to clarify 
the period of non-pharmacologic 
interventions.
APPENDIX K TOTAL BLOOD VOLUME
Total blood volume to be collected for each patient in this study is 
approximately 195.5 mL for scheduled tests (at maximum). An additional 
30 mL of blood may be collected in the event of follow-up for liver 
enzymes.
Total blood volume to be collected for each 
patient in this study is approximately 
195.5 mL for scheduled tests. An additional 
30 mL of blood may be collected in the event 
of follow-up for liver enzymes.
This change was made to be 
consistent with the non-concealed 
version of the protocol.


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APPENDIX A. CLINICAL LABORATORIES AND OTHER 
DEPARTMENTS AND INSTITUTIONS
Sponsor’s Authorized Representative
 
, Teva Branded Pharmaceutical Products R&D, 
Inc.
Sponsor’s Medical Expert/Contact Point 
Designated by the Sponsor for Further 
Information on the Study
Teva Branded Pharmaceutical Products R&D, Inc.
Coordinating Investigator
Sponsor’s Representative of Global Patient Safety 
and Pharmacovigilance
Teva Pharmaceutical Industries Ltd.
Contract Research Organization
Contract Manufacturing Organization
Central Clinical Laboratory
Central Electrocardiogram Evaluation
Bioanalytical Pharmacokinetics Evaluation
Teva Branded Pharmaceutical Products R&D, Inc. -
Special Bioanalytics
Bioanalytical Immunogenicity Evaluation
Teva Branded Pharmaceutical Products R&D, Inc. -
Special Bioanalytics
Biomarker Evaluation
TBD
Randomization and Trial Supply Management 
(RTSM) Vendor
e-diary Vendor
e-diary and Tablet Administrator


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Clinical Data Management System


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APPENDIX B. STUDY PROCEDURES AND ASSESSMENTS BY VISIT
1. Procedures for screening (Visit 1, day -35 [week -5])
The Screening Visit (Visit 1) will take place not more than 3 weeks before the Baseline 
Assessment Period Start (BAPS) Visit (Visit 2). The following procedures will be performed 
at Visit 1:

obtain written informed consent before any study-related procedures are performed

review inclusion and exclusion criteria

review medical and psychiatric history

record demographic characteristics

study assessments/pain reporting training

electronic diary (e-diary) training

dispense rescue medication

Pain Intensity-Numerical Rating Scale (PI-NRS)

2016 Fibromyalgia American College of Rheumatology (ACR; widespread pain 
index [WPI] and symptom severity [SS] scale score) examination

Mini-International Neuropsychiatric Interview

prior medication and treatment history

clinical laboratory tests

urine drug screen

alcohol (social history)

marijuana (cannabis), cannabidiol, or other cannabinoids (medicinal and social 
history)

full physical examination

electrocardiography

vital signs measurements (including height and weight)

serum follicle-stimulating hormone (FSH) test (for postmenopausal women only) and 
beta-human chorionic gonadotropin (β-HCG) serum pregnancy test (women)

inform patients of study restrictions and compliance requirements

assess concomitant medication



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2. Procedures for Phone Contact (Scheduling and Instructions [Day -33 through 
Day -15); Washout Period [7 to 19 days])
Phone contact will occur no later than day -15. The following procedures will take place:

prior medication tapering and washout

assess concomitant medication

inquire about adverse events

schedule BAPS Visit (Visit 2)
3. Procedures Before Administration of Investigational Medicinal Product(s) (BAPS 
Visit [Visit 2, day -14 (week -3) (±2 days)])
Patients who meet the inclusion and exclusion criteria at Visit 1 will continue to Visit 2, 
when initial baseline assessments will be conducted.
The following procedures will be performed at Visit 2:

review inclusion and exclusion criteria

study assessments/pain reporting training

e-diary data review/training

dispense/account rescue medication

provide e-diary

PI-NRS (recorded daily)

prior medication and treatment history

urine drug screen

abbreviated physical examination

vital signs measurements

urine pregnancy test for women of childbearing potential (serum pregnancy test may 
be completed to confirm, if warranted)

inform patients of study restrictions and compliance requirements

assess concomitant medication

review study compliance

 


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
PROMIS Sleep Disturbance SF8a weekly in e-diary

inquire about adverse events


review e-diary
4. Procedures During Administration of Investigational Medicinal Product 
(Double-Blind Treatment Period)
a. Randomization (Visit 3, day 1 [week 1])
The following procedures and assessments will be performed at Visit 3:

review inclusion and exclusion criteria

assign randomization/treatment number

study assessments/pain reporting training

e-diary data review/training

dispense/account rescue medication


prior medication and treatment history

clinical laboratory tests

urine drug screen

abbreviated physical examination

electrocardiography

vital signs measurements

urine pregnancy test for women of childbearing potential (serum pregnancy test may 
be completed to confirm, if warranted)

inform patients of study restrictions and compliance requirements

assess concomitant medication

review study compliance



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
blood sample for serum anti-drug antibody (ADA) concentration

 

inquire about adverse events

 Since Last Visit version

administration of IMP

review e-diary
b. Administration of Investigational Medicinal Product (Visits 4, 5, and 6, days 29 
[week 4], 57 [week 8], and 85 [week 12] ±7 days, respectively)
For Visits 4 and 5 (when at-home dosing is available), home visits are permitted for patients 
who are not able to go to the investigational center or if the investigational center staff are 
not able to see patients at the investigational center.
The following procedures and assessments will be performed at Visits 4, 5, and 6 (days 29 
[week 4], 57 [week 8], and 85 [week 12] ±7 days, respectively):

study assessments/pain reporting training (and as needed, for subsequent retraining 
throughout the study)

e-diary data review/training (and as needed, for subsequent retraining throughout the 
study)

dispense/account rescue medication

PI-NRS (recorded daily) 

clinical laboratory tests (Visit 6 [day 85] only)

urine drug screen

abbreviated physical examination

electrocardiography (Visit 6 [day 85] only)

vital signs measurements

urine pregnancy test for women of childbearing potential (serum pregnancy test may 
be completed to confirm, if warranted)

inform patients of study restrictions and compliance requirements

assess concomitant medication

review study compliance



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

blood sample for plasma concentration of IMP (Visit 6 [day 85] only)

blood sample for serum ADA concentration (Visit 6 [day 85] only)

 

inquire about adverse events

 Since Last Visit version

administration of IMP

review e-diary
5. End-of-Treatment/End-of-Study or Early Termination (Visit 7, day 113 [week 16] 
±7 days) 
The following procedures/assessments will be performed at Visit 7 (day 113 [week 16]):

account/collect rescue medication

PI-NRS (daily in e-diary) (Note: Collection ends the day before or the morning of 
Visit 7 if missed the day before)

clinical laboratory tests

urine drug screen

abbreviated physical examination

electrocardiography

vital signs measurements

urine pregnancy test for women of childbearing potential (serum pregnancy test may 
be completed to confirm, if warranted)

assess concomitant medication

review study compliance



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
Sleep Disturbance SF8a weekly in e-diary

IMD

blood sample for plasma concentration of IMP

blood sample for serum ADA concentration


inquire about adverse events

 Since Last Visit version

review e-diary

collect patient e-diary
6. Unscheduled Visits
An unscheduled visit may be performed at any time during the study at the patient’s and/or 
the investigator’s request and as deemed necessary by the investigator. The date and reason 
for the unscheduled visit will be recorded on the eCRF as well as any other data obtained 
from procedures and assessments. Procedures and assessments may be performed at the 
discretion of the investigator based on the reason for the visit. 


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APPENDIX C. 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;47(4):373-80; 
PMID:16546624]. J Allergy Clin Immunol 2006;117(2):391-7.


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APPENDIX D. QUALITY CONTROL AND QUALITY ASSURANCE
Protocol Amendments and Protocol Deviations and Violations
Protocol Amendments
No changes from the final approved (signed) protocol will be initiated without the prior written 
approval or favorable opinion of a written amendment by the IEC/IRB and national and local 
competent authorities, as applicable, except when necessary to address immediate safety 
concerns to the patients or when the change involves only nonsubstantial logistics or 
administration. The principal investigator at each investigational center, the coordinating 
investigator (if applicable), and the sponsor will sign the protocol amendment.
Protocol Violations
Any deviation from the protocol that affects, to a significant degree, (a) the safety, physical, or 
mental integrity of the patients in the study and/or (b) the scientific value of the study will be 
considered a protocol violation. Protocol violations may include non-adherence on the part of the 
patient, the investigator, or the sponsor to protocol-specific inclusion and exclusion criteria, 
primary objective variable criteria, or GCP guidelines; noncompliance to IMP administration; 
use of prohibited medications. Protocol violations will be identified and recorded by 
investigational center personnel in the eCRF. 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 terminate 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 
terminated the study early, no action will be taken but the violation will be recorded.
For Coronavirus Disease 2019 updates, see Appendix O.
Information to Study Personnel
The investigator is responsible for giving information about the study to all personnel members 
involved in the study or in any element of patient management, both before starting the study and 
during the course of the study (eg, when new personnel become involved). The investigator must 
ensure that all study personnel are qualified by education, experience, and training to perform 
their specific task. These study personnel members must be listed on the investigational center 
authorization form, which includes a clear description of each personnel member’s 
responsibilities. This list must be updated throughout the study, as necessary.
The study monitor is responsible for explaining the protocol to all study personnel, including the 
investigator, and for ensuring they comply with the protocol.


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


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APPENDIX E. ETHICS
Informed Consent
The investigator, or a qualified person designated by the investigator, should fully inform the 
patient of all pertinent aspects of the study, including the written information approved by the 
IEC/IRB. All written and oral information about the study will be provided in a language as 
nontechnical as practical to be understood by the patient. The patient should be given ample time 
and opportunity to inquire about details of the study and to decide whether or not to participate in 
the study. The above should be detailed in the source documents.
Written informed consent will be obtained from each patient before any study specific 
procedures or assessments are done and after the aims, methods, anticipated benefits, and 
potential hazards are explained. The patient’s willingness to participate in the study will be 
recorded in the informed consent form, which will be signed and personally dated by the patient 
and by the person who conducted the informed consent discussion. The investigator will keep the 
original informed consent forms, and copies will be given to the patients. It will also be 
explained to the patients that the patient is free to refuse participation in the study and free to 
terminate from the study at any time without prejudice to future treatment.
Competent Authorities and Independent Ethics Committees/Institutional Review Boards
Before this study starts, the protocol will be submitted to the national competent authority and to 
the respective IEC/IRB for review. As required, the study will not start at a given investigational 
center before the IEC/IRB and competent authority (as applicable) for the investigational center 
give written approval or a favorable opinion.
For Coronavirus Disease 2019 updates, see Appendix O.
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 eCRFs and other documents or 
image material submitted to the sponsor, patients will be identified not by their names, but by an 
identification number.
Personal medical information may be reviewed for the purpose of patient safety or for verifying 
data in the source and the eCRF. This review may be conducted by the study monitor, properly 
authorized persons on behalf of the sponsor, Global Quality Assurance (GCA), or competent 
authorities. Personal medical information will always be treated as confidential.


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APPENDIX F.
BIRTH CONTROL METHODS AND PREGNANCY 
TESTING
Contraception recommendations and pregnancy testing should encompass all IMPs as well as 
non-investigational medicinal products, eg, background therapy, and the measures to be followed 
should be based on the medicinal product with highest risk.
While hormonal contraception may be susceptible to interaction with an IMP that reduces the 
efficacy of the contraceptive method, eg, CYP 4A inducers, no adjustments in dosing should be 
necessary.
Although drug interaction studies have not been conducted with fremanezumab. Like other 
therapeutic antibodies, fremanezumab is expected to be primarily metabolized via proteolytic 
catabolism. Therefore, interaction with and impact on drug metabolizing enzymes (eg, CYP 
isoforms) is considered unlikely in humans
Furthermore, fremanezumab was tested for stimulation of pro-inflammatory cytokine release in 
human whole blood (Study PF-04427429/24Aug09/111320) and did not elicit significant 
cytokine release (tumor necrosis factor α, interleukin-6, interferon-γ, or interleukin-1β) in any 
donor including at concentrations up to 100 μg/mL. As such, there is also no reason to suspect 
that fremanezumab may influence CYP activity via cytokine release.
Women/Girls of childbearing potential are defined as:

not surgically (documented hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy) or congenitally sterile

not postmenopausal
Women/Girls of nonchildbearing potential are defined as:

surgically (documented hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy) or congenitally sterile

postmenopausal
Postmenopausal women:

1 year postmenopausal (no menses for 12 months without an alternative medical 
cause plus an increased concentration of follicle-stimulating hormone of more than 
35 U/L) in women not using hormonal contraception or hormonal replacement 
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Description of different birth control methods
Highly effective birth control methods:
Highly effective birth control methods are methods that can achieve a failure rate of less than 1% 
per year when used consistently and correctly are considered. Such methods include the 
following:

Combined estrogen and progestogen hormonal contraception (oral, intravaginal, 
transdermal) associated with inhibition of ovulation; these should be initiated at least 
7 days before the first dose of IMP

Progestogen-only hormonal contraception (oral, injectable, implantable) associated 
with inhibition of ovulation; these should be initiated at least 7 before the first dose of 
IMP

Intrauterine device (IUD) and intrauterine hormone-releasing system (IUS) need to be 
in place at least 2 months before screening visit (V1)

Bilateral tubal occlusion

Sexual abstinence is only considered a highly effective method if defined as 
refraining from heterosexual intercourse in the defined period. The reliability of 
sexual abstinence needs to be evaluated in relation to the duration of the clinical study 
and the preferred and usual lifestyle of the patient.

Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods), 
declaration of abstinence for the duration of a study, and withdrawal are not 
acceptable methods of contraception (according to Medicines and Healthcare 
Products Regulatory Agency).
Unacceptable birth control methods:
Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and lactational amenorrhoea method (LAM) are not acceptable 
methods of contraception. Female condom and male condom should not be used together.
Male contraception
Male patients must always use a condom including vasectomized men if their partners are of 
child-bearing potential.
Vasectomy:
Use of contraceptive methods applies also to vasectomized men.
Pregnant female partners of male study participants:
Male study participants must use condoms during intercourse if their female partners are 
pregnant.


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


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APPENDIX H. HANDLING, LABELING, STORAGE, AND 
ACCOUNTABILITY FOR IMP(S)
Storage and Security
The investigator or designee must confirm appropriate temperature conditions have been 
maintained for all IMPs received and any discrepancies are reported and resolved before use of 
the IMPs.
The test IMPs (fremanezumab and placebo IMP) must be stored under refrigeration at 2°C to 
8°C (36°F to 46°F), do not freeze, protect from light and avoid vigorous shaking.
Diversion is considered to have occurred when the legal supply chain of prescription medicinal 
products is broken, and medicinal products are transferred from a licit to an illicit channel of 
distribution or use.
Labeling
Supplies of IMPs will be labeled in accordance with the current ICH guidelines on GCP and 
Good Manufacturing Practice and will include any locally required statements. If necessary, 
labels will be translated into the local language.
Accountability
Each IMP shipment will include a packing slip listing the contents of the shipment and any 
applicable forms.
The investigator is responsible for ensuring that deliveries of IMPs and other study materials 
from the sponsor are correctly received, recorded, handled, and stored safely and properly in 
accordance with the Code of Federal Regulations (CFR), and used in accordance with this 
protocol.
Only patients enrolled in the study may receive IMPs and only authorized staff at the 
investigational center may supply or administer IMPs. All IMPs must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labeled storage conditions or appropriate instructions with access limited to the investigator and 
authorized staff at the investigational center.
The investigator (or designee) will instruct the patient to store the IMP according to the 
instructions on the label, if applicable; or will give instructions in an appropriate form.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for IMP accountability, reconciliation, and record maintenance (ie, receipt, 
reconciliation, and final disposition records).
A record of IMP accountability (ie, IMP and other study materials received, used, retained, 
returned, or destroyed) must be prepared and signed by the principal investigator or designee, 
with an account given for any discrepancies. Pre-filled syringes should never be used partially. 
Empty syringes should be destroyed at the investigational center after reconciliation is 
performed. If the investigational center does not have the capability to destroy the empty 
syringes, they should be sent back to the sponsor. Unused pre-filled syringes of IMP will be 
returned to the sponsor or designee.


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Further guidance and information pertaining to the preparation, handling, labeling, storage, and 
accountability for the IMP used in this study are provided in the Pharmacy Manual.


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APPENDIX I.
LIST OF PROHIBITED MEDICATIONS AND 
THERAPEUTIC INTERVENTIONS
These medication lists are not exhaustive; the investigator should check with the Medical 
Monitor about any drug not listed in this appendix. For the medications fluoxetine (Prozac) and 
naltrexone that are listed in the table below, only doses greater than the maximum listed dose are 
prohibited.
ANTIDEPRESSANTS 
TCAs and related compounds
Amitriptyline
Amoxapine
Clomipramine (Anafranil)
Desipramine (Norpramin)
Doxepin
Imipramine (Tofranil, Tofranil-PM)
Maprotiline
Nortriptyline (Pamelor)
Protriptyline (Vivactil)
Trimipramine (Surmontil)
Serotonin-Norepinephrine Reuptake Inhibitors
Desvenlafaxine (Pristiq)
Duloxetine (Cymbalta, Irenka)
Levomilnacipran (Fetzima)
Milnacipran (Savella)
Venlafaxine (Effexor, Effexor XR)
5-HT3 Receptor Antagonists
Vortioxetine (Trintellix) (formerly called Brintellix)
Noradrenergic Antagonists
Mirtazapine (Remeron, Remeron SolTab)
Monamine Oxidase Inhibitors
Isocarboxazid (Marplan)
Phenelzine (Nardil)
Tranylcypromine (Parnate)
Selegiline (EmSam)


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ANTIPSYCHOTICS/MOOD STABILIZERS
Antipsychotics
Aripiprazole (Abilify, Abilify Maintenna)
Asenapine (Saphris)
Cariprazine (Vraylar)
Chlorpromazine
Loxapine (Adasuve)
Olanzapine (Zyprexa, Zyprexa Zydis)
Quetiapine (Seroquel, Seroquel XR)
Risperidone (Risperdal, Risperdal Consta, Risperdal M-Tab)
Ziprasidone (Geodon)
Fluoxetine (Prozac) 60 mg or higher
Olanzapine and fluoxetine (Symbyax)
NEUROTOXINS
Botulinum Toxin A
NON BENZODIAZEPINE HYPNOTIC AGENTS
Eszopiclone (Lunesta)
OREXIN RECEPTOR ANTAGONISTS
Suvorexant (Belsomra)
MELATONIN RECEPTOR AGONISTS
Ramelteon (Rozerem)
PSYCHOTROPIC AGENTS
Armodafinil
Modafinil
Sodium Oxybate (Zyrem)


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OPIOIDS/OPIOID ANTAGONISTS
Oxycodone
Hydrocodone
Hydromorphone
Oxymorphone
Morphine
Fentanyl
Methadone
Buprenorphine
Meperidine
Codeine
Tramadol
Levorphanol
Tapentadol
Naltrexone ≥4.5 mg
ALPHA2-DELTA CALCIUM CHANNEL MODULATORS
Gabapentin (Fanatrex FusePaq; Gralise; Gralise Starter; Neuraptine; Neurontin)
Pregabalin (Lyrica; Lyrica CR)
SKELETAL MUSCLE RELAXANTS
Baclofen
Carisoprodol
Methocarbamol
CENTRAL NERVOUS SYSTEM ACTING AGENTS-BENZODIAZEPINES
Alprazolam
Chlordiazepoxide Hydrochloride
Clobazam
Clonazepam
Clorazepate Dipotassium
Diazepam
Estazolam
Flurazepam Hydrochloride
Lorazepam
Midazolam Hydrochloride
Oxazepam


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Quazepam
Temazepam
Triazolam
CALCITONIN GENE-RELATED PEPTIDE PATHWAY TARGETING TREATMENT 
OR COMPOUND
Anti-CGRP Antibodies
Eptinezumab-jjmr (Vyepti)
Galcanezumab-gnlm (Emgality)
Anti-CGRP Receptor Antibodies
Erenumab-aooe (Aimovig)
CGRP Receptor Antagonists/Oral Gepants
Ubrogepant (Ubrelvy)
Rimegepant (Nurtec ODT)
OTHER THERAPEUTIC INTERVENTIONS
Herbal agents (eg, St. John’s Wort)
Topical lidocaine within 1 month prior to screening
Capsaicin within 6 months prior to screening
Oral corticosteroids
NON-PHARMACOLOGIC INTERVENTIONS

Any procedures or mechanical/invasive interventions that could affect pain or any 
other symptom associated with FM (eg, nerve block, tender point injections, laser 
therapy, acupuncture, dry needling, spinal cord stimulation, transcutaneous electrical 
nerve stimulation [use of a TENS machine], intra thecal drug delivery by electronic 
pump.

Any new therapy taken within 90 days of the Screening Visit (Visit 1) or planned 
therapy concurrent with the study that could affect pain or any other symptom 
associated with FM (eg, physical therapy, massage, chirotherapy, psychotherapy, and 
counseling).


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APPENDIX J.
TOTAL BLOOD VOLUME 
Total blood volume to be collected for each patient in this study is approximately 150.8 mL for 
scheduled tests. Refer to the Laboratory Manual for details on blood sampling.
Total Blood Volumes
Visit number
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7
Total
Visit type
Screening 
visit
BAPS 
visit
Double-blind treatment
EOT/EOS 
or ET 
visit
Number of 
samples
6
0
9
0
0
9
9
33
Volume (mL)
31.7
0
39.7
0
0
39.7
39.7
150.8
See FDA Guidance (Guidance for Industry 2007) for acceptable blood volume loss per collection procedure.
BAPS = Baseline Assessment Period Start; EOS = end-of-study; EOT = end-of-treatment; ET = early termination; 
FDA = Food and Drug Administration.


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


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


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


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


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


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APPENDIX M. PUBLICATION POLICY
All unpublished information given to the investigator by the sponsor shall not be published or 
disclosed to a third party without the prior written consent of the sponsor.
The results of this study may be published or presented at scientific meetings. If this is foreseen, 
the investigator agrees to submit all manuscripts or abstracts to the sponsor before submission. 
This allows the sponsor to protect proprietary information and to provide comments.
The sponsor will comply with the requirements for publication of study results: 
“Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly Work in 
Medical Journals” (ICMJE 2017). Publication of the results will occur in a timely manner 
according to applicable regulations. In accordance with standard editorial and ethical practice, 
the sponsor will generally support publication of multicenter studies only in their entirety and not 
as individual investigational center data. In this case, a coordinating investigator will be 
designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International Committee of 
Medical Journal Editors authorship requirements:

substantial contributions to the conception or design of the work; or the acquisition, 
analysis, or interpretation of data for the work

drafting the work or revising it critically for important intellectual content

final approval of the version to be published

agreement to be accountable for all aspects of the work in ensuring that questions 
related to the accuracy or integrity of any part of the work are appropriately 
investigated and resolved
The publications committee established by the sponsor will oversee this process. Additional 
publications may follow. Policies regarding the publication of the study results are defined in the 
financial agreement.
No patent applications based on the results of the study may be made by the investigator nor may 
assistance be given to any third party to make such an application without the written 
authorization of the sponsor.


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APPENDIX N. RELEVANT MEDICATIONS ALLOWED FOR THE 
DURATION OF THE STUDY
Antidepressant Medications

Selective serotonin reuptake inhibitors including:

Fluoxetine (maximum daily dose <60 mg)

Citalopram (Celexa®, Cipramil)

Escitalopram (Lexapro®, Cipralex)

Paroxetine (Paxil®, Seroxat)

Fluvoxamine (Luvox®, Faverin)

Sertraline (Zoloft®, Lustral)
Analgesic Medications

Aspirin (maximum daily dose 325 mg) for cardiovascular prophylaxis; 
acetaminophen as a rescue medication (up to 1000 mg per dose and not to exceed 
3000 mg/day for all indications)

Nonsteroidal anti-inflammatory drugs are permitted provided the use has been stable 
(ie, per patient’s usual dosing regimen) for at least 1 month prior to screening and will 
remain unchanged throughout the study
Medications for Sleep

Zolpidem at doses ≤10 mg at bedtime

Melatonin

Antihistamines

Tricyclic antidepressants at low doses (amitriptyline [≤25 mg] or trazodone 
[≤150 mg])

Cyclobenzaprine (up to 10 mg)
Medications for Chronic Migraine Prevention

Except for those listed in Appendix I, all other therapies/medications are permitted.


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APPENDIX O. MANAGEMENT OF STUDY ACTIVITIES DURING 
COVID-19
This appendix is to address the modifications in study conduct during the Coronavirus Disease 
2019 (COVID-19) pandemic.
The changes specified in this appendix will be effective for the duration of the COVID-19 
pandemic. Once the centers/countries are able to resume normal functioning, this appendix will 
become void, except in the case of resurgence of COVID-19 or emergence of another crisis 
affecting normal per protocol conduct of the study.
The following sections are affected:
Section 3.1
General Study Design and Study Schematic Diagram
Patients who were either in the screening period or in the baseline assessment period, as of 
26 March 2020, were designated as screen failures. These patients will be invited to rescreen 
once the COVID-19 crisis has abated and the sponsor has granted approval to restart screening; 
the timing of restarting screening may also be dependent on the investigational center’s 
geographical location due to varying state and local regulations.
Patients randomized, as of 26 March 2020, will continue on study as per the protocol, if possible. 
The study staff at the investigational centers are to follow the guidelines provided by the Centers 
for Disease Control and Prevention with regards to COVID-19 personal protection and social 
distancing. The investigational center will inform the patient of the safeguards being taken with 
regards to COVID-19 and discuss their willingness to come to the site for upcoming visits. If an 
ongoing patient declines to go to the site, the Medical Monitor will be notified to discuss further 
plans for that patient.
The dates for the study duration will be revised as a result of the COVID-19 public health 
emergency.
Section 4.5
Rescreening
Any patient who is a screen fail due to the COVID-19 study enrollment hold will be allowed to 
screen one additional time.
Section 5.1.1.2
Dosing Visits and Dose Modification
Visits 1, 2, 3, and 6 must occur at the study site. For Visits 4 and/or 5 (when at-home dosing is 
available), home visits are permitted under the circumstances described above. Doses will be 
administered at the study site or at home, as applicable. IMP accountability remains the 
responsibility of the site as discussed in Section 5.2.3.
Appendix D. Quality Control and Quality Assurance
Deviations from the study conduct due to emergency situations (eg, the COVID-19 pandemic), 
including implemented contingency measures and their impact (eg, patient discontinuation from 
treatment with investigational product and/or study, alternative procedures used to collect critical 
safety and/or efficacy data, etc), will be described in the appropriate sections of the CSR as 
applicable.


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Appendix E. Ethics
For home visits, no new assessments are being implemented; only the location is changed. 
Hence, an Institutional Review Board (IRB) approval is not required prior to implementing the 
alternative options for assessments. The IRB will be notified for informational purposes if any 
alternate procedures are implemented. 
A COVID-19 Consent Addendum has been approved for investigational center use if alternate 
procedures or assessments need to be instituted prior to the implementation of this protocol 
amendment.

SAP_001.pdf: 
 
 
 
 
Statistical Analysis Plan 
 
 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Proof of Concept 
Study of the Efficacy and Safety of Fremanezumab for Treatment of Patients with 
Fibromyalgia 
 
 
Study Number TV48125-PN-20028 
 
 
NCT03965091 
 
 
SAP Approval Date: 8 February 2022 


Placebo-Controlled Study–Fibromyalgia
Statistical Analysis Plan
Study TV48125-PN-20028
1
 
Statistical Analysis Plan
Study TV48125-PN-20028 with Protocol Amendment 05
A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Proof of Concept Study of 
the Efficacy and Safety of Fremanezumab for Treatment of Patients with Fibromyalgia 
Phase 2
IND number: 141519;   NDA number: Not Applicable; EudraCT number: Not Applicable
Approval Date: 8th February 2022
Sponsor
Teva Branded Pharmaceutical
Products R&D, Inc.
145 Brandywine Parkway
West Chester, Pennsylvania 19380
United States of America
Prepared by:
, 
Teva Global Statistics


Placebo-Controlled Study–Fibromyalgia
Statistical Analysis Plan
Study TV48125-PN-20028
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STATISTICAL ANALYSIS PLAN APPROVAL
Study No.:
TV48125-PN-20028
Study Title:
A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Proof of 
Concept Study of the Efficacy and Safety of Fremanezumab for Treatment of Patients with 
Fibromyalgia
Statistical Analysis Plan for:
Interim Analysis
Integrated Summary of Efficacy
Final Analysis
Integrated Summary of Safety
Amendment: NA


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Study TV48125-PN-20028
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TABLE OF CONTENTS
TITLE PAGE...................................................................................................................................1
STATISTICAL ANALYSIS PLAN APPROVAL..........................................................................2
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..................................................7
INTRODUCTION ...........................................................................................................................9
1.
STUDY OBJECTIVES AND ENDPOINTS..............................................................10
1.1.
Primary and Secondary Study Objectives and Endpoints ..........................................10
1.2.
.......................................................................11
1.3.
Immunogenicity Objective and Endpoint...................................................................12
1.4.
Estimand for Primary Efficacy Endpoint ...................................................................12
2.
STUDY DESIGN .......................................................................................................14
2.1.
General Design ...........................................................................................................14
2.2.
Randomization and Blinding......................................................................................15
2.3.
Data Monitoring Committee.......................................................................................16
2.4.
Sample Size and Power Considerations .....................................................................16
2.5.
Sequence of Planned Analyses ...................................................................................16
2.5.1.
Planned Interim Analyses...........................................................................................16
2.5.2.
Final Analyses and Reporting.....................................................................................16
3.
ANALYSIS SETS ......................................................................................................18
3.1.
Intent-to-Treat Analysis Set........................................................................................18
3.2.
Modified Intent-to-Treat Analysis Set........................................................................18
3.3.
Safety Analysis Set.....................................................................................................18
3.4.
Per-Protocol Analysis Set...........................................................................................18
4.
GENERAL ISSUES FOR DATA ANALYSIS..........................................................19
4.1.
General........................................................................................................................19
4.2.
Specification of Baseline Values................................................................................19
4.3.
Handling Withdrawals and Missing Data...................................................................20
4.4.
Study Days and Visits.................................................................................................20
5.
STUDY POPULATION.............................................................................................22
5.1.
General........................................................................................................................22
5.2.
Patient Disposition......................................................................................................22
5.3.
Demographics and Baseline Characteristics...............................................................22


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5.4.
Medical History ..........................................................................................................22
5.5.
Prior Therapy and Medication....................................................................................23
5.6.
Childbearing Potential and Methods of Contraception ..............................................23
5.7.
Study Protocol Deviations..........................................................................................23
6.
EFFICACY ANALYSIS ............................................................................................24
6.1.
General........................................................................................................................24
6.1.1.
Pain Intensity-Numerical Rating Scale and Rescue Medication Use.........................24
6.1.2.
Baseline and Analysis Weeks for Data Collected Daily ............................................25
6.1.3.
Data Derivation for weekly average of PI-NRS.........................................................25
6.2.
Primary Efficacy Endpoint and Analysis ...................................................................26
6.2.1.
Definition....................................................................................................................26
6.2.2.
Primary Efficacy Analysis..........................................................................................26
6.2.3.
Sensitivity Analysis ....................................................................................................28
6.2.4.
Sub-Group Analyses...................................................................................................29
6.3.
Secondary Efficacy Endpoints and Analysis..............................................................29
6.3.1.
Change From Baseline to Week 12 in the Individual Components of the 
Fibromyalgia Impact Questionnaire Revised: Symptom Subscore, Impact 
Subscore, and Functional Subscore Score..................................................................30
6.3.2.
The Patient Global Impression of Change Rating at Week 12...................................31
6.3.3.
Percentage of Patients Who Experience a ≥30% or ≥50% Reduction in the 
Weekly Average of the Daily Average PI-NRS Score at Week 12............................32
6.3.4.
Change From Baseline to Week 12 in the Weekly Average of the Daily 
Worst PI-NRS Score Over the Past 24 Hours ............................................................33
6.3.5.
Change From Baseline to Week 12 in the Patient-Reported Outcomes 
Measurement Information System Sleep Disturbance Short Form 8a Score .............33
6.3.6.
Change from Baseline to Week 12 in the Patient-Reported Outcomes 
Measurement Information System Physical Function SF12a Score...........................34
6.3.7.
Change From Baseline To Week 12 In The Patient-Reported Outcomes 
Measurement Information Fatigue SF8a Score ..........................................................34
6.3.8.
Number (%) of Patients Who Did Not Complete the Treatment Due to Lack 
of Efficacy ..................................................................................................................35
6.4.
.................................................35
6.4.1.
 
............................................................................................................................35
6.4.2.
..............................................................................................36


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6.4.3.
..............................................36
6.4.4.
 
....................................................................37
6.4.5.
...................................................37
7.
MULTIPLE COMPARISONS AND MULTIPLICITY ............................................39
8.
SAFETY ANALYSIS ................................................................................................40
8.1.
General........................................................................................................................40
8.2.
Duration of Exposure to Study Drug..........................................................................40
8.3.
Adverse Events ...........................................................................................................40
8.4.
Deaths .........................................................................................................................41
8.5.
Clinical Laboratory Tests ...........................................................................................41
8.5.1.
Laboratory Values Meeting Hy’s Law Criteria..........................................................43
8.5.2.
Other Clinical Laboratory Tests .................................................................................43
8.6.
Physical Examinations................................................................................................43
8.7.
Vital Signs ..................................................................................................................44
8.8.
Electrocardiography....................................................................................................44
8.9.
Concomitant Medications or Therapies......................................................................45
8.10.
Columbia-Suicide Severity Rating Scale....................................................................45
9.
TOLERABILITY VARIABLES AND ANALYSIS..................................................46
10.
PHARMACOKINETIC ANALYSIS.........................................................................47
11.
PHARMACODYNAMIC ANALYSIS......................................................................48
12.
PHARMACOKINETIC/PHARMACODYNAMIC ANALYSIS..............................49
13.
BIOMARKER ANALYSIS........................................................................................50
14.
IMMUNOGENICITY ANALYSIS............................................................................51
15.
ANCILLARY STUDIES ANALYSIS.......................................................................52
16.
PLANNED INTERIM ANALYSIS ...........................................................................53
17.
STATISTICAL SOFTWARE ....................................................................................54
18.
CHANGES TO ANALYSES SPECIFIED IN THE STUDY PROTOCOL..............55
19.
REFERENCES ...........................................................................................................56


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LIST OF TABLES
Table 1:
Study Visits.................................................................................................................20
Table 2:
Analysis Weeks ..........................................................................................................25
Table 3:
Clinical Laboratory Tests ...........................................................................................41
Table 4:
Criteria for Potentially Clinically Significant Laboratory Values..............................42
Table 5:
Criteria for Potentially Clinically Significant Vital Signs..........................................44


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
ADA
anti-drug antibody
AE
adverse event
AESI
adverse events of special interest
AR
autoregressive
ARH
heterogeneous autoregressive correlation
BAPS
Baseline Assessment Period Start
CGRP
calcitonin gene-related peptide
CI
confidence interval
CRF
Case report form
CS
compound symmetry
CSC
clinical study center
CSH
heterogeneous compound symmetry
CSR
Clinical Study Report
C-SSRS
Columbia-Suicide Severity Rating Scale
CV
coefficient of variation
ECG
Electrocardiogram/Electrocardiography
EOS
End of study
EOT
End of treatment
ET
Early termination
EQ VAS
EQ Visual Analogue Scale
EQ-5D-5L
EuroQol-5D-5L
EudraCT
European Clinical Trials
FM
Fibromyalgia
FIQR
Fibromyalgia Impact Questionnaire Revised
GEE
generalized estimating equation
HADS
Hospital Anxiety and Depression Scale
IMD
Inventory of Medical Diagnoses
IMP
the investigational medicinal product
ITT
Intent-to-Treat
LOE
lack of efficacy
LS
Least square
MedDRA
Medical Dictionary for Regulatory Activities


Placebo-Controlled Study–Fibromyalgia
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Abbreviation
Term
MI
multiple imputation
mITT
Modified Intent-to-Treat
MMRM
Mixed model for repeated measures
PD
Protocol deviations 
PGIC
Patient Global Impression of Change
PI-NRS
Pain Intensity-Numerical Rating Scale
POMS-2A Short
Profile of Mood States 2 – Adult Short Form
PP
Per-Protocol
PROMIS
Patient-Reported Outcomes Measurement Information System
RTSM
Randomization and Trial Supply Management
SAP
Statistical Analysis Plan
SD
Standard Deviation
SE
Standard Error
SF
Short form
GPSP
Global Patient Safety and Pharmacovigilance
SI
standard international
SOC
system organ class
SS
symptom severity
ULN
upper limit of normal
WHO
World Health Organization


Placebo-Controlled Study–Fibromyalgia
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Study TV48125-PN-20028
9
INTRODUCTION
This Statistical Analysis Plan (SAP) describes the planned analysis and reporting for Teva 
Branded Pharmaceutical Products R&D, Inc. study TV48125-PN-20028, (A Multicenter, 
Randomized, Double-Blind, Placebo-Controlled, Proof of Concept Study of the Efficacy and 
Safety of Fremanezumab for Treatment of Patients with Fibromyalgia), and was written in 
accordance with SOP GBP_RD_702 (Statistical Analysis Plan).
The reader of this SAP is encouraged to read the study protocol for details on the conduct of this 
study, the operational aspects of clinical assessments, and the timing for completing the 
participation of a patient in this study. 
The SAP is intended to be in agreement with the protocol, especially with regards to the primary 
and all secondary endpoints and their respective analyses. However, the SAP may contain more 
details regarding these particular points of interest, or other types of analyses (e.g. other 
endpoints). When differences exist in descriptions or explanations provided in the study protocol 
and this SAP, the SAP prevails; the differences will be explained in the Clinical Study Report
(CSR).


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1.
STUDY OBJECTIVES AND ENDPOINTS
1.1.
Primary and Secondary Study Objectives and Endpoints
The primary and secondary study objectives and endpoints are as follows:
Objectives
Endpoints
The primary objective of the 
study is to estimate the 
treatment effect of 
fremanezumab administered 
subcutaneously in reducing 
pain in adult patients with 
Fibromyalgia (FM).
The primary efficacy endpoint is the change from baseline to 
week 12 in the weekly average of the daily average PI-NRS 
score over the past 24 hours.
A secondary objective is to 
evaluate the effect of 
fremanezumab on other 
efficacy measures, including 
pain, quality of life, sleep, 
fatigue, improvement in 
health, physical functioning, 
and mood.
The secondary efficacy endpoints are as follows:

change from baseline to week 12 in the individual 
components of the Fibromyalgia Impact 
Questionnaire Revised (FIQR): symptom 
subscore, impact subscore, and functional 
subscore score

responder rate of the Patient Global Impression of 
Change (PGIC) rating (percentage of patients
much improved or very much improved) at week 
12

the percentage of patients who experience a 
≥30% reduction in the weekly average of the daily 
average PI-NRS score at week 12

the percentage of patients who experience a 
≥50% reduction in the weekly average of the daily 
average PI-NRS score at week 12

change from baseline to week 12 in the weekly 
average of the daily worst PI-NRS score over the 
past 24 hours

change from baseline to week 12 in the 
Patient-Reported Outcomes Measurement 
Information System (PROMIS) Sleep Disturbance 
Short Form (SF) 8a score

change from baseline to week 12 in the PROMIS 
Physical Function SF12a score

change from baseline to week 12 in the PROMIS 
Fatigue SF8a score


Placebo-Controlled Study–Fibromyalgia
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Objectives
Endpoints

number (%) of patients who did not complete the 
treatment (Kaplan-Meier Survival Analysis) due 
to lack of efficacy
A secondary objective of the 
study is to evaluate the safety 
and tolerability of 
fremanezumab administered 
subcutaneously in adult 
patients with FM.
The safety and tolerability endpoints are as follows:

occurrence of adverse events

change from randomization to week 12 in the 
clinical laboratory tests (serum chemistry, 
hematology, and urinalysis)

change from baseline to week 12 in vital signs 
(pulse, respiratory rate, systolic and diastolic 
blood pressure, and oral body temperature 
measurements at each visit)

clinically significant changes in physical 
examination, including body weight

abnormal standard 12-lead electrocardiogram 
(ECG) findings

tolerability at the injection site including but not 
limited to pain, erythema, induration, and 
ecchymosis

occurrence of hypersensitivity/anaphylaxis 
reactions using standardized criteria (Appendix C 
of the study protocol)

suicidal ideation and behavior as measured by the 
Columbia-Suicide Severity Rating Scale (C-
SSRS)

number (%) of patients who did not complete the 
treatment (Kaplan-Meier Survival Analysis) due 
to adverse events
1.2.


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1.3.
Immunogenicity Objective and Endpoint
The immunogenicity objective and endpoint are as follows:
Objectives
Endpoints
To evaluate the immunogenicity 
of fremanezumab and the impact 
of anti-drug antibodies (ADAs) 
on clinical outcomes

incidence and characteristics of ADAs 
(eg, titers, kinetics, and neutralizing activities)
1.4.
Estimand for Primary Efficacy Endpoint
The combination of treatment policy and hypothetical strategy will be used for the primary 
efficacy endpoint to account for the intercurrent events. The four attributes of the estimand are 
defined as follows: 
A. Population: The patients with fibromyalgia met all inclusion criteria and met none of the 
exclusion criteria. 


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The modified intent-to-treat (mITT) analysis set defined in Section 3.2 will be the primary 
analysis set for efficacy. In the data analyses, the treatment will be assigned based on the 
treatment to which patients were randomized, regardless of which treatment they actually 
received. 
B. Variable: Change from baseline to week 12 in the weekly average of the daily average PI-
NRS score over the past 24 hours.  
C. Intercurrent events: Treatment discontinuation due to an adverse event, due to lack of 
efficacy, or due to other reasons.
For those who discontinue the treatment before week 12, no further efficacy data will be 
collected. The use of rescue medication for fibromyalgia pain will not be considered as an 
intercurrent event.
D. Population-level summary: The primary efficacy endpoint, the change from baseline to 
week 12 in the PI-NRS scores, will be analyzed using a Mixed Model Repeated Measures 
(MMRM) model with change from baseline in the weekly average of the daily average PI-
NRS score over the past 24 hours at weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 as the 
dependent variable, sex, age group at FM onset, week, treatment, and treatment by week 
interaction as fixed factors, and baseline average of the daily average PI-NRS score as a 
covariate. An adjustment for missing data due to adverse event or due to lack of efficacy on 
the PI-NRS scores will be on average return to baseline values, while due to all other reasons 
will be imputed assuming missing at random. With missing data imputed, each of the 500 
imputed data sets will be analyzed using the MMRM model. The results from the 500 
analyses will be combined using Rubin’s formulae. The least square (LS) mean estimates for 
the mean change from baseline to each time point, as well as the difference of the estimates 
between the fremanezumab and placebo group, with the corresponding standard error (SE), 
p-value and associated 95% confidence interval (CI) will be provided.
Sensitivity Analysis: The primary analysis will be repeated; however, the daily average pain 
scores measured on the days where the patient took rescue medication will be replaced with his 
or her PI-NRS score at the time of rescue medication use before the weekly average PI-NRS
scores are derived. On days where a patient uses rescue medication more than once, the mean 
PI-NRS score at the time of rescue mediation use for the day will be used as the pain score in 
place of the average pain intensity score for that day.


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2.
STUDY DESIGN
2.1.
General Design
This is a 21-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group 
study to evaluate the efficacy and safety of fremanezumab in adult patients with FM. 
Fremanezumab 225 mg, fremanezumab 675 mg, or placebo will be administered sc for 
4 monthly doses. The study will consist of a 17- to 35-day screening period (Visit 1, phone 
contact, a Baseline Assessment Period Start [BAPS] Visit [Visit 2]), and a 16-week double-blind 
treatment period (Visits 3, 4, 5, 6, and 7). Patients enrolled in the study will be male or female 
patients with FM with an average of the daily average PI-NRS score of ≥4 and ≤9 during the 14-
day baseline assessment period. Patients will be required to wash out of all prohibited 
concomitant medication(s) prior to the BAPS Visit (Visit 2).
Therefore, the total duration of patient participation in the study is planned to be 21 weeks, 
consisting of the screening period of up to 5 weeks (ranging from 17 to 35 days) and the 
double-blind treatment period of 16 weeks. The end-of-study (EOS) is defined as completion of 
the last visit of the last patient.
Note, there was the 14-week follow-up period prior to Study TV48125-PN-20028 
protocol amendment 04.
The study schematic diagram is presented in Figure 1.
Study procedures and assessments with their timing are summarized in Table 1 of the study 
protocol.


Placebo-Controlled Study–Fibromyalgia
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Figure 1:
Overall Study Schematic Diagram
a The screening period is up to 5 weeks and can range from 17 to 35 days. The duration of the washout period will be
7 to 19 days; suggested washout periods for commonly used analgesics are listed in the study protocol.
Note: For Visits 4 and 5 (when at-home dosing is available), home visits are permitted for patients who are not able 
to go to the investigational center or if the investigational center staff are not able to see patients at the
investigational center.
BAPS = Baseline Assessment Period Start; COVID-19 = Coronavirus Disease 2019; e-diary = electronic
diary; EOS = end-of-study; EOT = end-of-treatment; PK = pharmacokinetic; sc = subcutaneous; V = visit.
The follow-up period (14 weeks) in the protocol was removed in Study TV48125-PN-20028 
protocol amendment 04. The data collected in the follow-up period will be listed.
2.2.
Randomization and Blinding
This is a randomized, double-blind, placebo-controlled study. All the investigational medicinal 
products (IMPs) will be identical and indistinguishable. Patients, investigators, and all clinical 
study center (CSC) staff will remain blinded to treatment assignment during the study. Eligible 
patients will be randomly assigned via a qualified Randomization and Trial Supply Management 
(RTSM) system in a 1:1:1 ratio to fremanezumab at 225 mg sc or fremanezumab 675 mg sc, or 
placebo sc. Randomization will be stratified by sex (male/female) and age at FM onset (<40 
years old and ≥40 years old).


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Patients will be randomly assigned to treatment groups by means of a computer-generated 
randomization list. The generation of the randomization list and management of the RTSM 
system will be done by a qualified service provider. The specifications for randomization will be 
under the responsibility and oversight of Teva Global Statistics.
The sponsor’s clinical personnel (and delegates) involved in the study will be blinded to the 
identity of the IMPs until the database is locked for analysis and the IMP assignment is released. 
However, if a prioritized sample analysis is needed, bioanalytical and clinical pharmacology 
personnel may be unblinded.
In the event of an emergency, it will be possible to determine to which treatment group and dose 
a patient has been allocated by accessing the RTSM system. All investigational centers will be 
provided with details of how to access the system for code breaking at the start of the study. The 
Medical Monitor or equivalent should be notified, if possible, prior to unblinding or following 
unblinding. Any unblinding of the IMP performed by the investigator must be recorded in the 
source documents.
2.3.
Data Monitoring Committee
There will be no Independent Data Monitoring Committee for this study.
2.4.
Sample Size and Power Considerations
The sample size of 80 subjects per treatment group was selected based on expert consensus 
agreement at a scientific advisory board meeting; this sample size is expected to provide 
sufficient precision to estimate the treatment effect of fremanezumab versus placebo. Moreover, 
assuming a standard deviation (SD) of 2.2 for change from baseline in the weekly average of the 
daily average PI-NRS score, 80 patients per treatment group will provide at least 90% 
probability to observe the half length of the 95% confidence interval (CI) of the treatment 
difference between fremanezumab 225 mg sc or fremanezumab 675 mg sc and placebo less than 
0.74. In total, 240 patients will be enrolled in this study in a 1:1:1 randomization ratio.
2.5.
Sequence of Planned Analyses
2.5.1.
Planned Interim Analyses
There were two interim analyses for futility performed in this study. The details of the interim 
analyses were specified in seperate interim statistical analysis plans. To ensure study integrity, 
the interim analyses were performed by an independent third party; the study team were kept 
blinded. The decision was made to end this study for futility following the results of the second 
interim analysis.
2.5.2.
Final Analyses and Reporting
This study has been early terminated due to futility. All analyses identified in this SAP will be 
performed after study closure. This SAP and any corresponding amendments will be approved
before database lock, in accordance to SOP GBP_RD_702 (Statistical Analysis Plan).
The randomization codes will not be unblinded until this SAP has been approved, the database is 
locked, and the analysis populations are determined.


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3.
ANALYSIS SETS
3.1.
Intent-to-Treat Analysis Set
The intent-to-treat (ITT) analysis set will include all randomized patients.
In the ITT analysis set, treatment will be assigned based on the treatment to which patients were 
randomized, regardless of which treatment they actually received.
Demographics and baseline characteristics will use the ITT analysis set.
3.2.
Modified Intent-to-Treat Analysis Set
The modified intent-to-treat (mITT) analysis set is a subset of the ITT analysis set including only 
patients who received at least 1 dose of study drug and at least 1 post-baseline entry of daily 
average pain intensity using the PI-NRS.
In the mITT analysis set, treatment will be assigned based on the treatment to which patients
were randomized, regardless of which treatment they actually received. 
All efficacy analyses will use the mITT analysis set unless noted otherwise.
3.3.
Safety Analysis Set
The safety analysis set will include all randomized patients who received at least 1 dose of study 
drug. In the safety analysis set, treatment will be assigned based on the treatment patients 
actually received, regardless of the treatment to which they were randomized.
All safety analyses will use the safety analysis set unless noted otherwise.
3.4.
Per-Protocol Analysis Set
The per-protocol (PP) analysis set is a subset of the mITT analysis set including only patients 
without major protocol violations which will be determined by data review and documented 
before study unblinding. The PP analysis set will serve as supportive for the efficacy analyses.
In the PP analysis set, treatment will be assigned based on the treatment patients actually
received, regardless of the treatment to which they were randomized.
The primary efficacy endpoint and selected secondary efficacy endpoints will be analyzed using
PP analysis set.


Placebo-Controlled Study–Fibromyalgia
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4.
GENERAL ISSUES FOR DATA ANALYSIS
4.1.
General
Descriptive statistics for continuous variables include n, mean, SD, standard error (SE), median, 
minimum, and maximum. In addition, for fremanezumab concentration, percentage coefficient of 
variation (%CV) and geometric mean will also be calculated. Descriptive statistics for 
categorical variables include patient counts and percentages, missing category will be displayed 
as appropriate.
Summaries of potentially clinically significant abnormal values will include all postbaseline 
values (including scheduled, unscheduled, and early termination visits).
For by-visit analyses, if there are multiple assessments at a scheduled postbaseline visit then the 
last non-missing scheduled assessment at that visit will be used for the summary. If a visit has 
scheduled and unscheduled assessments, the scheduled assessment will be used for the analysis. 
If a visit only has unscheduled assessments, the unscheduled assessments will be used for 
analyses; if there are more than one unscheduled visits, the assessment from the last unscheduled 
visit will be used for analyses.
4.2.
Specification of Baseline Values
The baseline values are defined as the last non-missing assessments before the first dose of IMP 
unless otherwise specified.
Baseline value for the average of the daily average PI-NRS pain score is defined as the average 
of the daily average PI-NRS score over the last 14 days before the first dose of IMP drug (day -
14 to day -1) and will be calculated using formula [1].
Baseline value for the average of the daily worst PI-NRS pain score is defined as the average of 
the daily worst PI-NRS score over the last 14 days before the first dose of IMP (day -14 to 
day -1) and will be calculated using formula [1].
The baseline values for the following variables are measured on the day of the first study drug 
(day 1) before the first dose of study drug.

individual components of the FIQR: symptom subscore, impact subscore, and functional 
subscore score

PROMIS Physical Function SF12a score

PROMIS Fatigue SF8a score

HADS score

EQ-5D-5L

POMS-2A Short Form score
The baseline value for IMD assessment rating is measured at the screening visit.
PROMIS Sleep Disturbance SF 8a score are collected on e-diary weekly during BAPS. The 
baseline PROMIS Sleep Disturbance SF 8a scores will be the mean of the weekly scores
recorded during last 14 days before the first dose of IMP drug (day -14 to day -1). 


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4.3.
Handling Withdrawals and Missing Data
Missing data for the primary efficacy endpoint, efficacy endpoint for sensitivity analysis, and
selected secondary efficacy endpoints will be imputed with the multiple imputation (MI) method 
described in Section 6.2.2. All other endpoints will be not be imputed for missing data unless 
otherwise specified.
Dates that have incomplete information (the month and year or just the year is available) will be 
estimated for the purpose of calculating variables that are dependent on time if necessary. Day
will be estimated as the first day (01) of the month (if month and year of partial date are 
available) or middle (July 1) of the year (if only year is available), unless otherwise noted. The 
imputations for partial dates are only for calculation purpose. Original date variables will not be 
modified. Listings will list dates as collected.
4.4.
Study Days and Visits
Study visits are detailed in Table 1.
Table 1:
Study Visits
Study 
period
Screening Period
(Up to 5 weeks [17 to 35 days])
Double-Blind Treatment Period  
(16 weeks)
Screenin
g Visit
Phone
Contact 
(Washout)
Baseline 
Assessment 
Period
Random-
ization
(Dose 1)
Dose
2
Dose
3
Dose
4
Visit
V1
Phone 
Contact
V2 
(BAPS
Visit)
V3
V4
V5
V6
V7
(EOT/
EOS or 
ET)
Day and 
allowed
time 
windows
Week-5
Day -35
Day -33 
through 
Day -15
Day -14
(±2 days)
Day 1
Day 29
±7
days
Day 57
±7
days
Day 85
±7
days
Day 113
±7
days
BAPS=Baseline Assessment Period Start; EOT=End of treatment; ET=Early termination; EOS=End of Study.
There was a follow-up period (14 weeks) in the Study TV48125-PN-20028 protocol prior to 
amendment 04. The data collected in the follow-up period will be listed.
Study days will be numbered relative to the first day of IMP administration. The start of 
treatment (Day 1 at Visit 3) is defined as the date on which a patient takes the first dose of IMP, 
as recorded on the study drug administration CRF. Days will be numbered relative to treatment 
start (ie, ..., –2, –1, 1, 2, ...; with day 1 being the first day of IMP administration and day –1 
being the day before the first day of IMP administration).
‘Last Assessment’ will be derived for analysis purposes and is defined as the last observed 
postbaseline data, excluding the follow-up visit. For by-visit summaries, data from the ET visit 
will be included as one of the visits indicated in the database.
For data collected daily on e-diary, analysis weeks (week 1, week 2, …, etc.) will be derived for 
the purpose of efficacy endpoint analyses. Details are provided in Section 6.1.2.


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Data collected after week 12 will be included in descriptive summaries but will not be included 
in any inferential analyses.


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5.
STUDY POPULATION
5.1.
General
Patients enrolled in the study will be male and female patients, ≥18 to 75 years old, inclusive, 
with FM and an average of the daily average PI-NRS score of ≥4 and ≤9 during the last 14 days 
of the 14-day baseline assessment period.
For continuous variables, descriptive statistics (number [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.
The ITT analysis set will be used for all study population summaries unless otherwise specified. 
Summaries will be presented by treatment group and for all patients.
5.2.
Patient Disposition
Descriptive statistics will be used to summarize data from the following groups: patients 
screened; patients screened but not randomized and reason not randomized; patients who are 
randomized; patients randomized but not treated (and reason); patients in the ITT, mITT, safety,
and PP analysis sets; patients who complete the treatment and the study; and patients who 
discontinue from the treatment and the study. Data from patients who discontinue from treatment 
and the study will also be summarized by reason for discontinuation using descriptive statistics.
5.3.
Demographics and Baseline Characteristics
Patient demographic characteristics (age, sex, ethnicity, and race) and baseline characteristics 
will be examined to assess the comparability of the treatment groups and will be summarized 
using descriptive statistics. No inferential analyses will be performed. Demographic and baseline 
characteristics will be summarized using ITT analysis set.
Baseline characteristics include

age at time of FM onset or diagnosis of FM

month since FM onset

month since FM diagnosis

alcohol history

psychiatric history

ECG findings at screening
Month will be calculated as (date of informed consent - the date of the event + 1)/30.42. Rules 
for handling partial dates are in Section 4.3.
5.4.
Medical History
All medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). The incidence of medical history abnormalities will be summarized using 
descriptive statistics by system organ class (SOC) and preferred term. Patients are counted only 


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once in each preferred term and SOC category. Summaries will be presented by treatment group 
and for all patients.
5.5.
Prior Therapy and Medication
Any prior therapy or medication will be coded using the World Health Organization (WHO) 
Drug Dictionary. The incidence of prior therapies and medications, past fibromyalgia medication 
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. Prior therapies and medications will include all medications taken and therapies 
administered before the first day of study drug administration.
Past fibromyalgia medication will also be summarized separately.
5.6.
Childbearing Potential and Methods of Contraception
For female patients, information related to childbearing potential and menopause will be 
collected at the screening visit. Data will be listed.
For female and male patients, methods of contraception will be collected at the screening visit. 
Data will be listed.
5.7.
Study Protocol Deviations
All protocol deviations (PD) will be collected and entered in an excel spreadsheet. All PDs will 
be reviewed and approved by the study team prior to database lock. In addition, the important 
PDs will be also determined by study team before database lock. The important PDs will be 
summarized for overall and for each category using descriptive statistics and all PDs will be 
listed in a data listing.


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6.
EFFICACY ANALYSIS
6.1.
General
The mITT analysis set will be the main analysis set for all efficacy analyses. The PP analysis set 
will serve as supportive analysis set for analyses of the primary efficacy endpoint and following 
selected secondary efficacy endpoints:

responder rate of PGIC rating (percentage of patients much improved or very much 
improved) at week 12

change from baseline to week 12 in the weekly average of the daily worst PI-NRS 
score over the past 24 hours

the percentage of patients who experience a ≥30% reduction in the weekly average of 
the daily average PI-NRS score at week 12

the percentage of patients who experience a ≥50% reduction in the weekly average of 
the daily average PI-NRS score at week 12
For efficacy summaries and analyses using the last visit, this last visit should not include the 
follow-up visit which was scheduled in Study TV48125-PN-20028 prior to protocol amendment 
04. In addition, data collected after week 12 will be included in descriptive summaries but will 
not be included in any inferential analyses.
6.1.1.
Pain Intensity-Numerical Rating Scale and Rescue Medication Use
The PI-NRS is an 11-point pain intensity numerical rating scale where 0=no pain and 10=worst 
possible pain. The PI-NRS will be used to rate average FM pain intensity over the past week at 
screening via the site tablet at the screening visit. From Visit 2 to Visit 7 the PI-NRS will be 
recorded in the patient’s e-diary every evening (Evening Report) between 1800 and 2200 hours
for the following:

The average FM pain intensity over the past 24 hours

The worst FM pain intensity over the past 24 hours
If a patient cannot complete or forgets to complete the Evening Report, a Make-up Evening 
Report will become available for completion between 0300h and 1300h the next day. In case 
both the Evening Report and the Make-up Evening Report are completed, PI-NRS collected on 
the Evening Report will be used for analyses.
The Rescue Medication tab on the e-dairy will be available to patients 24 hours per day. Patients 
will record the following in the e-diary:

Time of rescue medication used for a specific breakthrough pain episode

Amount (tablets) of rescue medication used for a specific breakthrough pain episode

At-the-moment pain intensity just prior to the use of rescue medication
If a patient cannot record or forgets to record the rescue medication taken, the Evening Report
will be used to record any missed rescue medication taken. A patient can take 1 to 2 caplets with 
dose up to 1000 mg, a maximum of 6 caplets(3000 mg) in a 24-hour period.


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6.1.2.
Baseline and Analysis Weeks for Data Collected Daily
Baseline is defined as the last 14 days before the first dose of IMP (day -14 to day -1). Day 1 will 
be defined as the day of first dose of IMP (Visit 3). 
For data collected daily (eg. PI-NRS scores), analysis weeks will be derived using algorithm in 
Table 2. Analyses will be based on the derived analysis weeks.
Table 2:
Analysis Weeks
4-Week 
Interval 
Visit 
Dose
(n)
Target Injection
or Visit Day
Actual Injection or 
Visit Day
Analysis 
Week 
Analysis Week
Interval
1a
3
1
1
1
1
[1, v-22]
2
[v-21, v-15]
3
[v-14, v-8]
4
[v-7, v-1]
2a
4
2
29
v (2nd dosing day)
5
[v, x-22]
6
[x-21, x-15]
7
[x-14, x-8]
8
[x-7, x-1]
3a
5
3
57
x (3rd dosing day)
9
[x, y-22]
10
[y-21, y-15]
11
[y-14, y-8]
12
[y-7, y-1]
4b (last dose)
6
4
85
y (4th dosing day)
13
[y, y+6]
14
[y+7, y+13]
15
[y+14, y+20]
16
[y+21,y+27]
5
5
EOT
113
-
-
a In 4-week intervals before the last dose, the 4th week will be 7 days before the date of the injection, and counting 
backward by 7-day increments to define remaining weeks. The 1st week of these 4-week intervals will include all 
remaining days in the interval.
b The weeks after the last dose, an analysis week will be defined as a 7-day interval counting onward.
6.1.3.
Data Derivation for weekly average of PI-NRS 
The weekly average of an efficacy variable in an analysis week will be calculated as follow:
           
∑	

	 	 	 	  
	
 
  
 	 	

	 	 	 	  
	
  [1]
Where the efficacy variable will be

Daily average PI-NRS pain score over the past 24 hours

Daily worst PI-NRS pain scores over the past 24 hours 


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If all of the data are missing within an analysis week, the average of the efficacy variable within 
the analysis week will be missing.
6.2.
Primary Efficacy Endpoint and Analysis
6.2.1.
Definition
The primary efficacy endpoint is the change from baseline to week 12 in the weekly average of 
the daily average PI-NRS score over the past 24 hours.
Baseline is defined as the last 14 days before the first dose of IMP (Visit 3). The analysis weeks 
for post-baseline will be derived using rule described in Table 2.
The baseline and post baseline weekly average of the daily average PI-NRS pain scores over the 
past 24 hours will be derived using formula [1], respectively.
6.2.2.
Primary Efficacy Analysis
The primary efficacy endpoint will be analyzed using a MMRM model with change from 
baseline in the average of the daily average PI-NRS score over the past 24 hours at weeks 1, 2, 3, 
4, 5, 6, 7, 8, 9, 10, 11, and 12 as the dependent variable, sex, age group at FM onset, week, 
treatment, and treatment by week interaction as fixed factors, and baseline average of the daily 
average PI-NRS score as a covariate. The heterogeneous autoregressive correlation structure
[ARH (1)] for repeated observations within patients will be used, and the denominator degrees of 
freedom will be estimated using Kenward-Roger’s approximation. An adjustment for missing 
data due to lack of efficacy or adverse events assumes the PI-NRS scores will be on average 
return to baseline values. Missing data (due to early treatment discontinuation or missing e-dairy 
recording in an entire analysis week) will be imputed 500 times to generate 500 complete data 
sets using the SAS procedure PROC MI following the 3 steps below.
Notes, if ARH(1) does not converge, then simpler covariance structures with less parameters will 
be used in the following order until the model converges: autoregressive (1) (AR[1]); 
heterogeneous compound symmetry (CSH); and compound symmetry (CS).
Step 1: The monotone missing pattern will be induced by the Markov Chain Monte Carlo 
method in the PROC MI procedure using seed number 4751523.
The average of the daily average PI-NRS score up to and including week 12 will be imputed by 
using following SAS code to impute the arbitrary missing data and to make the missing data 
pattern monotonic:
PROC MI DATA=name  NIMPUTE= 500 SEED=4751523 OUT= MI_MONOTONE; 
        BY TRT01PN AGEATFMONST SEX; 
        MCMC IMPUTE= MONOTONE; 
        VAR BASE WEEK1 … WEEK12; 
RUN;
Where TRT01PN denotes the planned treatment group; AGEATFMONST denotes the age group 
at FM onset; BASE denotes the baseline average of the daily average PI-NRS score; WEEK1, . . 
., WEEK12 denote the weekly average of the daily average PI-NRS score in weeks. In bold are 
the SAS key words.


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Step 2: Once the arbitrary missing data are imputed, the following SAS code will be used to 
impute the monotone missing data.
The remaining missing data at subsequent weeks will be imputed using the regression method for 
the monotone pattern with seed number 4751523 and adjustment for covariates including 
baseline value and all values at preceding weeks.
PROC MI DATA= MI_MONOTONE NIMPUTE= 1 SEED= 4751523
OUT= MI_COMPLETE; 
        CLASS TRT01PN AGEATFMONSET SEX; 
        MONOTONE REG;
       VAR TRT01PN AGEATFMONSET SEX BASE WEEK1 … WEEK12; 
RUN;
MI_COMPLETE will be transposed to a new data set (WEEKPI0) with each week as a row.
Step 3: Use by-week mean change from baseline to adjust those who discontinued treatment due 
to lack of efficacy (LOE) or adverse event (AE) before week 12.
The initially missing and now imputed data for patients who discontinued from the study drug 
due to LOE or AE will be center adjusted at the mean baseline value. That is, the final imputed 
score will be equal to the imputed score under missing at random minus the observed mean 
change from baseline score at the post baseline time point.
DATA WEEKPI;
        SET WEEKPI0;
        CHANGEi = AVALi - BASE;
        IF DTREAS IN ('LACK OF EFFICACY', 'ADVERSE EVENT') AND IMP= 1
        THEN DO;
              CHANGEi = CHANGEi - MWEEK_CHG;
        END;
RUN;
Where AVALi denotes the value of the post baseline weekly average of the daily average 
PI-NRS after missing data imputation; CHANGEi denotes the change from baseline after 
missing data imputation; MWEEK_CHG denotes the change from baseline calculated without 
missing data imputation; DTREAS denotes the reason for treatment discontinuation.
Step 4: Each of the 500 imputed data sets described above steps will be analyzed using the 
MMRM. SAS code is:
ODS OUTPUT LSMEANS= LS DIFFS = DIFF (WHERE = (week = _week)); 
PROC MIXED DATA= WEEKPI (WHERE= (WEEK>= 1)); 
      BY _IMPUTATION_;
      CLASS SUBJID TRT01PN WEEK AGEATFMONSET  SEX;
       MODEL CHANGEi= BASE TRT01PN AGEATFMONSET SEX WEEK 
                                            TRT01PN*WEEK/DDFM=KR;
       REPEATED WEEK/SUBJECT= SUBJID TYPE= ARH(1); 
      LSMEANS TRT01PN*WEEK / DIFF CL;
RUN;
ODS OUTPUT CLOSE;


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Where _IMPUTATION_ denotes the numbering of imputations; SUBJID denotes the subject ID; 
WEEK denotes the analysis week (12 levels: weeks 1 to 12).
Step 5: The results from the 500 analyses from Step 4 will be combined using Rubin’s formulae 
(PROC MIANALYZE). The least square (LS) mean estimates for the mean change from 
baseline to each time point, as well as the difference of the estimates between the fremanezumab 
and placebo group, with the corresponding SE, p-value and associated 95% CI will be provided.
(a) For LS means
PROC SORT DATA= LS; 
      BY WEEK TRT01PN _IMPUTATION_;
RUN;
ODS OUTPUT PARAMETERESTIMATES= LSM_O; 
PROC MIANALYZE DATA= LS; 
      BY WEEK TRT01PN;
      MODELEFFECTS ESTIMATE; 
      STDERR STDERR; 
RUN;
ODS OUTPUT CLOSE;
Where ESTIMATE and STDERR are LS mean and standard error from Step 4.
(b) For treatment difference, treatment difference CI and p-values
PROC SORT DATA= DIFF; 
      BY WEEK TRT01PN _TRT01PN _IMPUTATION_;
RUN;
ODS OUTPUT PARAMETERESTIMATES= DIFF_O; 
PROC MIANALYZE DATA= DIFF; 
        BY WEEK TRT01PN _TRT01PN; 
        MODELEFFECTS ESTIMATE; 
         STDERR STDERR; 
RUN;
ODS OUTPUT CLOSE;
The observed data (ie, without imputation for missing data) will be summarized using descriptive 
statistics by analysis weeks (baseline, weeks 1 to 16).
6.2.3.
Sensitivity Analysis
Sensitivity analyses will be performed to address the assumptions in the primary model. The 
primary analysis will be repeated; however, the daily average PI-NRS scores measured on the 
days where the patient took rescue medication will be replaced as follows:

If a patient took rescue medication once on a day, the PI-NRS score immediately before 
using rescue medication will be used as the daily average PI-NRS score for that day.


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
If a patient took rescue medication more than once on a day, the mean value of PI-NRS 
scores immediately before using rescue mediation uses for the day will be used as the 
daily average PI-NRS score for that day.
Note, if the PI-NRS score immediately before using rescue medication is not recorded, the daily 
average PI-NRS scores will not be replaced. 
After the replacement, the baseline and post baseline weekly average of the daily average 
PI-NRS pain scores over the past 24 hours will be derived using formula [1], respectively. The 
data will be analyzed in the manner analogues to the primary endpoint as described in
Section 6.2.2.
6.2.4.
Sub-Group Analyses
Sub-group analyses will be performed on the primary and selected secondary efficacy endpoints 
for sex and age group at FM onset (<40 vs ≥40 years) based on observed values only using 
descriptive statistics. The selected secondary endpoints are:

Change from baseline to week 12 in the individual components of the Fibromyalgia 
Impact Questionnaire Revised (FIQR): symptom subscore, impact subscore, and 
functional subscore score

Patient’s Global Impression of Change (PGIC) by visit

Change from baseline in the weekly average of the daily worst pain PI-NRS score by 
analysis week
Sub-group analysis will be based on mITT and/or PP analysis sets.
In addition, the primary endpoint will also be summarized by the following subgroups using 
descriptive statistics:

PI-NRS BL ≥5/<5,

PI-NRS BL ≥6/<6;

PI-NRS BL ≥7/<7;

Enrollment prior to/post Study TV48125-PN-20028 protocol amendment 05;

Enrollment prior to/post start of Covid-19 pandemic using the date of 26 Mar 2020 
(site contact date) to represent the start of the pandemic;

NSAIDs/no NSAIDs use at any time during the study (with NSAIDs to be defined by 
clinical review)
6.3.
Secondary Efficacy Endpoints and Analysis
The secondary efficacy endpoints are listed in Section 1.1. Analysis will be based on mITT and 
PP analysis sets.
Missing data for the following secondary endpoints will be imputed using the MI method
detailed in Section 6.2.2:


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
the percentage of patients who experience a ≥30% reduction in the weekly average of 
the daily average PI-NRS score at week 12

the percentage of patients who experience a ≥50% reduction in the weekly average of 
the daily average PI-NRS score at week 12

change from baseline to week 12 in the weekly average of the daily worst PI-NRS 
score over the past 24 hours
There will be no imputation for missing data for all other secondary efficacy endpoints unless 
noted otherwise.
6.3.1.
Change From Baseline to Week 12 in the Individual Components of the 
Fibromyalgia Impact Questionnaire Revised: Symptom Subscore, Impact 
Subscore, and Functional Subscore Score
The FIQR is a commonly used instrument in the evaluation of FM patients. It contains
21 questions in 3 domains: function (9 questions), overall impact (2 questions), and symptoms 
(10 questions). Questions are graded on a 0 to 10 numeric scale with 10 being the worst. All 
questions are framed in the context of the last 7 days. The sub-total scores (subscores) and total 
scores will be calculated by ICON using the scoring guidance [The Revised Fibromyalgia Impact 
Questionnaire (FIQR): validation and psychometric properties] and will be provided in the 
database. The sub-total score for each domain is the summation of scores in the domain. The 
function sub-total score ranges from 0 to 90; overall impact sub-total score ranges from 0 to 20; 
the symptoms sub-total score ranges from 0 to 100. According to the scoring guidance, the FIQR 
total score is calculated as (the function sub-total score divided by 3) + the overall impact sub-
total score + (the symptoms sub-total score divided by 2). Thus FIQR total score ranges from 0 
to 100. 
The FIQR will be assessed at BAPS visit and visits 3 to 7 (weeks 1, 4, 8, 12, and 16).
The change from baseline in FIQR symptom sub-score, impact sub-score, functional sub-score, 
and total score will be analyzed, respectively, using a MMRM method with change from baseline 
in the FIQR score at weeks 4, 8, and 12 as the dependent variable, sex, age group at FM onset, 
week, treatment, and treatment by week interaction as fixed factors, and the baseline FIQR score
as a covariate. ARH(1) for repeated observations within patients will be used, and the 
denominator degrees of freedom will be estimated using Kenward-Roger’s approximation. 
Missing total score will be considered as missing at random. 
Notes, if ARH(1) does not converge, then simpler covariance structures with less parameters will 
be used in the following order until the model converges: AR[1]; CSH; and CS.
The LS mean estimates for the mean change from baseline as well as the difference of the 
estimates between the fremanezumab and placebo group, with the corresponding SE, p-value and 
associated 95% CI will be provided. The results from all visits will be presented.
SAS codes are:
ODS OUTPUT LSMEANS= LS DIFFS = DIFF (WHERE = (AVISIT = _AVISIT)); 
PROC MIXED DATA= name; 
      CLASS SUBJID TRT01PN AVISIT AGEATFMONSET  SEX;


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       MODEL CHANGE= BASE TRT01PN AGEATFMONSET SEX AVISIT
                                          TRT01PN*AVISIT/DDFM=KR;
       REPEATED AVISIT/SUBJECT= SUBJID TYPE= ARH(1); 
      LSMEANS TRT01PN*AVISIT / DIFF CL;
RUN;
ODS OUTPUT CLOSE;
Where AVISIT denotes the study visit/week; BASE denotes the baseline value for the FIQR 
scores.
In addition, the FIOR scores will be summarized using descriptive statistics for all visits.
6.3.2.
The Patient Global Impression of Change Rating at Week 12
The PGIC scale evaluates all aspects of patients’ health and assesses if there has been an 
improvement or decline in clinical status since the start of the study. Patients will record 
responses to the PGIC scale visits 6 and 7 (weeks 12 and 16). Improvement is recorded on a 
7-point scale, with 1 indicating very much improved, 4 indicating no change, and 7 indicating 
very much worse:

1 = Very Much Improved

2 = Much Improved

3 = Minimally Improved

4 = No Change

5 = Minimally Worse

6 = Much Worse

7 = Very Much Worse
For analysis purpose, a dichotomous scale of ‘Yes’ or ‘No’ will be derived. Scale “much 
improved” or “very much improved” will be considered improved (Yes), and all other 
non-missing responses will be considered not improved (No). Missing category will be presented 
as appropriate. 
The response variable (yes or no) at week 12 will be analyzed using a logistic regression model
with the treatment, age group at FM onset, and sex as explanatory factors. Missing category will 
not be included.
SAS code is:
ods output diffs = dif LSMeans = ls;
PROC GENMOD DATA =name;
       CLASS TRT01PN STRATAR SEX;
       MODEL AVALCAT1 = TRT01PN STRATAR SEX / DIST=BIN TYPE3;
   LSMEANS trt01pn/exp DIFF CL;
RUN;
ods output close;


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data ls;
  set ls;
    ** p = estimated response rate;
         p = logistic(estimate);
         p l = logistic(Lower) ;
       p_u = logistic(Upper);
run;
Where AVALCAT1 denotes the responses with ‘yes’ for improved and ‘no’ for not improved.
In addition, the PGIC data will be summarized as a categorical variable using descriptive 
statistics for all visits, including missing category as appropriate.
6.3.3.
Percentage of Patients Who Experience a ≥30% or ≥50% Reduction in the 
Weekly Average of the Daily Average PI-NRS Score at Week 12
The weekly average of the daily average PI-NRS score with missing data imputation from the 
500 imputed data sets derived as described in steps 1 to 3 of Section 6.2.2 will be used to 
calculate the pain intensity reduction (%) from baseline in the weekly average of the daily 
average PI-NRS score using formula [2].
 !"#$%" & #'" −)*!+ !"#$%" & #'"
 !"#$%" & #'"
× 100% [2]
The percentage of patients who experience ≥30% reduction and ≥50% reduction in the weekly 
average of the daily average PI-NRS score at week 12 will be analyzed using a generalized 
estimating equation (GEE) method where the dependent variable is ≥30% reduction (Yes/No) or 
≥50% reduction (Yes/No), respectively,
 
SAS code for GEE model:
ods output LSMeans = ls;
PROC GENMOD DATA =name;
       BY _IMPUTATION_;
        CLASS SUBJID TRT01PN WEEK STRATAR SEX;
        MODEL AVALCAT = BASE TRT01PN WEEK STRATAR SEX 
                                         TRT01PN*WEEK/ DIST=BIN TYPE3;
       REPEATED SUBJECT = SUBJID / TYPE = AR(1);
    LSMEANS trt01pn*week/exp DIFF CL; 
RUN;
ods output close;
Where AVALCAT denotes the responses with ‘yes’ for ≥30% or ≥50% or ‘no’ for <30% or 
<50% pain intensity reduction, respectively.
The 500 sets of results from above analyses will be combined using Rubin’s formulae (PROC 
MIANALYZE). 
PROC SORT DATA= LS; 


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      BY WEEK TRT01PN _IMPUTATION_;
RUN;
ODS OUTPUT PARAMETERESTIMATES= LSM_O; 
PROC MIANALYZE DATA= LS; 
      BY WEEK TRT01PN; 
      MODELEFFECTS ESTIMATE; 
      STDERR STDERR; 
RUN;
DATA LSM_O; 
  SET LSM O; 
  EXPESTIMATE = EXP(ESTIMATE);
  P = 100*EXPESTIMATE/(1 + EXPESTIMATE);
  P LL = 100*EXP(LCLMEAN)/(1 + EXP(LCLMEAN));
  P UL = 100*EXP(UCLMEAN)/(1 + EXP(UCLMEAN));
RUN;
In addition, the mean percentage of reduction and its associated 95% CI will be reported by 
week.
A plot of percentage of improvement versus percentage of patients meeting the improvement 
level at week 12 will be presented based on observed data and missing data at week 12 will be 
deemed as pain intensity increased from baseline. The x-axis representing percentage of 
improvement will be from >= 0 to 100% by an increment of 10%, ie., the x-axis will be at cutoff 
points ≥ 0%, ≥10%, ≥20%, …, ≥90% and 100% while y-axis will be percent of patients meet the 
cutoff points. The percentage of improvement will be calculated using formula [2].
6.3.4.
Change From Baseline to Week 12 in the Weekly Average of the Daily Worst 
PI-NRS Score Over the Past 24 Hours
The weekly average of the daily worst PI-NRS score over the past 24 hours will be analyzed in a 
manner analogous to the primary endpoint as described in Section 6.2.2. The dependent variable 
is the change from baseline in the weekly average of the daily worst PI-NRS scores. The 
covariate will be baseline average of the daily worst PI-NRS scores.
6.3.5.
Change From Baseline to Week 12 in the Patient-Reported Outcomes 
Measurement Information System Sleep Disturbance Short Form 8a Score
The PROMIS sleep disturbance Short Form 8a (SF8a) scale contains 8 items and assesses sleep 
disturbance over the past 7 days. One item assessing overall sleep quality use a scale of very 
poor, poor, fair, good, or very good. Other 7 items use a scale of not at all, a little bit, somewhat, 
quite a bit, or very much. Each item of the PROMIS sleep disturbance SF8a is on 5-point scales 
(1 to 5), with 1 for the lowest sleep disturbance and 5 for the highest sleep disturbance. The total
score ranges from 8 to 40 (highest sleep disturbance). Collection of the PROMIS sleep 
disturbance SF8a will start the day of the BAPS Visit (Visit 2) and will be administered weekly 
via the e-diary. The total raw score ranging from 8 to 40 (highest sleep disturbance) will be 
calculated as the summation of 8 non-missing scores. If any of 8 items has a missing score, the 
total raw score will be missing. The calculated total raw score will be converted into t-score 


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using the scoring table (PROMIS-Sleep Disturbance Scoring Manual). All questions must be 
answered in order to produce a valid score using the scoring table. The analysis will be based on 
t-score.
The change from baseline to week 12 in t-score of the PROMIS sleep disturbance SF8a will be 
analyzed using MMRM method in manner analogous to the analysis as described in 
Section 6.3.1. The dependent variable is the change from baseline in the t-score of the PROMIS 
sleep disturbance SF8a at analysis weeks 1 to 12 (12 levels). BASE is the t-score of the PROMIS 
sleep disturbance SF8a at baseline. Missing will be considered as missing at random. The results
from all visits will be presented using descriptive statistics.
Summary statistics will include data from all analysis weeks.
6.3.6.
Change from Baseline to Week 12 in the Patient-Reported Outcomes 
Measurement Information System Physical Function SF12a Score
The PROMIS physical function scale measures self-reported capability rather than actual 
performance of physical activities. This includes the functioning of one’s upper extremities 
(dexterity), lower extremities (walking or mobility), and central regions (neck, back), as well as 
instrumental activities of daily living, such as running errands over the past 7 days. A single 
physical function capability score is obtained from a SF. The PROMIS physical function SF12a 
scale contains 12 items with 5-point scales (1 to 5) for each item with a total score ranging from 
12 to 60. A lower score indicates more limited physical disability.
The PROMIS physical function SF12a will be assessed at BAPS Visit (visit 2) and visits 3 to 7
(weeks 1, 4, 8, 12, and 16).
The total raw score will be calculated as the summation of 12 non-missing scores for patients 
who can walk 25 feet or summation of 6 non-missing scores for patients who cannot walk for 25 
feet. The calculated total raw score will be converted into scale score using the scoring tables
(PROMIS-Physical Function Scoring Manual). Different scoring tables will be used for patients 
who can walk and patients who cannot walk. All questions must be answered in order to produce 
a valid score using the scoring table. The analysis will be based on the scale score.
The change from baseline to week 12 in the scale score of PROMIS physical function SF12a will 
be analyzed using MMRM method in manner analogous to the analysis as described in 
Section 6.3.1. The dependent variable is the change from baseline in the scale score of PROMIS 
physical function SF12a at weeks 4, 8, and 12 (3 levels). BASE is the scale score of PROMIS 
physical function SF12a at baseline. Missing will be considered as missing at random. The
results from all visits will be presented using descriptive statistics.
Summary statistics will include data from all visits.
6.3.7.
Change From Baseline To Week 12 In The Patient-Reported Outcomes 
Measurement Information Fatigue SF8a Score
The PROMIS Fatigue SF8a contains 8 items with 5-point scales (1 to 5) for each item over the 
past 7 days. The total score ranges from 8 to 40 (highest level of fatigue). The PROMIS fatigue 
SF8a will be assessed at BAPS Visit (visit 2) and visits 3 to 7 (weeks 1, 4, 8, 12, and 16).


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The total raw score will be calculated as the summation of 8 non-missing scores. The calculated 
total raw score will be converted into t-score using the scoring table (PROMIS-Fatigue Scoring 
Manual). All questions must be answered in order to produce a valid t-score using the scoring 
table. The analysis will be based on t-score.
The change from baseline to week 12 in the t-score of the PROMIS Fatigue SF8a will be 
analyzed using MMRM method in manner analogous to the analysis as described in 
Section 6.3.1. The dependent variable is the change from baseline in the t-score of the PROMIS 
Fatigue SF8a at weeks 4, 8, and 12 (3 levels). BASE will be the t-score of PROMIS fatigue SF8a
from the baseline. Missing will be considered as missing at random. The results from all visits
will be presented using descriptive statistics.
Summary statistics will include data from all visits.
6.3.8.
Number (%) of Patients Who Did Not Complete the Treatment Due to Lack of 
Efficacy
Time to treatment discontinuation will be assessed for all patients and will be measured from the 
date of the first dose of study medication to the date of treatment completion or treatment 
discontinuation before visit 7. Time to treatment discontinuation is defined as the date of EOT -
the date of 1st dosing of IMP + 1. Patients who completed the treatment will be censored at the 
date of EOT. Patients who did not complete the treatment due to reasons other than lack of 
efficacy will be censored at the date of ET. Patients who are lost to follow-up will be censored at 
the date of their last visit.  
Time to treatment discontinuation will be analyzed using Kaplan-Meier survival analysis 
method. Number (%) of patients who do not complete the treatment due to lack of efficacy (the 
event) and patients censored will be presented. Kaplan-Meier estimates (median time to 
treatment discontinuation due to lack of efficacy, survival probability at weeks 4, 8, 12 and 16) 
and survival plot will also be presented.
6.4.
 
6.4.1.
 
 
 
 
 
 


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
 
 
 
 
 
 
 
 
 
 
6.4.2.
 
 
 
 
 
 
 
 
 
6.4.3.
 
 


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6.4.4.
 
 
 
 
 
 
6.4.5.
 
 
 
 


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7.
MULTIPLE COMPARISONS AND MULTIPLICITY
No multiplicity adjustment is planned for this study.


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8.
SAFETY ANALYSIS
8.1.
General
The safety analysis set will be used for all safety analyses. Summaries will be presented by 
treatment group as actually received unless otherwise stated.
In the Study TV48125-PN-20028 protocol amendment 04, the data collections had been 
changed:

Some data are not collected as they were prior to protocol amendment 04 at some 
visits; for example, clinical laboratory data are no longer collected at visits 4 and 5.

Follow-up visit was removed
This section reflects data collections in the study including data collected prior to Study 
TV48125-PN-20028 protocol amendment 04. For by-visit summaries, all data collected in the 
study will be summarized. 
8.2.
Duration of Exposure to Study Drug
Duration of exposure to study drug (days) for the individual patient is the number of days patient 
received drug (last day of study drug – first day of study drug + 28). 
Number (%) of patients receiving 1 dose, 2 doses, 3 doses, and 4 doses and duration of treatment 
(days) will be summarized by treatment group using descriptive statistics.
8.3.
Adverse Events
An adverse event (AE) is any untoward medical occurrence in a patient administered a 
pharmaceutical product which does not necessarily have to have a causal relationship with this 
treatment.
For recording of AE, the study period is defined for each patient as the time period from 
signature of the informed consent form (ICF) to the end of the follow-up period or the early 
termination visit for patients who discontinue from the study for any reason. Any AE occurring
on or after the first dose of study drug is considered a treatment-emergent AE (TEAE). All AE 
summaries will be conducted for TEAEs.
The following are considered protocol-defined adverse events of special interest (AESI) to be 
sent to the sponsor’s Global Patient Safety and Pharmacovigilance (GPSP) Department for 
evaluation:

ophthalmic-related adverse events of at least moderate severity, as determined by the 
investigator

severe hypersensitivity reactions 
All AEs will be coded using MedDRA. The incidence of AEs will be summarized using 
descriptive statistics by SOC and preferred term (PT). Each patient will be counted only once in 
each PT or SOC category for the analyses of safety. 


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Summaries will be presented for all AEs (overall and by severity), AEs determined by the 
investigator to be related to test IMP (ie, reasonable possibility) (defined as related or with 
missing relationship) (overall, overall by severity, serious AEs, and AESI), serious AEs, AESI, 
AEs causing discontinuation from treatment, AEs causing early termination from the study, 
injection site AEs, and AEs leading to death. 
Listings of AEs, AESI, serious AEs, injection site AEs, and AEs leading to early termination will 
be presented separately.
8.4.
Deaths
If any patient dies during the study all relevant information will be discussed in the patient’s 
narratives included in CSR.
8.5.
Clinical Laboratory Tests
Clinical laboratory tests (serum chemistry, hematology, coagulation, and urinalysis) will be 
performed at the time points detailed in Table 1 in the study protocol using a central laboratory. 
Clinical laboratory tests will be performed using a central laboratory. Specific laboratory tests to 
be performed are provided in Table 3.
Table 3:
Clinical Laboratory Tests
Serum Chemistry
Hematology and Coagulation
Urinalysis
Calcium
Phosphate
Sodium
Potassium
Chloride
Creatinine
Glucose
Blood urea nitrogen (BUN)
Urate
Alanine aminotransferase (ALT)
Aspartate aminotransferase (AST)
Lactate dehydrogenase (LDH)
Gamma-glutamyl transpeptidase 
(GGT)
Alkaline phosphatase
Bicarbonate
Carbon dioxide
Protein
Albumin
Bilirubin
Direct bilirubin
Hepatitis B
Hemoglobin
Hematocrit
Erythrocytes
Platelets
Leukocytes

Neutrophils

Lymphocytes

Eosinophils

Monocytes

Basophils
Lymphocytes atypical
Prothrombin International 
Normalized Ratio (INR)
Protein
Glucose
Ketones
Hemoglobin
pH
Specific gravity
Microscopic tests

Bacteria

Erythrocytes

Leucocytes

Crystals

Casts
Laboratory test results will be presented in standard international (SI) units.


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Summary statistics for chemistry, hematology, coagulation, and urinalysis laboratory tests will 
be presented at baseline, week 4, week 8, week 12, week 16, and last assessment. Laboratory 
values and changes from baseline to week 4, week 8, week 12, week 16, and last assessment will 
be summarized using descriptive statistics. 
Shifts (below, within, and above the normal range) from baseline to week 4, week 8, week 12, 
week 16, and last assessment will be summarized using patient counts.
Summaries of potentially clinically significant abnormal values will include all postbaseline 
values (including scheduled, unscheduled, and withdrawal visits). The incidence of potentially 
clinically significant abnormal values will be summarized for laboratory variables using 
descriptive statistics with the criteria specified in Table 4.
Table 4:
Criteria for Potentially Clinically Significant Laboratory Values
Test
Criterion value
Serum chemistry
  Alanine aminotransferase (ALT)
≥3x ULN
  Aspartate aminotransferase (AST)
≥3x ULN
  Alkaline phosphatase (ALP)
≥3x ULN
  Gamma-glutamyl transpeptidase (GGT)
≥3x ULN
  Lactate dehydrogenase (LDH)
≥3x ULN
  Blood urea nitrogen (BUN)
≥10.71 mmol/L
  Creatinine
≥177 μmol/L
  Uric acid              Men
≥625 mol/L
                              Women
≥506 mol/L
  Bilirubin (total)
≥34.2 μmol/L
Hematology
  Hematocrit           Men
<0.37 L/L
                               Women
<0.32 L/L
  Hemoglobin         Men
≤115 g/L
                               Women
≤95 g/L
  White blood cell (WBC) counts
≤3 x 109/L 
≥20 x 109/L
  Eosinophils
≥10%
  Absolute neutrophil counts (ANC)
≤1 x 109/L
  Platelet counts
≤75 x 109/L 
≥700 x 109/L
Urinalysis
  Blood (HGB)
≥2 unit increase from baseline
  Glucose
≥2 unit increase from baseline


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Test
Criterion value
  Ketones
≥2 unit increase from baseline
  Total protein
≥2 unit increase from baseline
ULN=upper limit of normal range.
Listings for potentially clinically significant abnormal laboratory data will be presented.
8.5.1.
Laboratory Values Meeting Hy’s Law Criteria
All occurrences of possible drug-induced liver injury that meet Hy's law criteria, defined as all of 
the below, must be reported by the investigator to the sponsor as a serious adverse event:

ALT or AST increase of >3× the ULN

total bilirubin increase of >2× the ULN

absence of initial findings of cholestasis (ie, no substantial increase of alkaline 
phosphatase)
An adverse event that does not meet any of the criteria for seriousness listed above will be 
regarded as a non-serious adverse event.
The serious adverse events will be summarized as indicated in Section 8.3.
8.5.2.
Other Clinical Laboratory Tests
At the screening visit, patients will be tested for human immunodeficiency virus (HIV), hepatitis 
B surface antigen (HBsAg), hepatitis C antibody, and thyroid stimulating hormone. Data will be 
listed.
Beta-human chorionic gonadotropin tests in serum will be performed for all women of 
childbearing potential at the screening visit. Data will be listed.
Follicle-stimulating hormone (FSH) test (for postmenopausal women only) will be performed at 
screening and baseline visit for data collected up to and including Study TV48125-PN-20028 
protocol amendment 04, but at screening only for data collected following Study TV48125-PN-
20028 protocol amendment 05 The data will be summarized using descriptive statistics.
A urine drug screen will be performed at the time points specified in Table 1 in the study 
protocol. Data will be listed.
8.6.
Physical Examinations
Physical examinations, including height (to be measured at the screening visit only) and weight, 
will be performed at the time points specified in Table 1 in the study protocol. Any physical 
examination finding that is judged by the investigator as a clinically significant change 
(worsening) compared with a baseline value will be considered an adverse event, recorded on the 
eCRF, and monitored as described in the study protocol.
Descriptive statistics for weight and height will be provided. Abnormal physical examination 
findings will be summarized by visits.


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8.7.
Vital Signs
Vital signs (blood pressure [systolic/diastolic], respiratory rate, oral body temperature, and pulse) 
will be measured at the time points detailed in Table 1 in the study protocol. 
Summary statistics for vital signs (blood pressure [systolic/diastolic], respiratory rate, oral body 
temperature, and pulse) will be presented at baseline, week 4, week 8, week 12, week 16 (end of 
treatment), week 30 (end of study), and last assessment. Vital signs values and changes from 
baseline to each visit will be summarized using descriptive statistics.
Summaries of potentially clinically significant abnormal values will include all postbaseline 
values (including scheduled, unscheduled, and withdrawal visits). The incidence of potentially 
clinically significant abnormal values will be summarized using descriptive statistics with the 
criteria specified in Table 5. Systolic and diastolic blood pressure will be included in all 
summaries.
Table 5 specifies the criteria for identifying vital signs as potentially clinically significant 
abnormal values. Note that in order to qualify as potentially clinically significant abnormal, a 
value needs to meet both criteria below: ie, have a value beyond the criterion value and a change 
of at least the magnitude specified in the change relative to baseline column.
Table 5:
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
Listings for potentially clinically significant abnormal laboratory data will be presented.
8.8.
Electrocardiography
A 12-lead ECG will be recorded at the time points detailed in Table 1 of the study protocol.
All ECG results outside of the reference ranges will be judged by the investigator as belonging to 
one of the following categories:

abnormal and not clinically significant

abnormal and clinically significant


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Any ECG finding that is judged by the investigator as clinically significant (except at the 
screening visit) will be considered an adverse event and recorded on the source documentation 
and in the eCRF.
Shifts (normal and abnormal) from baseline to overall result interpretation, week 12, week 16 
(end of treatment), and last assessment will be summarized using patient counts. For overall 
result interpretation the worst postbaseline finding for the patient (the abnormal finding if there 
are both normal and abnormal findings) will be used in the summaries. Summary statistics for 
ECG variables will be presented. Actual values and changes from baseline to week 12, week 16 
(end of treatment), and last assessment will be summarized using descriptive statistics.
8.9.
Concomitant Medications or Therapies 
Concomitant therapies and medications, including medications that are taken on an as needed 
basis and occasional therapies, will be monitored during the study. Details of prohibited 
medications may be found in the study protocol. All concomitant medications will be coded 
using the WHO Drug Dictionary.
The incidence of concomitant therapies and medications will be summarized using descriptive 
statistics by therapeutic class category and preferred term. Patients are counted only once in each 
therapeutic class, and only once in each preferred term category. Concomitant therapies and 
medications will include all medications taken after the 1st dose of study drug administration up 
to the end of study as defined in the study protocol.
Similarly the prohibited medications will be summarized separately. 
8.10.
Columbia-Suicide Severity Rating Scale
The C-SSRS will be used to assess the patient’s suicidal ideation (severity and intensity) and 
behavior. The C-SSRS Baseline/Screening version will be administered by certified site staff at 
Visit 1, and the C-SSRS Since Last Visit version will be completed by certified site staff at all 
other time points, as described in Table 1 of the study protocol. Any significant findings on the 
C-SSRS require evaluation by the site investigator.
Patients having positive findings will be listed.


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9.
TOLERABILITY VARIABLES AND ANALYSIS
Spontaneous reports of injection site reactions will be recorded as adverse events according to 
the following severity assessment criteria:

Spontaneous reports of injection site erythema, induration, and ecchymosis will be 
assessed and recorded by site personnel and categorized according to the following 
measurements: 5 to ≤50 mm (mild), >50 to ≤100 mm (moderate), and >100 mm 
(severe).

Spontaneous reports of local pain after the injection will be recorded as mild, 
moderate, or severe according to patient’s self-report.

Appropriate treatment may be provided if necessary, in which case it must be 
recorded as concomitant medication.
Local tolerability findings (eg, erythema, induration, ecchymosis, and occurrence of injection 
site pain) will be listed and summarized descriptively.
Injection site adverse events will be summarized as indicated in Section 8.3.


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10.
PHARMACOKINETIC ANALYSIS
There are no prespecified pharmacokinetic endpoints. 
Fremanezumab plasma concentration will be summarized using descriptive statistics by active 
treatment groups and each planned sampling time point (samples from patients who received 
placebo will not be analyzed). The summary will be based on the safety analysis set. The plasma 
concentration will be listed by active treatment groups, scheduled visits, and time points.
For summary displays of plasma concentration data, values below the limit of quantitation 
(BLQ) will be treated as 0. If the mean concentration at a time point is less than the lower limit 
of quantitation (LLOQ), then “BLQ” will be reported in place of summary statistics. Values 
below LLOQ will be imputed as ½*LLOQ for calculation of geometric mean and geometric CV. 
The LLOQ of fremanezumab is 250 ng/mL.


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11.
PHARMACODYNAMIC ANALYSIS
Details of the pharmacodynamic analysis will be provided in a separate SAP. 


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12.
PHARMACOKINETIC/PHARMACODYNAMIC ANALYSIS
Details of the pharmacokinetic/pharmacodynamic analysis will be provided in a separate SAP.


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13.
BIOMARKER ANALYSIS
Details of the biomarker analysis will be provided in a separate SAP.


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14.
IMMUNOGENICITY ANALYSIS
Details of the immunogenicity analysis will be provided in a separate SAP.


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15.
ANCILLARY STUDIES ANALYSIS
No ancillary analyses are planned for this study.


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16.
PLANNED INTERIM ANALYSIS
There were two interim analyses for futility performed in this study. The details of the interim 
analyses were specified in seperate interim statistical analysis plans. To ensure study integrity, 
the interim analyses were performed by an independent third party; the study team were kept 
blinded. The decision was made to end this study for futility following the results of the second 
interim analysis.


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17.
STATISTICAL SOFTWARE
All data listings, summaries, and statistical analyses will be generated using SAS® version 9.4 or 
later.


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18.
CHANGES TO ANALYSES SPECIFIED IN THE STUDY 
PROTOCOL
NA.


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19.
REFERENCES
Arthritis Research & Therapy 2009, 11:R120 (doi:10.1186/ar2783)
The Patient-Reported Outcomes Measurement Information System. Fatigue Scoring Manual. 
Available at 
http://www.healthmeasures.net/images/PROMIS/manuals/PROMIS_Fatigue_Scoring_Manual.p
df. Retrieved 15 May 2018.
The Patient-Reported Outcomes Measurement Information System. Physical Function Scoring 
Manual. Available at 
http://www.healthmeasures.net/images/PROMIS/manuals/PROMIS_Physical_Function_Scoring
_Manual.pdf. Retrieved 15 May 2018.
The Patient-Reported Outcomes Measurement Information System. Sleep Disturbance Scoring 
Manual. Available at 
http://www.healthmeasures.net/images/promis/manuals/PROMIS_Sleep_Disturbance_Scoring_
Manual.pdf. Retrieved 15 May 2018.