An Exploratory, Prospective, Randomized, Pragmatic Open Label Cohort Study to Evaluate the Comparative Effectiveness of Eptinezumab in the United States
Phase: PHASE4
Conditions: Migraine
Sponsor: H. Lundbeck A/S

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Study 19766N – Clinical Study Protocol
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Clinical Study Protocol
Early Value of Eptinezumab in the Community (EVEC) 
An exploratory, prospective, randomized, pragmatic open label 
cohort study to evaluate the comparative effectiveness of 
eptinezumab in the United States 
Real World Effectiveness of Eptinezumab in Migraine
Eptinezumab
Study No.:
19766N
IND No.:
114647
Sponsor:
Lundbeck LLC (Lundbeck)
Deerfield, Illinois 60015, United States
Edition No.:
3.0
Date of edition:
07 Jul 2022 
Edition history: 
Edition 2.0 (protocol amendment 1), 02 Jun 2022
Edition 1.0 (original protocol), 04 May 2022
This document is the property of Lundbeck LLC and Lundbeck LLC is the holder of any and 
all related intellectual property rights, including, but not limited to, copyrights. This document 
is confidential. It is not to be copied or distributed to other parties without prior written 
authorization from Lundbeck LLC.
NCT05284019

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Abstract – Study 19766N
Title: Early Value of Eptinezumab in the Community (EVEC) Study: An exploratory, 
prospective, randomized, pragmatic, open-label, cohort study to assess the comparative 
effectiveness of eptinezumab in the United States 
Rationale and Background
Migraine is a debilitating disorder with an estimated prevalence of self-reported migraine or 
severe headache in the United States (US) among adults at 15.3% (95% confidence interval 
[CI]: 14.75, 15.85. In the US, it is estimated that there are 36 million people with migraine. 
Eptinezumab (Vyepti®) is a humanized immunoglobulin G1 (IgG1) monoclonal antibody 
(mAb) that binds to the calcitonin gene-related peptide (CGRP) ligand and blocks its binding 
to CGRP receptors.  It is indicated for the prevention of migraine in adults. Randomized 
controlled trials have shown that eptinezumab is efficacious in reducing mean monthly 
migraine days (MMD) versus placebo. However, there is a need to determine the comparative 
effectiveness of eptinezumab relative to other advanced preventive medications (i.e.,
subcutaneous [SC] anti-CGRP injectables and onabotulinumtoxinA [Botox]) used routinely in 
clinical practice. This type of evidence will further assist clinicians, payers and patients in 
making informed decisions in migraine preventive care.
Study Aim
This exploratory study has multiple objectives within the overall aim to examine how 
eptinezumab compares to other advanced preventive medications in a real-world community 
setting. These objectives include exploring the comparative effectiveness on patient reported 
outcomes including participant-identified most bothersome symptoms (PI-MBS), good days 
and bad days, quality of life (QOL), and healthcare resource utilization (HRU). The impact of 
mediating factors including monthly migraine days, early prevention and perceived stress on 
these outcomes will be evaluated in this process. Finally, we will assess participant 
preferences for shared decision making, patient satisfaction with their treatment and 
confidence in managing their own health. 
Study Design
This is an exploratory, prospective, randomized, cohort study to be conducted in adult 
participants with episodic migraine (EM) or chronic migraine (CM). Participants will be 
recruited from sites that can offer all therapeutic options. A total of 200 participants will be 
enrolled in the study. Participants will be classified as living with either EM or CM based 
upon their medical history. Within these strata, the participants living with EM will be 
randomized to eptinezumab or other advanced preventive medication (i.e., erenumab, 
fremanezumab or galcanezumab) in a 1:1 manner. Those experiencing chronic migraine will 
be randomized to eptinezumab, subcutaneous (SC) CGRPs, or Botox in a 3:2:1 manner. 
Participants who are randomized to a SC CGRP will be permitted to select treatment with the 
injectable of their choice (i.e., erenumab, fremanezumab or galcanezumab). Participant data 
will be collected at multiple time points throughout the study. The daily migraine status,

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symptom data, and acute migraine medication usage will be collected daily via a study-
specific smartphone application (app). QOL data and HRU data will be collected two ways, 
via the smartphone application and the site staff.  QOL assessments include the 
EuroQol-5 Dimension-5 Level (EQ-5D-5L), Headache Impact Test (HIT-6), Good 
Day/Bad Day scale and the Migraine Disability Assessment (MIDAS). All PROs will be 
completed directly by the participants via the app, with the exception of the Infusion 
Satisfaction Survey (ISS), that will be completed via paper questionnaire. Participants will 
complete the EQ-5D-5L and Good Day/Bad Day scale on a weekly basis, the HIT-6 monthly, 
and the MIDAS every 3 months. HRU will be tracked via participant input into the app and 
site staff led interviews. 
Participants will be trained to report any healthcare interactions into the app (e.g., office 
visits, urgent care visits, picking up prescription medication). In addition, the site staff will 
interview participants monthly to determine if any healthcare system interactions occurred. 
Several additional measures are planned to assess participant preferences regarding shared 
decision making and satisfaction with their treatment. 
Study Objectives
The outcomes in this exploratory study will be the following: 
1. Patient-identified most bothersome symptom (PI-MBS): This will be measured daily
using the PI-MBS. Participant will select the symptom that they find most impairs her or 
him at the time of reporting and rate the severity of that symptom. The difference between 
randomization groups evaluated at 4-, 12- and 24-weeks following randomization
2. Good day/Bad Day scale: The participant will report the number of "good days" and "bad 
days" they had in the previous week on a weekly basis using the Good Day/Bad Day scale. 
The difference between randomization groups evaluated at 4, 12, and 24 weeks.
3. EuroQol 5-Dimension, 5-Level Quality of life Scale (EQ-5D-5L): The participant will 
complete the EQ-5D questionnaire on a weekly basis to indicate their preference for their 
current health state. The difference between randomization groups evaluated at 4, 12, and 
24 weeks.
4. Health resource utilization: The participant will report their use of health services and 
medications on a daily basis using the smartphone app. The difference over time between 
the randomization groups will be evaluated at 4, 12, and 24 weeks.
5. 6-item Headache Impact Test (HIT-6): The participant will report the impact of 
headache on their quality of life using the six-item HIT-6 scale. This will be done each 
month. The difference in change over time between randomization groups will be 
evaluated at 4, 12, and 24 weeks. 
6. Migraine Disability Assessment (MIDAS): The participant’s perception of their degree 
of disability will be evaluated by the MIDAS scale. This will be measured quarterly. The 
difference in change over time between randomization groups will be evaluated at 12 and 
24 weeks. 
7. Treatment Satisfaction Questionnaire for Medication (TSQM): The participant’s 
reported satisfaction with treatment will be evaluated at the study closeout visit (i.e., 
visit #9). This will be compared between randomization groups at week 24. 

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8. Medication Switching: The frequency of switching of migraine preventive medication 
from the medication administered at baseline will be compared between the randomization 
groups from baseline to week 24.
Additional Outcomes (not between group comparisons)
1.
9-item Shared Decision-Making Questionnaire (SDM-Q-9):  The participant will 
report their satisfaction with shared decision-making using SDM-Q-9 following 
education on treatment options. This will be evaluated at screening and week 24. 
2. SURE Scale:  The participant will report their readiness to decide or determine whether 
their comfort with their treatment decision using the SURE scale. This will be evaluated at 
screening. 
3. 10-item Patient Activation Measure (PAM-10): The participant will report their 
knowledge, skills, and confidence to manage his or her health condition via the PAM-10. 
This will be evaluated at screening and weeks 12 and 24. 
4. Infusion Satisfaction Survey (ISS):  Participants initiating therapy on eptinezumab will 
describe the satisfaction with care with the ISS at baseline and week 12.

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Table of Contents
List of Panels.....................................................................................................................................9
List of Tables & Figures .................................................................................................................10
List of Abbreviations and Definitions of Terms.............................................................................11
Major Changes Since Last Edition.................................................................................................12
Treatment and Follow-up of Adverse Events.............................................................................12
1
Introduction............................................................................................................................13
Background...................................................................................................................13
1.1.1
Overview .......................................................................................................13
1.1.2
Clinical Data..................................................................................................13
Rationale for the Study..................................................................................................14
2
Objectives ...............................................................................................................................14
3
Study Design...........................................................................................................................15
Overview of the Study Design.......................................................................................15
Rationale for the Study Design......................................................................................18
3.2.1
Study Design Justification..............................................................................18
Additional Study Rationale and Considerations .............................................................19
4
Ethics ......................................................................................................................................20
Ethical Rationale...........................................................................................................20
Informed Consent..........................................................................................................20
Personal Data Protection ...............................................................................................21
Institutional Review Board............................................................................................21
5
Study Population ....................................................................................................................22
Number of Participants..................................................................................................22
Participant Recruitment.................................................................................................22
Selection Criteria ..........................................................................................................23
Participants with Medication Overuse Headache ...........................................................24
Withdrawal Criteria.......................................................................................................24
6
Investigational Medicinal Products........................................................................................25
Treatment Regimen.......................................................................................................25
IMPs, Formulations, and Strengths................................................................................26
Method of Assigning Participants to Treatment .............................................................27
6.3.1
Change in Treatment ......................................................................................27
IMP Accountability.......................................................................................................28
7
Concomitant Medication........................................................................................................28
8
Study Visit Plan......................................................................................................................28
Overview ......................................................................................................................28
Screening Visit (Visit 1)................................................................................................34
Process for Randomization to Treatment Arms..............................................................34
Baseline Visit (Visit 2)..................................................................................................35
Visits 3 & 4 (Days 28 & 56; +/- 3 days).........................................................................36
Visit 5 (Day 84; +/- 3 days)...........................................................................................36

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Visits 6 & 7 (Days 112 & 140; +/- 3 days).....................................................................37
End of Treatment (Visit 8; Day 186 +7 days) / Early Termination .................................37
Withdrawal Visit...........................................................................................................37
Safety Follow-up Visit ..................................................................................................38
End-of-Study Definition................................................................................................38
9
Assessments ............................................................................................................................39
Screening and Baseline Procedures and Assessments.....................................................39
9.1.1
Diagnostic Assessments .................................................................................39
9.1.2
eDiary ............................................................................................................40
9.1.3
Efficacy and Clinical Outcomes Assessments.................................................40
Healthcare Resource Utilization ....................................................................................42
Safety Assessments .......................................................................................................43
9.3.1
Vital Signs .....................................................................................................43
Treatment Compliance ..................................................................................................43
10
Adverse Events and Adverse Drug Reactions........................................................................43
Definitions....................................................................................................................43
10.1.1
Adverse Event Definitions..............................................................................43
10.1.2
Adverse Event Assessment Definitions...........................................................44
Pregnancy .....................................................................................................................45
Recording Adverse Events ............................................................................................46
Reporting Serious Adverse Events.................................................................................46
Treatment and Follow-up of Adverse Events .................................................................47
11
Data Handling and Record Keeping ......................................................................................47
Data Collection .............................................................................................................47
11.1.1
Electronic Case Report Forms ........................................................................47
11.1.2
Electronic Diary (eDiary) ...............................................................................48
11.1.3
Patient Data....................................................................................................48
11.1.3.1
Recording of Patient Data...............................................................48
11.1.3.2
Clinical Outcome Assessments .......................................................48
11.1.3.3
Serious Adverse Event Fallback Forms...........................................48
11.1.4
External Data .................................................................................................48
Retention of Study Documents at the Site......................................................................49
11.2.1
eCRF data ......................................................................................................49
11.2.2
Other Study Documents..................................................................................49
12
Monitoring Procedures...........................................................................................................49
13
Audits and Inspections ...........................................................................................................50
14
Protocol Compliance ..............................................................................................................50
15
Study Termination..................................................................................................................50
16
Statistical Methodology ..........................................................................................................51
Responsibilities.............................................................................................................51
Analysis Population ......................................................................................................51
Safety Analyses.............................................................................................................51
16.3.1
Analysis of Adverse Events............................................................................51
16.3.2
Sample Size and Power ..................................................................................51
Statistical Analysis Plan................................................................................................51
17
Clinical Study Report and Publications.................................................................................52

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Data Ownership ............................................................................................................52
Clinical Study Report....................................................................................................52
Summary of Clinical Study Results ...............................................................................52
Publications ..................................................................................................................52
18
Indemnity and Insurance .......................................................................................................52
19
Finance....................................................................................................................................52
Site Agreements............................................................................................................52
Financial Disclosure......................................................................................................52
References .....................................................................................................................................105

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Appendices
Appendix I
Clinical Study Protocol Authentication and Authorization
Appendix II        The American Headache Society Position Statement on Integrating New 
Migraine Treatments into Clinical Practice
Appendix III
Patient-Identified Most Bothersome Symptom (PI-MBS)
Appendix IV
The 9-Item Shard Decision Making Questionnaire (SDM-Q-9)
Appendix V
Decision Guide
Appendix VI
The SURE Test
Appendix VII
The Patient Activation Measure (PAM)
Appendix VIII
EuroQoL-5Dimension-5Level (EQ-5D-5L) 
Appendix IX
Good Day / Bad Day Scale
Appendix X
Perceived Stress Scale (PSS)
Appendix XI
Migraine Disability Assessment (MIDAS)
Appendix XII
Infusion Satisfaction Survey
Appendix XIII
Treatment Satisfaction Questionnaire for Medication (TSQM)
Appendix XIV
Headache Impact test (HIT-6) 
Appendix XV
Healthcare Resource Utilization
Appendix XVI
Healthcare Resource Utilization Follow-Up Questionnaire
Appendix XVII   Medication Overuse Headache Criteria

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List of Panels
Panel 1
eDiary Collected Assessments at Visit 1
Panel 2
eDiary Collected Assessments at Visit 2
Panel 3
Post-Baseline eDiary Collected Assessments
Panel 4
Assessments Administered via Site Staff

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List of Tables & Figures
Table 1
Criteria for Chronic Migraine Diagnosis per ICHD-3
Figure 1
Randomization Design

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List of Abbreviations and Definitions of Terms
ADR         
adverse drug reaction
AE
adverse event
AHS
American Headache Society
AUC
area under curve
Botox                       onabotulinumtoxinA
CGRP                     calcitonin gene-related peptide
CI
Confidence interval
CM
chronic migraine
CRF/eCRF
case report form/electronic Case Report Form
CRO                       clinical research organization
eDiary
electronic diary
EM
episodic migraine 
EQ-5D-5L
EuroQol-5 Dimension – 5 Level
EVEC
Early Value of Eptinezumab in the Community
HIT-6
Headache Impact Test
ICSR
individual case safety report
ICHD 3rd ed
International Classification of Headache Disorders 3rd edition
IgG1
immunoglobulin G1
IV
Intravenous
mAb
monoclonal antibody
MBS                       Most Bothersome Symptom questionnaire
MIDAS
Migraine Disability Assessment questionnaire
MMD                     monthly migraine days
MOH
medication overuse headache
ORC
Observational Research Committee
OTC
over-the-counter
PAM-10
Patient Activation Measure – 10 items
PI-MBS
Patient Identified-Most Bothersome Symptom 
QOL
quality of life
SADR
serious adverse drug reaction
SAE
serious adverse event
SOC                       
standard of care
SDM-Q-9
Shared Decision-making Questionnaire
TSQM
Treatment Satisfaction Questionnaire for Medication
US
United States
Advanced 
preventive 
medications
The collective term used to describe the non-eptinezumab treatment arms in 
EVEC consisting of onabotulinumtoxinA and subcutaneous anti-CGRP 
injectables (i.e., erenumab, fremanezumab and galcanezumab)

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Major Changes Since Last Edition
The following summarizes the major changes since the last edition of this CSP.
Chapter/
Section 
Number
Chapter/Section Title
Change
Abstract
Section 1. 2
Deleted:  Monthly migraine days (MMD) removed as an outcome
Abstract
Section 1.3
Deleted:  Monthly migraine days (MMD) removed as an outcome
Section 2 Objectives
Deleted:  Monthly migraine days (MMD) removed as an outcome
Added:    Final sentence of section revised to note that MMD will be 
               considered as a mediating factor 
Section 
5.3
Exclusion Criteria
Updated: Exclusion criteria #4 revised to note that participants who
               have taken gepant medications for prevention are excluded.
               This was added with the recent approval of these
               medications for prevention by the FDA.
Section 
8.2
Screening Visit (Visit 1)
Updated: Increased interval allowed between screening to the
               baseline visit from 14 to 21 days to allow more flexibility
               for participants   
Section 
8.3
Baseline Visit (Visit 2)
Updated: Increased interval allowed between screening to baseline
               visit from 14 to 21 days to allow more flexibility for
              participants. Change made in first and second paragraphs. 
Section 
8.6
Visit 5 (Day 84+ 3 days) 
Added:    Following was added to encourage in-person visits and
               maintain equal treatment between the study arms: “To
              maintain equivalence with the those receiving eptinezuamab
              and Botox it is preferable that this visit occur in person for
               those receiving the subcutaneous anti-CGRP as well,
               however, it is acceptable to conduct this visit via telephone
             or videoconference.”  
Section 
8.10
Safety Follow-up Visit
Deleted: Removed reference to adverse drug reaction (ADR) as all
             adverse events will be recorded.
Section 
9.3.2
Adverse Drug Reactions
Deleted: Entire section removed since all adverse events will be
              collected
Section 
10
Adverse Events and 
Adverse Drug Reactions
Updated: Minor changes made to section to make it consistent with
              interventional study SOP. 
Section 
10.1.1
Adverse Event Definitions
Deleted: Removed definition of adverse drug reactions
Added:    Added definition of “Suspected unexpected serious adverse
               reaction” (SUSAR) consistent with interventional study
              SOP
Section 
10.2
Pregnancy 
Added:    Added language to third paragraph to address data collection
               for pregnant persons who do not choose to enroll in the
              Lundbeck data collection. 
Section 
10.5
Treatment and Follow-up of 
Adverse Events
Updated: Corrected name of department receiving reports.
Section 
10.6
Compilation of Safety 
Information
Deleted:  No longer required as all adverse events will be collected

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1
Introduction
Background
1.1.1
Overview
Vyepti® (eptinezumab-jjmr) is a humanized immunoglobulin G1 (IgG1) monoclonal 
antibody (mAb) that binds to the calcitonin gene-related peptide (CGRP) ligand and blocks its 
binding to the α and β-CGRP receptors.  It is indicated for the prevention of migraine in 
adults.1 While the mechanism by which eptinezumab exerts its clinical effect is unknown, it is 
characterized by inhibition of nociceptive signaling, CGRP-mediated neurogenic 
inflammation and vasodilation.2
It is estimated that the prevalence of self-reported migraine or severe  headache in the United 
States (US) among adults is 15.3% (95% confidence interval [CI] 14.75-15.85).3 The 
cumulative lifetime incidence of migraine was estimated to be 43% in women and 18% in 
men in a self-reported survey of 120,000 US households.4 In the US, it is estimated that there 
are 36 million people with migraine.5 Based on 2013 Medical Expenditure Panel Survey 
(MEPS) data, the US prevalence of chronic migraine (CM), defined as headache occurring 
≥15 days/month for 3 months with migraine features on ≥8 days/month, is estimated at 1.8% 
of the population or 4.2 million adults.6,7
1.1.2
Clinical Data
The efficacy and safety of eptinezumab was evaluated as a preventive treatment of migraine 
in two phase III, randomized, double-blind, placebo-controlled six-month studies: 
PROMISE-1 which enrolled patients with episodic migraine (EM), and PROMISE-2 which 
enrolled patients with CM.8,9
In PROMISE-1, 888 adults with frequent EM (baseline average of approximately 8.6 mean 
migraine days/month) were randomized and treated with eptinezumab 30 mg, 100 mg, or 
300 mg or placebo intravenously (IV) every three months for two doses. The primary study 
endpoint was mean change from baseline in monthly migraine days (MMDs) over weeks 1-12 
following the first infusion. Results for eptinezumab 100 mg (-3.9) and 300 mg (-4.3) 
demonstrated a statistically significant reduction in mean MMDs from baseline (p=0.1082 
and p=0.0001, respectively) vs. placebo (-3.2).8 In PROMISE-2, 1,072 adults with CM were 
randomized and treated with eptinezumab 100 or 300 mg or placebo IV every three months 
for two doses. The primary study endpoint was mean change from baseline in MMDs over 
weeks 1-12 following the first infusion. Results for eptinezumab 100 mg and 300 mg 
demonstrated a statistically significant reduction in mean MMDs from baseline (-7.7 and -8.2 
respectively) vs. placebo (-5.6) over weeks 1-12 (p<0.0001 both doses).9 Eptinezumab was 
found to reduce the prevalence of episodic and chronic migraine in weeks 1 - 24 of treatment 
(two infusions) in PROMISE-1 and PROMISE-2.10

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Rationale for the Study
There are three other preventive migraine medications in the same class as eptinezumab [i.e., 
anti-CGRP monoclonal antibodies (mAbs)] and they include: erenumab, fremanezumab and 
galcanezumab. All three of these medications are approved for the prevention of 
migraine.11,12,13 A key point of difference is that the other three anti-CGRP mAbs are 
subcutaneous injectables. Another important therapy option for migraine prevention is 
onabotulinumtoxinA (Botox). However, Botox is approved for the prevention of migraine in 
patients with CM only.14 Botox is an intramuscular injection and is often considered at the 
same point in the treatment algorithm as anti-CGRP mAbs for patients who require more 
advanced care for migraine relief.15    
While there is strong scientific evidence of the efficacy of eptinezumab versus placebo in 
randomized controlled trials, there is limited understanding of how eptinezumab compares to 
other anti-CGRP mAbs or Botox on migraine prevention in real-world settings. Therefore, we 
propose an exploratory, six-month, prospective, randomized, cohort study to evaluate the 
“Early Value of Eptinezumab in the Community (EVEC).” This exploratory study will 
provide important learnings to help direct future studies to examine how eptinezumab 
compares to other advanced preventive medications in a real-world community setting. 
2
Objectives
This exploratory study has multiple objectives within the overall aim to examine how 
eptinezumab compares to other advanced preventive medications in a real-world community 
setting. These objectives include exploring the comparative effectiveness on patient reported 
outcomes (PROs) including and healthcare resource utilization (HRU). In addition, we will 
assess participant preferences for shared decision making, participant satisfaction with their 
treatment and confidence in managing their own health. Specifically, the objectives of EVEC 
include:
1.
Patient-identified most bothersome symptom (PI-MBS): This will be measured on a 
daily basis using the PI-MBS. Participant will select the symptom that they find most 
impairs her or him at the time of reporting and rate the severity of that symptom. The 
difference between randomization groups evaluated at 4, 12 and 24 weeks following 
randomization.
2. Good day/Bad Day scale: The participant will report the number of "good days" and 
"bad days" they had in the previous week on a weekly basis using the Good Day/Bad Day 
scale. The difference between randomization groups evaluated at 4, 12, and 24 weeks.
3. EuroQol 5-Dimension, 5-Level Quality of life Scale (EQ-5D-5L): The participant will 
complete the EQ-5D questionnaire on a weekly basis to indicate their preference for their 
current health state. The difference between randomization groups evaluated at 4, 12, and 
24 weeks
4. Health resource utilization: The participant will report their use of health services and 
medications on a daily basis using the smartphone app. The difference over time between 
the randomization groups will be evaluated at 4, 12, and 24 weeks.

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5. 6-item Headache Impact Test (HIT-6): The participant will report the impact of 
headache on their quality of life using the six-item HIT-6 scale. This will be done each 
month. The difference in change over time between randomization groups will be 
evaluated at 4, 12, and 24 weeks. 
6. Migraine Disability Assessment (MIDAS): The participant’s perception of their degree 
of disability will be evaluated by the MIDAS scale. This will be measured quarterly. The 
difference in change over time between randomization groups will be evaluated at 12 and 
24 weeks.
7. Treatment Satisfaction Questionnaire for Medication (TSQM): The participants 
reported satisfaction with treatment will be evaluated at the study closeout visit (i.e., visit 
#9). This will be compared between randomization groups at week 24
8. Medication Switching: The frequency of switching of migraine preventive medication 
from the medication administered at baseline will be compared between the randomization
groups from baseline to week 24.
Additional Outcomes (not between group comparisons)
1.
9-item Shared Decision-Making Questionnaire (SDM-Q-9):  The participant will 
report their satisfaction with shared decision-making using SDM-Q-9 following 
education on treatment options. This will be evaluated at screening and week 24. 
2. SURE Scale:  The participant will report their readiness to decide or determine whether 
their comfort with their treatment decision using the SURE scale. This will be evaluated at 
screening. 
3. 10-item Patient Activation Measure (PAM-10): The participant will report their 
knowledge, skills, and confidence to manage his or her health condition via the PAM-10. 
This will be evaluated at screening and weeks 12 and 24. 
4. Infusion Satisfaction Survey (ISS):  Participants initiating therapy on eptinezumab will 
describe the satisfaction with care with the ISS at baseline and week 12
The impact of mediating factors including monthly migraine days, early prevention and 
perceived stress on these outcomes will be evaluated.
3
Study Design
Overview of the Study Design
This study has been designed in accordance with the Declaration of Helsinki.16
This is an exploratory, prospective, randomized, pragmatic, open-label cohort study of 
200 participants receiving preventive treatment for EM or CM headache in the US.
Participants must have a history of > 8 migraine days in two of the past three months prior to 
enrollment and have documented failure to at least two previous oral preventive treatments 
per the American Headache Society (AHS) Consensus Statement (see Appendix II). 

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This study will be conducted in compliance with the protocol, Good Clinical Practice,17 and 
applicable regulatory requirements.
Participants will be recruited from sites that are capable of administering all therapies within 
the study in an outpatient setting.
After giving consent, participants will be classified as living with either EM or CM per 
ICHD-3 guidelines (see Table 1) based upon their medical history. Within these strata, the 
participants living with EM will be randomized to eptinezumab or SC CGRP (i.e., erenumab, 
fremanezumab or galcanezumab) in a 1:1 manner. Those experiencing CM will be 
randomized to eptinezumab, SC CGRP, or Botox in 3:2:1 manner.  Participants randomized to 
the SC CGRP injectable arm will be free to select treatment with any anti-CGRP injectable of 
their choice (i.e., erenumab, fremanezumab or galcanezumab). Please see Figure 1 for further 
details on the randomization design. 
Figure 1: Randomization Design
Participants will be followed prospectively for 24 weeks; a follow-up phone call will be made 
to each participant 8 weeks after study completion at the End of Treatment/Early Termination 
Visit. At Screening, all participants will be trained to use an eDiary (as a smartphone 
application) that will prompt participants to report their headache status on a daily basis, any 
related symptoms and any use of acute migraine medications. In addition, the eDiary will also 
prompt participants three times each week to report any interactions with the healthcare 
system (e.g., office visits, emergency room visits/urgent care visits, hospitalizations, 

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prescription medication, etc.). The site staff will also follow-up with participants at each study
visit to record additional details of HRU recorded in the eDiary, record HRU not reported in 
the eDiary, and record reasons for any changes in prescription or over-the-counter (OTC)
medications. QOL data and HRU data will be collected from participants via the smartphone 
application (app) and from the site staff via the EDC.  QOL assessments include the EQ-5D-
5L, HIT-6, Good Day/Bad Day scale and MIDAS. Participants will complete the EQ-5D-5L 
and Good Day/Bad Day scale on a weekly basis, the HIT-6 monthly, and the MIDAS every 
3 months via the eDiary. 
Participant preferences in making a treatment selection will be measured using the SDM-Q-9 
(at Screening and Week 24). Participant confidence in the treatment selection they made will 
be measured via the SURE test (at the Screening Visit only). Participants’ knowledge, skill 
and confidence in managing their own health will be assessed at screening, week 12 and week 
24 via the PAM-10 instrument. Participants’ satisfaction with their treatment experience will 
be assessed at week 24 via the TSQM. The SDM-Q-9, SURE test, PAM, and TSQM will be 
completed electronically.
For participants on eptinezumab, satisfaction with their infusion experience will be assessed 
via the Infusion Satisfaction Survey after each infusion (at Visit 2 and Visit 5) using a paper 
questionnaire.  
Rationale for the Study Design
EVEC is an exploratory, prospective, randomized, pragmatic, open-label study. This design 
allows for the collection of real-world data to better understand how eptinezumab compares to
other advanced preventives for prevention of migraines. 
3.2.1
Study Design Justification
Justification for two treatment groups
Eptinezumab is the fifth treatment option made available to people living with migraine for 
prevention of migraine attacks. As such the decision that insurers and prescribers must make 
is, “What benefit does this new treatment create over those options currently available?” In 
particular, payers must consider whether to add eptinezumab to their formulary. Thus, 
whether eptinezumab improves efficacy over the basket of available treatments is the key 
question, rather than whether it is superior to a single treatment. 
Justification for 6-month observation period
It is known that patients experience an early onset of efficacy with eptinezumab, and pooled 
analyses with other advanced preventives indicate that this early onset provides a comparative 
advantage to eptinezumab. However, less is known regarding the sustainability of this 
advantage. The durability of effect is a key element in the decision making of payers, thus 
6 months is considered the minimum relevant period of observation. 

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Justification for an open-label study
EVEC is intended to be a real-world evidence study to answer the question for patients, 
prescribers and payers seeking to know the comparative effectiveness of eptinezumab in 
actual clinical practice. In the real-world, patients and their professional caregivers 
(physicians and staff) know what medication the patient receives; therefore, the same 
principal applies here. In addition, masking participants to treatment assignment in this study 
would require that every participant receive at least two of the following: 1) monthly sham 
injection; 2) 30 in-office sham injections in their head and face quarterly; or 3) a quarterly 
sham infusion. While this may reflect an internally valid study design, it is far from a 
real-world clinical experience. 
Justification for use of an active comparator/no placebo
As noted above, this is a real-world study to evaluate the comparative effectiveness of 
eptinezumab against other advanced preventives for migraine. The justification for 
comparison to a “market basket” of current treatments is noted above in the “Justification for 
two treatment groups.” We note here that we consider only an active comparator and no 
placebo because in a real-world setting no patient would receive a placebo. So only active 
comparators are considered.
Additional Study Rationale and Considerations
Study Population
Most payers in the US, as well as AHS treatment guidelines, require failure of two generic 
oral preventive medications before initiating treatment with an advanced preventive. 
Therefore, this is the target population for this study. While many payers require failure of at 
least one advanced preventive therapy before initiation of eptinezumab, this is due to 
economic, not clinical, considerations. Therefore, a purpose of EVEC is to assist payers in 
understanding the economic and clinical cost, if any, to patients and society of these 
decisions. In addition, we are limiting the sample to people experiencing at least 8 migraine 
days per month as these patients (i.e., high-frequency EM and CM patients) are those most 
likely to be referred for advanced preventive therapy. 
Selection of doses
Dosing of all medications will be consistent with each product’s FDA approved label. 
Treating physicians and their patients might use any dosage consistent with labelling and 
good clinical practice. 
Primary objective
This is a pilot study, as such, there is no primary objective. All objectives are exploratory. 

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4
Ethics
Ethical Rationale
EVEC will provide patients, prescribers and payers important information regarding the 
comparative effectiveness of the studied treatments for migraine prevention to support 
decision making by these stakeholders. Information comparing the effectiveness of these 
treatments in a real-world setting is not currently available from any scientific source. 
Randomization to the various treatments included in the study is justified due to the equipoise 
that is created by this lack of information.  
The participant will be fully informed about the study including the risks and benefit of 
his/her participation in the study.
The participant may withdraw from the study at any time, for any reason, specified or 
unspecified, and without penalty or loss of benefits to which the participant is otherwise
entitled. 
In accordance with Good Clinical Practice,17 qualified medical personnel at Lundbeck will 
be readily available to advise on study-related medical questions. Safety data will be reviewed 
regularly by Lundbeck’s U.S. Pharmacovigilance department to ensure that prompt action is 
taken, if needed.
In accordance with Good Clinical Practice,17 the investigator will be responsible for all 
study-related medical decisions.
Informed Consent
No study-related procedures, including any screening procedures, may be performed before 
the investigator has obtained written informed consent from the participant.
Changing (for example, discontinuing or down-tapering) a participant’s concomitant 
medications prior to the Screening Visit to ensure that the participant meets the selection 
criteria is a study-related activity and must not occur before the Informed Consent Form has 
been signed.
It is the responsibility of the investigator or person designated by the investigator to obtain
written informed consent from the participant.  The informed consent process may be 
delegated, however, the requirements for the delegates must be documented prior to the start 
of the study.  National laws must always be adhered to when allowing potential delegation.  
Any delegation must be documented in the site delegation log.
The investigator must identify vulnerable participants, that is, participants whose willingness 
to participate in this study might be unduly influenced by the expectation, regardless of 
whether it is justified, of benefits associated with participation, or of a retaliatory response 

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from senior members of a hierarchy in case of refusal to participate. Participants thus 
identified must be excluded from participation in the study.
Prior to obtaining written informed consent, the investigator or a designee must explain to the 
participants the aims and methods of the study and any reasonably expected benefits and 
foreseeable risks or inconveniences to the patients.
The participants must be informed:

that their participation in the study is voluntary and that they are free to withdraw 
from\ the study at any time without justifying their decision

of their right to request a copy of their personal data from the study via the 
investigator

of the possibility of withdrawing consent (see section 8.9) of their right to receive 
information about the study results from the investigator on the patients’ own 
initiative; the results will be available approximately 1 year after the end of the study
The participants must be informed that persons authorized by Lundbeck and authorized 
personnel from certain authorities (domestic, foreign, data protection agencies, or institutional 
review boards [IRBs]) may view their medical records. The participants must also be 
informed that de-personalized copies of parts of their medical records may be requested by 
authorized personnel from certain authorities (domestic, foreign, data protection agencies, or 
IRBs) for verification of study procedures and/or data. The confidentiality of the patients will 
in all cases be respected. The participants must be given ample time and opportunity to 
enquire about details of the study prior to deciding whether to participate in the study.
It is the responsibility of the investigator to ensure that all questions about the study are 
answered to the satisfaction of the participants. Prior to allowing a participant to participate in 
the study, an Informed Consent Form must be signed and dated by the participant and signed
and dated by the investigator or a designee on the same day. The participants must be given a 
copy of the signed Informed Consent Form.
Personal Data Protection
The data collected in this study will be processed in accordance with the specifications 
outlined in the Danish Data Protection Act and the European Union legislation18 to ensure that 
requirements regarding personal data protection are met. If an external organization will 
process data on behalf of Lundbeck, a contractual procedure will be signed between
Lundbeck or delegate and the external organization to ensure compliance with the 
above--mentioned legislation.
Institutional Review Board
This study will be conducted only after Lundbeck has received confirmation that the 
regulatory authorities have approved or confirmed notification of the study and that written 
approval of the protocol has been granted by the appropriate IRB.

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The investigator must not allow any participants to participate in the study before receiving 
confirmation from Lundbeck or the CRO that the required approvals and/or notifications have 
been received. Permission for an investigator to start enrollment will be provided to the 
investigator in writing from Lundbeck or the CRO.
The IRB must be informed when specific types of protocol amendments have been made and 
written approval must be obtained before implementation of each amendment, if required by 
local law.
If applicable, interim reports on the study and reviews of its progress will be submitted to the 
IRB by the investigator at intervals stipulated in its guidelines.
5
Study Population
Number of Participants
Two hundred participants are planned for enrollment into the trial.
Adult participants with at least 8 or more migraine days per month, in two of the last three 
months prior to enrollment, who are being seen at participating sites and who meet the other 
inclusion and exclusion criteria will be invited to participate in the study. 
The informed consent will include an explanation of the following:
1.
Prior to randomization, participants will complete a decision exercise using a decision 
guide created to inform participants on treatment options for migraine prevention. Then 
participants will complete the SDM-Q-9 to indicate what they think would be their 
preferred migraine prevention treatment (see Appendix IV), followed by completion of
the SURE Test (see Appendix VI).
2.
The consent form will inform the patient that the treatment preference indicated after the 
review of the decision guide will not impact the treatment to which they are randomized.  
Additionally, the consent form will clearly indicate that should the patient not agree to 
initiate treatment with the medication to which they were randomized, their participation 
in the study will be discontinued. 
3.
Regardless of the treatment the participant is randomized to, the cost of the study 
medication (i.e., eptinezumab, Botox, erenumab, fremanezumab or galcanezumab) and 
administration will be covered by Lundbeck for the six-month duration of the trial.  
Participant Recruitment
Participants will be competitively recruited from approximately 10 sites in the US that offer 
all therapeutic options in the study.  
The investigators will be notified immediately when the recruitment period comes to an end.

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Selection Criteria
Participant selection is based on the inclusion and exclusion criteria listed below.
Participants who meet each of the inclusion criteria and none of the exclusion criteria at the 
Screening Visit and prior to first medication dose at Baseline (Visit 2) are eligible to 
participate in this study.
Inclusion Criteria
1.
The participant is able to read and understand the Informed Consent Form.
2.
The participant has signed the Informed Consent Form.
3.
The participant is aged ≥18 years of age.  
4.
Have a diagnosis of migraine per IHS ICHD-3 guidelines at least 12 months prior to 
screening.
5.
Have a history of ≥ 8 migraine days/month in two of the previous three months as 
confirmed by the treating physician through medical records.
6.
Have a history of failure of at least 2 previous oral migraine preventive treatments as 
defined in the AHS Consensus Statement (see Appendix II).15
7.
Be able to understand the clinical description of treatment options and have the capability 
to participate fully in making their treatment preferences known.
8.
Be willing to accept randomization to any of the possible study medications if allocated 
to that treatment arm. 
9.
Have no restriction in venous access that would restrict the ability to receive infusion 
treatment.
10. Be willing and capable of completing daily reports and other participant reported 
outcome measures using a smartphone-based application. 
11. Have their own smartphone or tablet and agree to allow the study application to be 
downloaded to it.
12. Agree to not post any personal medical data or information related to the study on any 
website or social media site (e.g., Facebook, Twitter) during the study. 
13. Be able to read, understand and complete all required forms and questionnaires in 
English.
Exclusion Criteria
1.
The participant has previously been enrolled in this study.
2.
The participant is a member of the study personnel or of their immediate families or is a 
subordinate (or immediate family member of a subordinate), to any of the study 
personnel.
3.
The participant has a history of severe drug allergy or hypersensitivity, or known 
hypersensitivity or intolerance to either eptinezumab, erenumab, fremanezumab, 
galcanezumab or their excipients.
4.
The participant has previous history of use of any of the study drugs (i.e. eptinezumab, 
Botox, erenumab, fremanezumab or galcanezumab). Participants who have used oral 

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CGRP inhibitors atogepant or rimegepant for prevention are also excluded. Note that 
only previous Botox use for treatment of migraine is exclusionary. Prior use of Botox for 
cosmetic purposes is allowed. Participants with a history of acute use of rimegepant or 
ubrogepant (but not for prevention) are permitted to enroll. 
5.
The participant has a diagnosis of CM and has hypersensitivity to botulinum toxin 
preparation or to any of the components in the formulation.
6.
The participant has used opioids or butalbital-containing products greater than 4 days per 
month in the last month.
7.
The participant is pregnant, <6 months post-partum, or breastfeeding.
8.
The participant has a disease or takes medication that could, in the investigator’s opinion, 
interfere with the assessments of safety, tolerability, or efficacy, or interfere with the 
conduct or interpretation of the study.
9.
The participant is, in the investigator’s opinion, unlikely to comply with the protocol or is 
unsuitable for any reason.
Participants with Medication Overuse Headache
Participants with a dual diagnosis of CM along with medication overuse headache (MOH) 
attributable to regular acute medication overuse (e.g. triptans, ergotamine, or combination 
analgesics greater than 10 days per month) are eligible for enrollment in the study. 
Participants with CM and MOH who use opioids or butalbital-containing products greater 
than 4 days per month will be excluded. The participant’s clinician will determine if 
participants meet the criteria for MOH. The ICHD-3 criteria19 (listed below) and MOH 
checklist (see Appendix XVII) will be provided to the clinical sites for them to make their 
assessments. The participant’s MOH status will be noted in the CRF.
ICHD-3 criteria for MOH:

Headache occurring on ≥15 days/month in a participant with a pre-existing headache 
disorder

Regular overuse for >3 months of one or more drugs that can be taken for acute and/or 
symptomatic treatment of headache 

Not better accounted for by another ICHD-3 diagnosis.
Withdrawal Criteria
Information on participants who withdraw from the study will be collected in the withdrawal 
section of the CRF.
A participant must be withdrawn from the study if:

the participant withdraws their consent (defined as a participant who explicitly takes 
back their consent); section 8.9 states how the patient’s data will be handled

the participant is lost to follow-up (defined as a participant who fails to comply with 
scheduled study visits or contact, who has not actively withdrawn from the study, and 

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for whom no alternative contact information is available [this implies that at least two 
documented attempts have been made to contact the patient])

the investigator considers it, for safety and/or study compliance reasons, in the best
interests of the participant that they be withdrawn from treatment

All participants will be permitted to withdraw at their choice or upon advice of their 
treating physician. Information collected from the participant prior to withdrawal will 
remain in the study data set.
No participant will be withdrawn from the study due to non-compliance with treatment. As 
this is a pragmatic real-world study, the failure to comply with treatment is considered a 
real-world outcome. However, an investigator may withdraw a participant from the study 
based upon their medical judgement if they deem continued involvement in the study is 
detrimental to the participant’s welfare.
Products purchased with study-specific vouchers cannot be used for an off-label indication. 
Participants must meet the criteria for CM at baseline in order to be randomized to 
onabotulinumtoxinA (Botox®). Participants who do not comply with this requirement will be 
withdrawn from the study. 
Participants who become pregnant will be withdrawn from the study and counselled to enroll 
in the Lundbeck pregnancy registry. The Lundbeck pregnancy registry is a prospective, 
observational study in the United States that will be initiated prior to the end of this trial.   
Participants who withdraw will not be replaced.
6
Investigational Medicinal Products
Treatment Regimen
Participants will be randomized to their initial migraine prevention medication. Participants 
must receive the first dose of their allocated medication at the Baseline Visit (Visit 2). 
However, during the remainder of the study observation period, treatment choices will be 
based upon the treating clinician’s judgement and the participant’s preference (See Section 
6.3.1 below for more details). No additional direction will be given by the CRO or the study 
sponsor.  However, any participant wishing or needing to switch to an alternate medication 
outside of the study-specific guidelines for doing so, as described in Section 6.3.1, will need 
to be withdrawn from the study.  Participants switching to an advanced preventive medication 
other than their initially assigned treatment in accordance with Section 6.3.1 will be permitted 
to remain in the study. There will be no restrictions on the use of other migraine related 
medications during the study period for acute or preventive treatment if those medications are 
prescribed by the participant’s treating physician. However, products purchased with study-
specific vouchers cannot be used for an off-label indication. Participants must meet the 
criteria for CM at baseline in order to be randomized to onabotulinumtoxinA (Botox®). Any 
changes in migraine preventive medications, prescribed or OTC, will be reported in the 
smartphone application by the participant. The reason for any treatment change will be 

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investigated by the study coordinator and recorded in the CRF. Any adverse events identified 
as the cause of a medication switch (e.g. lack of efficacy) will be reported according to 
Section 10.3.
IMPs, Formulations, and Strengths
IMPs for this trial will not be supplied directly by Lundbeck. Medications for this study will 
be obtained using pharmacy voucher cards. These cards will allow for study-specific 
advanced preventive medications to be obtained from the local pharmacy without cost; the 
voucher cards will not be used for any other medications including acute migraine 
treatments. Study-specific voucher cards will be used to cover the cost of any study-specific 
advanced preventive medications, provided it is used per the FDA approved label.
After randomization is complete, study site personnel will need to obtain the first dose of 
medication to be administered to the participant during the Baseline Visit (Visit 2).
Participants who will be using subcutaneous anti-CGRP injectables will be instructed on how 
to use the voucher card at the retail pharmacy of their choice to cover the cost of their anti-
CGRP medication throughout the study. For participants assigned to Botox or eptinezumab, 
study staff will need to obtain these medications using the voucher cards prior to Visit 5 to 
ensure the medication is available for administration during the visit. 
The IMPs to be used in this study are: 
Eptinezumab – Participants allocated to the eptinezumab arm will begin treatment using 
eptinezumab which is available as a 100 mg/mL or 300 mg/mL solution, as per the product 
label. The first dose will be given at baseline during visit 2 and the second dose will be given 
during visit 5 at week 12 (see Panel 4). 
OnabotulinumtoxinA – Participants allocated to Botox will be given the first dose at 
baseline during visit 2 and the second dose will be given during visit 5 at week 12 (see Panel 
4). Botox will be given as per the product label for the treatment of migraine.
Erenumab – Participants will be trained to self-administer the first dose at baseline during 
visit 2, and then will self-administer doses 2-6 monthly as per the product label. Participants 
will be given a voucher card to obtain follow-up doses of this medication for the next 
5 months. Erenumab will be given as per the product label for either the 70 mg or 140 mg 
doses. Note that this protocol defines the term, “monthly” as every 28 days.
Fremanezumab – Participants will be trained to self-administer the first dose at baseline 
during visit 2. Following the baseline dose, the participant will either administer 225 mg 
monthly for months 2 – 6 or administer 675 mg 3 months after the baseline dose (quarterly). 
Participants will be given a voucher card to obtain follow-up doses of this medication either 
for the next 5 months or for 1 additional refill 3 months post-baseline. Fremanezumab will be 
given as per the product label. Note that this protocol defines the term, “monthly” as every 
28 days, and “quarterly,” as every 84 days.

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Galcanezumab – Participants will be trained to self-administer the first dose at baseline 
during visit 2. At the advisement of the provider, participants may receive a 240 mg loaded 
dose at baseline followed by monthly doses of 120 mg for months 2 - 6. Participants will be 
given a voucher card to obtain follow-up doses of this medication for the next 5 months. 
Galcanezumab will be given as per the product label. Note that this protocol defines the term, 
“monthly” as every 28 days.
Method of Assigning Participants to Treatment
Each participant will be assigned a unique study ID by the EDC system, and that number will 
be used to identify that patient throughout the study.  Although assignment of treatments to 
patients will be randomized, all treatments will be open-label; there will be no blinding to 
treatment received.  The randomization scheme for assigning participants to one of the 
treatment arms is illustrated in Figure 1.
6.3.1
Change in Treatment
Participants may switch to an alternative preventive treatment in either treatment cohort after 
they have received their initial treatment with the medication to which they were randomized.
Such a decision may be made upon recommendation of their treating clinician or participant 
preference. The site staff will investigate the reason for treatment change with both the 
treating clinician and participant. The use of medications, including gepants, for relief of 
acute migraine symptoms in either treatment arm is permitted and will be recorded in the
smartphone application.  
For all participants, the treatment to which they are initially assigned must be the treatment 
given at Baseline (Visit 2). Switching of medication is not permitted prior to administration of 
the first dose of medication.  For participants who receive eptinezumab or Botox as their 
initial treatment and elect to switch to a subcutaneous anti-CGRP injectable (i.e., erenumab, 
fremanezumab or galcanezumab), they may not do so until week 12 (visit 5), after the 
treatment window for their initial treatment has ended.  Participants who receive eptinezumab 
or Botox at week 12 (Visit 5) will not be permitted to switch their treatment for the remaining 
duration of the study.
Participants initially treated with a subcutaneous anti-CGRP injectable may only switch to 
eptinezumab, or Botox at week 12 (visit 5) due to the design of the study.   However, these 
participants may switch to another of the subcutaneous anti-CGRP injectable medications at 
any time, once the treatment window for their previous injection has ended.  
No changes in treatment will be permitted after Visit 7.
All changes in treatment are to be documented in the eCRF.
If a participant wishes to switch their medication, but does not meet the specified criteria to do 
so, as stated above, they should be withdrawn from the study and be treated as per standard of 
care by their physician.

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IMP Accountability
Treatment type, along with the date(s) on which treatments are administered, will be recorded 
in the eCRF.
The investigator and the pharmacist (if applicable) must agree to only dispense study-specific 
IMP to participants enrolled in the study.  The investigator or the pharmacist (if applicable) 
must maintain an adequate record of the receipt and distribution of the study-specific IMPs
that they obtain for study participants (see Section 6.2). This record must be available for 
inspection at any time.
7
Concomitant Medication
Concomitant medication is any medication other than the IMPs that are taken during the study 
from Screening up until the participant completes the study at Visit 8.  This includes all 
prescription and over-the-counter medications, as well as vitamins and supplements.  In 
addition, if a patient receives a COVID-19 vaccination while enrolled in the trial, each dose of 
the vaccine received should be entered as a concomitant medication.
Details of all concomitant medication being taken at the time of the Screening Visit must be 
recorded in the eCRF at the first visit. Any changes (including reason for changes) in 
concomitant medication must be recorded at each subsequent visit.
For any concomitant medication for which the dose was increased due to worsening of a 
concurrent disorder after enrollment in the study, the worsening of the disorder must be 
recorded as an adverse event and the medication with the increase dosage should be reported 
as a new concomitant medication.
For any concomitant medication initiated due to a new disorder after enrollment in the study, 
the disorder must be recorded as an adverse event.
8
Study Visit Plan
Overview
An overview of the procedures and assessments to be conducted during the study and their 
timing is presented in Panel 1, Panel 2, Panel 3, and Panel 4.  Details are in section 9.
After completing or withdrawing from the study, the patient must be treated in accordance 
with usual clinical practice.

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Panel 4: Assessments Administered via Site staff
Study procedures
Screening Visit
Baseline 
Visit
Monthly 
Follow-Up
Monthly
Follow-Up
Monthly
Follow-Up
End of 
Treatment / 
Early 
Termination
Safety Follow-Up
Day 0
Days 28 & 56 
(+/- 3 days)
Day 84 (+/- 3 
days)
Days 112 & 140(+/- 3 
days)
Day 168 (+ 7 
days)
56 days (+/- 5 days) after 
End of Treatment / Early 
Termination
Visit 1
Visit 2
Visits 3-4 (f)
Visit 5(g)
Visits 6-7 (f)
Visit 8 (f)
Visit 9
Written informed consent

Review inclusion and exclusion 
criteria


Demography

Medical history inclusive of 
migraine, psychiatric, cardiac and family 
medical history

Vital signs

Concomitant medications and use of 
tobacco products






Adverse events (continuous 
monitoring)(a) 







Adverse drug reactions (continuous 
monitoring)





Administration of Decision Guide 


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Study procedures
Screening 
Visit
Baseline 
Visit
Monthly 
Follow-Up
Monthly
Follow-Up
Monthly
Follow-Up
End of Treatment 
/ Early 
Termination
Safety Follow-Up
Day 0
Days 28 & 56 
(+/- 3 days)
Day 84 (+/- 3 
days)
Days 112 & 
140(+/- 3 days)
Day 168 (+ 7 days)
56 days (+/- 5 days) 
after End of 
Treatment / Early 
Termination
Visit 1
Visit 2
Visits 3-4 (f)
Visit 5(g)
Visits 6-7 (f)
Visit 8 (f)
Visit 9
Randomization to treatment arm
(d)  
Participant training on eDiary

Participant training on CGRP 
administration (b)

Administration of Treatment
(e)
(h)
Infusion Satisfaction Survey (c)


Provide instructions to obtain 
additional doses of CGRP (a)

Review eDiary use
  



Healthcare Resource Utilization





eDiary close out

(a) AE monitoring begins upon signing ICF 
(b) Only for participants in CGRP arm 
(c) Only for participants receiving eptinezumab treatment; completed using paper questionnaire
(d) will need to be performed by site after participant qualifies in order for site to be prepared for appropriate treatment at Visit 2
(e) eptinezumab infusion, Botox or CGRP
(f)Conducted via telephone or videoconference 
(g) Conducted on site only for participants receiving Eptinezumab infusion or Botox; conducted via telephone or videoconference for those in CGRP group
(h) Eptinezumab infusion or Botox, those receiving subcutaneous anti-CGRP medications are also encouraged to attend in person (see section 8.6 below). 

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Screening Visit (Visit 1)
Screening assessments are to be conducted within 21 days of the participant’s initial treatment 
at the Baseline Visit (Visit 2) to allow the investigator sufficient time to review the 
participant’s medical history and determine if the participant is eligible for study participation.
The Investigator, or qualified designee, will conduct the following procedures at this visit and 
record the data in the eCRF:

Conduct of Informed Consent procedures

Assignment of participant identification number (automatically assigned by EDC 
system)

Review of inclusion and exclusion criteria

Demography

Medical history

Includes migraine history, psychiatric history, cardiac history and family migraine
history

Vital signs

Concomitant medications and use of tobacco products

Review of AEs

Download smartphone app to participant’s phone or tablet

Participant training on use of eDiary

Administration of Decision Guide
Participants who provide consent and are confirmed by site study staff to be eligible will be 
provided with the following PROs at the time of screening for completion via their eDiary:

SDM-Q-9

SURE test

PAM-10
In addition, participants will complete the Daily Headache Status Report beginning with the 
screening visit.
Re-screening of patients who screen fail will be allowed.
Process for Randomization to Treatment Arms
Participants will be randomized to their respective treatment arms after determining eligibility 
to participate at the Screening Visit and prior to Baseline (Visit 2). Randomization will be 
completed in the EDC system. Participants with episodic migraine will be randomized to 
eptinezumab or SC CGRP (i.e. erenumab, fremanezumab or galcanezumab) in a 1:1 manner. 
Those experiencing chronic migraine will be randomized to eptinezumab, SC CGRP, or 
Botox in 3:2:1 manner.  Participants randomized to the SC CGRP injectable arm will be free 

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to select treatment with any anti-CGRP injectable of their choice (i.e. erenumab, 
fremanezumab or galcanezumab). Please see Figure 1 for further details on the randomization 
design. 
Baseline Visit (Visit 2)
This visit is to occur within 21 days of Visit 1.  Prior to the participant arriving for the 
Baseline Visit, the treatment arm for the participant will need to be determined, and the first 
dose for administration will need to be obtained. 
At the time of the Screening visit, the participant, with assistance from the site, will record the 
expected date of the Baseline visit within the app. This date can be modified, as needed, to 
accommodate rescheduled appointments within the allowable 21-day window from Screening 
to Baseline. On the day of Baseline, the app will notify the participant to complete their 
Baseline PROs. Prior to treating the participant, the site will confirm the completion of the 
Baseline PROs.  
On the day of the visit, the participant will complete the following assessments in their eDiary 
prior to initiation of treatment (see Panel 2): 

EQ-5D-5L 

PSS 

MIDAS 

HIT-6 

PI-MBS
The participant will also complete the Daily Headache Status Report in their eDiary on this 
date.  This may occur before or after the visit, depending on the time of the visit.
The Investigator, or qualified designee, will conduct the following procedures at this visit and 
record the data in the eCRF:

Review of inclusion and exclusion criteria (prior to treatment)

Review of AEs (prior to treatment)

Review of concomitant medications and tobacco use (prior to treatment)

Review of eDiary use

Review Healthcare Resource Utilization

Participant training on self-injections of subcutaneous anti-CGRP mAbs (for 
participants assigned to this treatment arm)

Administration of first treatment

Infusion Satisfaction Survey (post-treatment; for participants receiving eptinezumab 
only)

Review of ADRs (starting after treatment administration)

Provide instructions for how to obtain additional doses of subcutaneous anti-CGRP 
injectables to participant for future use (for participants assigned to this treatment arm)

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
Review participant instructions until next visit

Schedule next visit
Administration of the first treatment will consist of either the participant’s first treatment with 
eptinezumab or Botox or the participant’s first injection of a subcutaneous anti-CGRP mAb.  
For participants in the subcutaneous anti-CGRP arm, the first dose should be self-
administered by the participant under the supervision of the site staff.
Visits 3 & 4 (Days 28 & 56; +/- 3 days)
These visits will be conducted via telephone or videoconference. Both visits have a window 
of +/- 3 days.
The Investigator, or qualified designee, will conduct the following procedures at this visit and 
record the data in the eCRF:

Review of AEs and ADRs

Review of concomitant medications and tobacco use

Review of eDiary use

Review Healthcare Resource Utilization

Review participant instructions for next visit

Schedule next visit
Visit 5 (Day 84; +/- 3 days)
This visit will only be conducted on site for patients who need to receive their second 
treatment of eptinezumab or Botox.  To maintain equivalence with the those receiving 
eptinezuamab and Botox it is preferable that this visit occur in person for those receiving the 
subcutaneous anti-CGRP as well, however it is acceptable to conduct this visit via telephone 
or videoconference.  This visit has a window of +/-3 days.
The Investigator, or qualified designee, will conduct the following procedures at this visit and 
record the data in the eCRF:

Review of AEs and ADRs

Review of concomitant medications and tobacco use

Administration of treatment (second eptinezumab treatment OR second Botox 
treatment)

Infusion Satisfaction Survey (post-treatment; for participants receiving eptinezumab 
only)

Review Healthcare Resource Utilization

Review of eDiary use

Review participant instructions until next visit

Schedule next visit

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Visits 6 & 7 (Days 112 & 140; +/- 3 days)
These visits will be conducted via telephone or videoconference. Both visits have a window 
of +/- 3 days.
The Investigator, or qualified designee, will conduct the following procedures at this visit and 
record the data in the eCRF:

Review of AEs and ADRs

Review of concomitant medications and tobacco use

Review Healthcare Resource Utilization

Review of eDiary use

Review participant instructions for next visit

Schedule next visit
End of Treatment (Visit 8; Day 186 +7 days) / Early Termination
This visit will be conducted via telephone or videoconference. The End of Treatment visit has 
a window of + 7 days.
The Investigator, or qualified designee, will conduct the following procedures at this visit and 
record the data in the eCRF:

Review of AEs and ADRs

Review of concomitant medications and tobacco use

Review Healthcare Resource Utilization

Close out of eDiary

Schedule next visit
Withdrawal Visit
Participants who withdraw from the study prior to Visit 8 will be asked to complete an Early 
Termination Visit, if at all possible. The visit must be scheduled as soon as possible after 
withdrawal. All information collected at an Early Termination Visit s to be recorded in the 
Visit 8 forms of the eCRF.
In addition, all assessments normally scheduled to be completed by the participants at Visit 8 
in the eDiary (Panel 3) will be completed on the day of the Early Termination Visit.  In order 
for the PROs to be provided to the participant via the smartphone application on the day of the 
Early Termination Visit, site study staff will need to complete the End of Treatment form 
within the EDC system and select the reason for early termination. The completion of this 
form will notify the CRO to send the Early Termination PROs to the participant and 
discontinue any future notifications for PRO completion.

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No new information will be collected from participants who withdraw from the study, except 
information collected in relation to the scheduled Withdrawal Visit or needed for the follow-
up of adverse events (section 10.5).
The reason for withdrawal must be recorded in the eCRF.
For a participant who withdraws consent:

if the participant withdraws consent during a visit and then agrees to it being the final 
visit, the investigator will complete the visit as a Withdrawal Visit and all the data 
collected up to and including that visit will be used

if the participant withdraws consent during a telephone conversation, the investigator 
will ask the participant if they will attend a Withdrawal Visit. If the participant:
agrees to attend a Withdrawal Visit, all the data collected up to and including that visit 
will be used
refuses to attend an Early Termination Visit, the investigator should attempt to follow 
the participant’s safety and future treatment; any information collected will only be 
recorded in the patient’s medical records
If the participant explicitly requests that their data collected from the time of withdrawal of
consent onwards not be used, this will be respected.
Safety Follow-up Visit
A safety follow-up will be conducted to capture AEs that occur during the Safety Follow-up 
Period as well as to follow up on the outcome of adverse events ongoing at the end of the 
Treatment Period (at Visit 8 / Early Termination). This visit will be conducted via telephone 
or videoconference.  The Investigator, or qualified designee, will contact the participant 8 
weeks (56 days, +/- 5 days) after their final visit (Visit 8 or Early Termination Visit) to record 
any new AEs and to follow-up on any AEs that were ongoing at the end of their previous 
visit.  This visit is required for all participants who received at least one dose of any 
treatment; this visit is not required for participants who screen fail.
For adverse events that were ongoing at the end of the Treatment Period and that resolved 
during the Safety Follow-up Period, the stop date must be recorded. For non-serious adverse 
events still ongoing at the safety follow-up, the Ongoing Adverse Event checkbox on the 
Adverse Event Form must be ticked. SAEs must be followed until the event has recovered, 
stabilized, or recovered with sequelae.
End-of-Study Definition
The end of the study for an individual participant is defined as the last protocol-specified 
contact with that patient. The overall end of the study is defined as the last protocol-specified 
contact with the last patient ongoing in the study.

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9
Assessments
Screening and Baseline Procedures and Assessments
Demographics and Baseline Characteristics
The following participant characteristics will be collected by the investigator at the time of 
screening and entered into the eCRF:
Socio-demographic variables

Year of birth

Sex

Marital status

Race/ethnicity

Zip code

Highest educational level attained

Current employment status
Clinical variables

Number of migraine days in each of the past three months (note that this must be 
confirmed with the treating physician prior to enrollment)

Previous use of oral preventive medications

Migraine symptoms experienced in the seven days prior to enrollment

Migraine history (including age at time of first attack and classification of migraine as 
CM, EM, and MOH)

Migraine related medication history

Vital signs (height, weight, blood pressure, pulse, respiration)

All current medications being taken (including prescription, OTC, 
vitamins/supplements, vaccinations)

Medication allergies

Medical and psychiatric history

Cardiac history

Family medical history of migraines (parents and siblings)

Use of tobacco or vaping products, or any other nicotine product
9.1.1
Diagnostic Assessments
IHS ICHD-3 guidelines sections 1.1, 1.2 and 1.3 for Migraine or Chronic Migraine are the 
diagnostic criteria to be used when assessing participant eligibility (see Table 1). Fulfilment 
of criteria for EM or CM according to the inclusion criteria in this protocol will be confirmed 
by the investigator from the participant’s medical record.

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A migraine day for both chronic and episodic migraine is defined as any day with a headache 
that meets the chronic migraine definition as outlined in the IHS guidelines (section 1.3.1.1) 
for controlled trials of preventive treatment of chronic migraine in adults. This is defined as a 
day with a headache that lasts at least 4 hours; meets ICHD-3 criteria C and D for migraine 
without aura (1.1), B and C for migraine with aura (1.2), or ICHD-3 criteria for probable 
migraine (1.5); or a day with a headache of a minimum 30-minute duration that is 
successfully treated with a triptan, ergotamine, or other migraine-specific acute medication.
9.1.2
eDiary
The participants will be instructed to complete an eDiary daily from the Screening Visit until 
the End of Treatment/Early Termination Visit. The eDiary will be an application that 
participants can use on their smartphone or tablet.  The eDiary consists of applications and 
reports which will be used to derive the migraine and headache endpoints, and health related 
quality of life endpoints. At the Screening Visit, the participant must be assisted with the
provisioning and training of the eDiary. During the End of Treatment/Early Termination
Visit, eDiary close out will be performed. 
At the Screening Visit, the site staff will assist the participant in downloading the eDiary 
application to their smartphone or tablet.  Each participant will receive comprehensive 
training from site staff on the use of the eDiary. Site staff will also instruct participants on the 
requirement for timely and daily completion of the eDiary. The assessments to be completed 
by the participants using the eDiary are detailed in Panel 1, Panel 2 and Panel 3
9.1.3
Efficacy and Clinical Outcomes Assessments
All participant reported outcomes will be collected online using the eDiary unless specifically 
stated otherwise below.
The following participants-reported outcomes will be measured:

Daily headache status – to be reported as part of the participant’s daily report in the 
eDiary. This is how participant’s migraine days and data for the PI-MBS is also 
captured. The participant will receive a push notification from the eDiary on their 
smartphone or tablet asking them to answer a series of questions (see Panel 3 for 
details).

Patient-Identified Most Bothersome Symptom (PI-MBS) – The PI-MBS is a 
modified version of the Most Bothersome Symptom (MBS) tool that is commonly 
used in acute migraine prevention studies. In the traditional MBS, patients are asked to 
identify which symptom of their migraines is most bothersome to them from a list of: 
nausea/vomiting, photophobia or phonophobia. The PI-MBS is a modified version of 
this tool and does not restrict patients to select their most bothersome symptom from 
the aforementioned three categories. Instead, in the PI-MBS, patients are prompted to 
describe in their own words which symptom of their migraine is most bothersome to 
them. The PI-MBS data will be captured daily via the smartphone app when 
participants are prompted to report if they had a headache (see Appendix III). 

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
Decision guide – the research team at Lundbeck partnered with Northwestern 
University to create a decision guide that provides patients information on the 
treatment options being utilized in this study. Decision guides help people choose 
between two or more healthcare options based on what is most important to them. The 
participant will review the decision guide, as provided by the site staff, when receiving 
study information at the time of screening (Visit 1). After the participant has 
sufficiently reviewed the material the site staff will ask the participant what their 
choice for treatment is based on reading the decision guide. Once the decision has 
been documented, the participant will electronically complete the SDM-Q-9, followed 
by the SURE test, to determine if there is any decision conflict or regret with the 
participant’s decision. The informed consent will ensure participants are aware that 
they may be randomized to a treatment arm that is not in accordance with their 
treatment decision (see Appendix V). 

9-item Shared Decision-Making Questionnaire (SDM-Q-9) - The 
SDM-Q-9 measures the extent to which patients are involved in the process of 
decision-making from the perspective of the patient.  The questionnaire contains nine 
items, each describing one step of the SDM process.20 It was developed to assess the 
degree to which patients feel involved in the decision-making process. The items are 
scored from 0 to 5 on a six-point Likert scale ranging from ″completely disagree″ (0) 
to ″completely agree″ (5); (see Appendix IV).

The SURE test – the SURE test is a brief screening questionnaire the patient uses to 
assess their readiness and capacity to decide or to determine whether they are 
comfortable with their decision (see Appendix VI). 

The Patient Activation Measure (PAM-10) – The Patient Activation Measure 
evaluates the knowledge, skills, and confidence a patient has in managing his or her 
health conditions.21 In this study the 10-item Patient Activation Measure (PAM) tool 
will be utilized. PAM-10 uses a four-point Likert scale of agreement-disagreement to 
respond to each item. PAM is scored on a scale from 0 to 100 from which four levels 
of activation have been identified: Level 1 (0.0–47.0) low activation suggesting that 
the person does not yet understand their role in healthcare to Level 4 (72.5–100) 
indicating that the person is proactive and engaged in recommended health behaviors
and management of health conditions.22 (see Appendix VII). 

EuroQoL-5Dimension-5Level – The EQ-5D-5L is a utility elicitation instrument 
that asks participants five questions to capture their quality of life over the previous 
day. Each question captures a “dimension” of life (self-care, mobility, 
anxiety/depression, pain/discomfort, usual activities).  For each dimension, the 
participant is asked to respond on one of five levels of problems that they might have 
with the activities covered by the dimension ranging from “no problems” to “extreme 
problems/cannot do (see Appendix VIII).

Good Day/Bad Day Scale – The Good Day/Bad Day Scale measures patients’ global 
perception of the effect of symptoms on the life of people living with migraine by 
asking how many “good days” and “bad days” they had over the past week. The total
number of days reported is required to total 7 (see Appendix IX). 

Perceived Stress Scale (PSS) - The Perceived Stress Scale (PSS) is a classic stress 
assessment instrument. The tool, measures how different situations affect feelings and 

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perceived stress. The questions ask about feelings and thoughts during the last month. 
(see Appendix X).

Migraine Disability Assessment (MIDAS) – The MIDAS Questionnaire was 
developed to assess headache-related disability. It is a 5-item instrument which assigns 
a disability score to patients based on the number of days in the past 3 months that 
patients report activity limitations due to migraine23 (see Appendix XI).  

Infusion Satisfaction Survey – All participants receiving eptinezumab (regardless of 
initial treatment assignment) will complete a brief survey describing their satisfaction 
with the infusion experience after each infusion while on site using a paper 
questionnaire (see Appendix XII).

Treatment Satisfaction Questionnaire for Medication (TSQM) – All participants
will complete the TSQM at the end of the study (Visit 8 or Early Termination Visit) to 
measure their satisfaction with their medication (see Appendix XIII).

Headache Impact Test (HIT-6) – The HIT-6 was designed to provide a global 
measure of adverse headache impact.  This 6-item scale measures the adverse impact 
of headache on social functioning, role functioning, vitality, cognitive functioning and 
psychological distress, as well as the severity of headache pain24 (see Appendix XIV).
Healthcare Resource Utilization
All participants will be counselled at the time of enrollment to report any interaction with the 
healthcare system using the smartphone app (see Appendix XV). Participants will receive 
push notifications from the smartphone application on a periodic basis (3 times per week) to 
remind them of this requirement. Interactions to be reported include:

Physician office visits

Outpatient service use (i.e., lab visits, imaging, rehabilitation, etc.)

Outpatient surgery

Urgent care visits

Emergency room visits

Inpatient services

Changes in prescription drug use (other than for migraine care; new medication or 
medication change)
As part of the monthly study visits the study coordinator will review the participant’s reported 
utilization using the Healthcare Resource Utilization Follow-Up Questionnaire (see Appendix 
XVI). They will confirm with the participant each entry made into the smartphone application
and, in doing so, will obtain additional detail regarding each interaction. 
The coordinator should ask if there were any additional healthcare interactions that were not 
reported. If so, they should note those in the CRF and, for each, ask the questions provided in 
the Healthcare Resource Utilization Follow-Up Questionnaire (see Appendix XVI).
If any AEs or SAEs are noted as a result of this review by the site staff, those should be 
documented appropriately in the patient chart and the eCRF.

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Validation of the reported healthcare use will be conducted by acquiring the insurance records 
of participants who agree to the option of allowing their records to be used for this purpose. 
Safety Assessments
See Chapter 10 for further information on adverse events.
9.3.1
Vital Signs
The investigator may appoint a designee to measure vital signs, provided this is permitted 
according to local regulations and provided the investigator has trained the designee how to 
measure vital signs. The investigator must take responsibility for reviewing the findings.
Pulse rate and blood pressure will be measured in a manner consistent with the site’s 
standard operating procedures.  
Any out-of-range vital sign considered clinically significant by the investigator must be 
recorded as an adverse event on an Adverse Event Form.
Treatment Compliance
Treatment compliance will be assessed by recording the date of each treatment administration 
in the eCRF.  This will consist of on-site administration of treatment with eptimezumab or 
Botox as administered at Visit 2 and 5, and initial treatment with erenumab, fremanezumab or 
galcanezumab at Visit 2.  For subsequent injections of erenumab, fremanezumab or 
galcanezumab, the site staff will verify the date administered during the monthly study visits.
10 Adverse Events
Definitions
10.1.1
Adverse Event Definitions25
Adverse event – is any untoward medical occurrence in a patient or clinical study patient 
administered a medicinal product and which does not necessarily have a causal relationship 
with this treatment.
An adverse event can therefore be any un-favorable and unintended sign (including clinically 
significant out-of-range values from relevant tests, such as clinical safety laboratory tests, 
vital signs, ECGs), symptom, or disease temporally associated with the use of a medicinal 
product, regardless of whether it is considered related to the medicinal product.
It is Lundbeck policy to collect and record all adverse events, including pre-treatment adverse 
events, that is, those that start after the patient has signed the Informed Consent Form and 
prior to the first dose of IMP.

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Serious adverse event – is any adverse event that:

results in death

is life-threatening (this refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have 
caused death had it been more severe)

requires inpatient hospitalization or prolongation of existing hospitalization

results in persistent or significant disability/incapacity

is a congenital anomaly/birth defect
is medically important (this refers to an event that may not be immediately life-threatening or 
result in death or hospitalization, but may jeopardize the patient or may require intervention to 
prevent any of the SAEs defined above)
Examples of medically important events are intensive treatment for allergic bronchospasm; 
blood dyscrasia or convulsions that do not result in hospitalization; or development of drug 
dependency or drug abuse.
Planned hospitalizations or surgical interventions for a condition that existed before the 
patient signed the Informed Consent Form and that did not change in intensity are not adverse 
events. Emergency room visits that do not result in admission to the hospital are not 
necessarily SAEs; however, they must be evaluated to determine whether they meet any of the 
SAE definitions (for example, life-threatening or other serious [medically important] event).
Non-serious adverse event – is any adverse event that does not meet the definition of an SAE.
If there is any doubt as to whether an adverse event meets the definition of an SAE, a 
conservative viewpoint must be taken, and the adverse event must be reported as an 
SAE.
Suspected unexpected serious adverse reaction – is any adverse event that is assessed as 
serious, unexpected (its nature or intensity is not consistent with the current version of the 
USPI/labelling for any of the IMPs), and related to a medicinal product by either the 
investigator or Lundbeck.  
Overdose – is a dose taken by a patient that exceeds the dose prescribed to that patient. Any 
overdose (and associated symptoms) must, at a minimum, be recorded as a non-serious 
adverse event.
10.1.2
Adverse Event Assessment Definitions 
Assessment of Intensity
The investigator must assess the intensity of the adverse event using the following definitions, 
and record it on the Adverse Event Form in the eCRF:

Mild – the adverse event causes minimal discomfort and does not interfere in a 
significant manner with the patient’s normal activities.

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
Moderate – the adverse event is sufficiently uncomfortable to produce some 
impairment of the patient’s normal activities.

Severe – the adverse event is incapacitating, preventing the patient from participating 
in the patient’s normal activities.
Assessment of Causal Relationship
The investigator must assess the causal relationship between the adverse event and the IMP 
using the following definitions, and record it on the Adverse Event Form and the Serious 
Adverse Event Form (if applicable), in the eCRF:

Probable – the adverse event has a strong temporal relationship to the IMP or recurs 
on rechallenge, and another etiology is unlikely or significantly less likely.

Possible – the adverse event has a suggestive temporal relationship to the IMP, and an 
alternative etiology is equally or less likely.

Not related – the adverse event has no temporal relationship to the IMP or is due to 
underlying/concurrent disorder or effect of another drug (that is, there is no causal 
relationship between the IMP and the adverse event).
An adverse event is considered causally related to the use of the IMP when the causality 
assessment is probable or possible.
For pre-treatment adverse events, a causality assessment is not relevant.
Assessment of Outcome
The investigator must assess the outcome of the adverse event using the following definitions, 
and record it on the Adverse Event Form in the eCRF:

Recovered – the patient has recovered completely, and no symptoms remain.

Recovering – the patient’s condition is improving, but symptoms still remain.

Recovered with sequelae – the patient has recovered, but some symptoms remain (for 
example, the patient had a stroke and is functioning normally, but has some motor 
impairment).

Not recovered – the patient’s condition has not improved and the symptoms are 
unchanged (for example, an atrial fibrillation has become chronic).

Death
Pregnancy
Although not necessarily considered an adverse event, a pregnancy in a patient in the study 
must be recorded on an Adverse Event Form in the eCRF, even if no adverse event associated 
with the pregnancy has occurred. Pregnancies must be reported to Lundbeck using the same 
expedited reporting timelines as those for SAEs.

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An uncomplicated pregnancy should not be reported as an SAE; hospitalization for a normal 
birth should not be reported as an SAE. If, however, the pregnancy is associated with an SAE, 
the appropriate serious criterion must be indicated on the Adverse Event Form. Examples of 
pregnancies to be reported as SAEs (medically important) are spontaneous abortions, 
stillbirths, and malformations.
Participants who become pregnant will be withdrawn from the study and counselled to enroll 
in the Lundbeck pregnancy registry. The Lundbeck pregnancy registry is a prospective, 
observational study in the United States that will be initiated prior to the end of this trial. If a 
participant does not wish to participate in the Lundbeck pregnancy registry, then the 
investigator must follow up on the outcome of the pregnancy and report it on a Pregnancy 
Form (paper). The follow-up must include information on the neonate at least up until the age 
of 1 month.
Recording Adverse Events
Adverse events (including pre-treatment adverse events) and adverse drug reactions must be 
recorded on an Adverse Event Form. The investigator must provide information on the 
adverse event / drug reaction, preferably with a diagnosis, or at least with signs and 
symptoms; start and stop dates; intensity; causal relationship to the IMP; action taken; and 
outcome. If the adverse event is not related to the IMP, an alternative etiology must be 
recorded, if available. If the adverse event is an overdose, the nature of the overdose must be 
stated (for example, medication error, accidental overdose, or intentional overdose). If the 
intensity changes during the course of the adverse event, this must be recorded on the Adverse 
Event Form.
If the adverse event is serious, this must be indicated on the Adverse Event Form.
Furthermore, the investigator must report the SAE to Lundbeck immediately (within 24 
hours) after becoming aware of it (see section 10.4).
If individual adverse events are later linked to a specific diagnosis, the diagnosis should be 
reported and linked to the previously reported adverse events.
Reporting Serious Adverse Events
The investigator must report SAEs to Lundbeck immediately (within 24 hours) after 
becoming aware of them by completing the Adverse Event Form in the eCRF.
The initial entry of the SAE in the Adverse Event Form must contain as much information as 
possible and, if more information about the patient’s condition becomes available, the 
Adverse Event Form must be updated with the additional information.

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If the investigator cannot report the SAE in the eCRF within 24 hours of becoming aware of 
the event, then he or she must complete and sign the Serious Adverse Event Fallback Form 
and send it to Lundbeck Global Patient Safety, US at:
Fax:
+1 (847) 282-1003
email:
gpsus_query@lundbeck.com
Lundbeck will assume responsibility for reporting SAEs to the authorities in accordance with 
local requirements.
It is the investigator’s responsibility to be familiar with local requirements regarding reporting 
SAEs to the IRB and to act accordingly.
Treatment and Follow-up of Adverse Events
Patients with adverse events must be treated in accordance with usual clinical practice at the 
discretion of the investigator.
The investigator must follow up on non-serious adverse events until resolution or the Safety 
Follow-up Visit, whichever comes first. At the Safety Follow-up Visit, information on new 
SAEs, if any, and stop dates for previously reported adverse events must be recorded.
The investigator must follow up on all SAEs until the patient has recovered, stabilized, or 
recovered with sequelae, and report to Lundbeck all relevant new information using the same 
procedures and timelines as those for the initial Serious Adverse Event Form.
SAEs that are spontaneously reported by a patient to the investigator within 30 days after the 
Safety Follow- up Visit must be reported to Lundbeck via the e-mail address noted in Section 
10.4.  In this case, an e-mail describing the reported SAE will be sufficient; Lundbeck Global 
Patient Safety US will follow-up should additional information be required.
These SAEs will be recorded in the Lundbeck safety database.
11 Data Handling and Record Keeping
Data Collection
11.1.1
Electronic Case Report Forms
eCRFs will be used to collect the data related to the study as collected by the Investigators (or 
designees) at study visits (see Panel 4).
The eCRFs use third party software to capture data via an online system on a device. When 
the investigator enters data in the eCRF (ideally during the visit or as soon as possible 
[<3 days] thereafter), the data will be securely transmitted to a central database over a secured 
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Access to the system will only be granted after appropriate and documented training. Written 
instructions for using the system will be provided along with the training.
Electronic signatures will be used where signatures are required on pages and/or visits. 
Automated data entry checks will be implemented where appropriate; other data listings may 
be reviewed and evaluated for accuracy by the sponsor and/or representatives from the CRO. 
All entries, corrections, and changes must be made by the investigator or a delegate.
11.1.2
Electronic Diary (eDiary)
An eDiary, which is an app that will be downloaded to each participant’s smart phone or 
tablet, will be used to collect information from the participants throughout the course of the 
study, from Visit 1 through Visit 8 (see Panel 1, Panel 2 and Panel 3).  
The eDiary uses third party software to capture data via an online system on a mobile device. 
When the participant enters data in the eDiary, the data will be transmitted via a protected 
SSL to a central database where it will be securely stored, and all data entries will be logged 
in an audit trail. No entries will be able to be modified, once entered.  Participants will be 
provided instructions on how to use the eDiary at Visit 1 by the site staff.  Access to the 
system (for site staff, CRO staff and Lundbeck staff) will only be granted after appropriate 
and documented training.  
11.1.3
Patient Data
11.1.3.1
Recording of Patient Data
All participant data collected by a participating site will be documented in the participant’s 
medical record or a study-specific record (paper or electronic format) and will contain
information to support all data entered into the EDC.
11.1.3.2
Clinical Outcome Assessments
Clinical outcomes will be recorded by participating sites into the EDC system as per Panel 4
11.1.3.3
Serious Adverse Event Fallback Forms
Serious Adverse Event Fallback Forms must be used when the eCRF cannot be accessed.
11.1.4
External Data
All electronic data will be transferred using a secure method accepted by Lundbeck.
The following electronic data will be transferred by the CRO / third-party vendor and kept in 
a secure designated storage area outside the eCRF:

eDiary data

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Retention of Study Documents at the Site
11.2.1
eCRF data
If a site closes before the study has been completed, the investigator will continue to have 
read-only access to the eCRF until the study has been completed. The change to read-only 
status will take place once all data for the site has been reviewed and the forms have been 
locked.  After the study has been completed, all user access to the eCRF will be revoked. 
Renewed access to the eCRF will be given if corrections or updates to the database are 
required.
At the end of the study, the site will be provided with all data related to the site (including 
eCRF data, queries, and the audit trail) using a secure electronic medium; the secure storage 
of these data at the site is the responsibility of the investigator. When confirmation of receipt 
of the data has been received from all sites, all user access to the eCRF will be revoked.  If, 
for some reason, the data are not readable for the full retention period (25 years or in 
accordance with national requirements, whichever is longer), the investigator may request that 
the data be re-sent by the sponsor.
11.2.2
Other Study Documents
The investigator must keep the investigator’s set of documents in the investigator TMF / 
Essential Documents Binder for at least 25 years after the Clinical Study Report has been 
approved or in accordance with national requirements, whichever is longer. Lundbeck will 
remind the investigator in writing of this obligation when the Clinical Study Report Synopsis 
is distributed to the site.
If off-site storage is used, a study-specific binder will remain at the site after the other study-
specific documents have been shipped for off-site storage. This binder is considered part of 
the investigator TMF and must be kept in a secure place by the site for the required period of 
time. The binder must contain, at a minimum, the following documents: a copy of the 
Investigator TMF Index, a certified copy of the Patient Identification Code List, and a 
Retrieval Form.
When the required storage period has expired, the documents may be destroyed in accordance 
with regulations.
12 Monitoring Procedures
During the study, the CRO will review the study data on an ongoing basis to identify 
incorrect, inconsistent, and missing data. Any discrepancies or clarifications will be identified 
and directed to the sites using the query tool within the EDC system. Sites will be required to 
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13 Audits and Inspections
Authorized personnel from Medical, Regulatory and Clinical Quality Assurance,
H. Lundbeck A/S, and quality assurance personnel from business partners may audit the 
study at any time to assess compliance with the protocol and the principles of Good Clinical 
Practice and all other relevant regulations.
The investigator must be aware that representatives from regulatory authorities may also wish 
to inspect source data, such as medical records. The investigator must notify Lundbeck, 
without delay, of an announced inspection by a regulatory authority.
During audits and inspections, the investigator must permit direct access to all the source 
documents, including medical records and other documents pertinent to the study.
During audits and inspections, the auditors and inspectors may request relevant parts of 
medical records. No personal identification apart from the screening numbers will appear on 
these copies.
Patient data will not be disclosed to unauthorized third parties, and patient confidentiality will 
be respected at all times.
14 Protocol Compliance
Lundbeck has a “no-waiver” policy, which means that permission will not be given to deviate 
from the protocol.
If a deviation occurs, the investigator or designee must inform the CRO and they must review, 
discuss, and document the implications of the deviation.
15 Study Termination
Lundbeck or a pertinent regulatory authority may terminate the study or part of the study 
at any time. The reasons for such action may include, but are not limited to, safety 
concerns.
If the study is terminated or suspended, the investigator must promptly inform the patients and 
ensure appropriate therapy and follow-up. Furthermore, the investigator and/or sponsor must 
promptly inform the IRB and provide a detailed written explanation. The pertinent regulatory 
authorities must be informed in accordance with national regulations.
If the risk/benefit evaluation changes after the study is terminated, the new evaluation must be 
provided to the IRB if it will have an impact on the planned follow- up of the patients who 
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16 Statistical Methodology
Responsibilities
Biostatistics, Lundbeck LLC, will perform the statistical analyses for this study.  
Analysis Population
The eligible population will comprise all participants who give their informed consent and 
met the selection criteria. All participants completing at least one daily report after receiving 
their initial treatment at the Baseline Visit will be considered in the analysis sample. All data 
collected from participants who withdraw from the study will be collected up until the date of 
the withdrawal.
The safety population will consist of all participants who receive at least one infusion of 
eptinezumab.  
Safety Analyses
16.3.1
Analysis of Adverse Events
Adverse event and adverse drug reaction data will be tabulated and reported.  No additional 
analyses are planned.
16.3.2
Sample Size and Power
EVEC is an exploratory study, as such the sample size was considered secondary to the ability 
of the study to provide exploratory information concerning the objectives. However, for 
illustrative purposes we provide the power analysis here. Based upon the PROMISE trials and 
Phase IIIa studies of other medications to be evaluated in EVEC we expect to see a 2-day 
difference in the average monthly migraine days (MMD) at 13 weeks and a standard deviation 
of 6.0 around this measure. Based on this we expect to have 83% power to assess this 
difference with a sample size of 200 participants, assuming no significant loss to follow-up.  
Statistical Analysis Plan
A Statistical Analysis Plan describing the handling of data issues and the planned statistical 
analyses in more detail will be prepared by Lundbeck LLC, before the study is completed.

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17 Clinical Study Report and Publications
Data Ownership
The data collected in this study are the property of Lundbeck.
Clinical Study Report
Upon completion of the study, a Clinical Study Report will be prepared by Regulatory 
Medical Writing, Lundbeck LLC.
Summary of Clinical Study Results
Upon completion of the study and when the study results are available, the patient has the 
right to be informed by the investigator about the overall study results.
Publications
The results of this study will be submitted for publication.
Lundbeck will submit results information to ClinicalTrials.gov for this study.
The primary publication based on this study must be published before any secondary 
publications. Authors of the primary publication must fulfil the criteria defined by the 
ICMJE.26
18 Indemnity and Insurance
In the event of study-related injuries or deaths, insurance for the patients and indemnity of the 
investigators and those of their employees, servants, or agents whose participation in this 
study has been documented are provided. Insurance and liability will be in accordance with 
applicable laws and Good Clinical Practice.
19 Finance
Site Agreements
The financial agreements with each site are addressed in one or more documents. Both parties 
must sign the agreements before each site is initiated.
Financial Disclosure
All the investigators, including sub-investigators, participating in the study must complete a 
Financial Disclosure Form

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Appendix I
Clinical Study Protocol
Authentication and Authorization

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Clinical Study Protocol
Authentication and Authorization
Study title:
Early Value of Eptinezumab in the Community (EVEC)
Study No.:
19766N
Edition No.:
2.0
Date of edition: 02 June 2022
This document has been signed electronically.  The signatories are listed below.
Authentication
I hereby confirm that I am of the opinion that the ethical and scientific basis of this study is 
sound.
Study Lead:
Global Patient Safety
responsible:
Authorization
I hereby confirm that I am of the opinion that the ethical and scientific basis of this study is 
sound.
Head of HEOR and Value 
Evidence:
PPD
PPD
PPD

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Appendix II
The American Headache Society Position Statement on 
Integrating New Migraine Treatments into Clinical Practice

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Appendix III
Patient-Identified Most Bothersome Symptom (PI-MBS)

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Appendix IV
The 9-Item Shared Decision Making Questionnaire (SDM-Q-9)

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Appendix V
Decision Guide

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Appendix VI
The SURE Test

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Appendix VII
The Patient Activation Measure (PAM-10)

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Appendix VIII
EuroQoL-5Dimension-5Level (EQ-5D-5L)

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Appendix IX
Good Day / Bad Day Scale

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Appendix X
Perceived Stress Scale (PSS)

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Appendix XI
Migraine Disability Assessment (MIDAS)

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Appendix XII
Infusion Satisfaction Survey

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Appendix XIII
Treatment Satisfaction Questionnaire for Medication (TSQM)

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Appendix XIV
Headache Impact Test (HIT-6)

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Appendix XV
Healthcare Resource Utilization

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Appendix XVI
Healthcare Resource Utilization Follow-Up Questionnaire

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Appendix XVII
Medication - Overuse Headache Criteria (MOH)

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