Clinical trial NCT05284019
Conditions: Migraine
Sponsor: H. Lundbeck A/S
Start date: 2022-03-04; Completion date: 2023-04-14
Enrollment: 32 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to examine how eptinezumab compares to other advanced preventive medications in a real-world community setting in adult participants with episodic migraine (EM) or chronic migraine (CM). These objectives include exploring the comparative effectiveness on patient reported outcomes.

Detailed description:

Arms: arm 1: Participants will receive eptinezumab via intravenous (IV) infusion on Day 0 and Day 84. arm 2: Participants are free to select treatment from one of 3 calcitonin gene-related peptide (CGRP) inhibitors: erenumab, fremanezumab, or galcanezumab. CGRP inhibitors will be administered via subcutaneous (SC) injection on Day 0 and then, per product label. arm 3: Onabotulinumtoxin-A will be administered via intramuscular (IM) injection on Day 0 and Day 84.
Interventions: intervention 1: Eptinezumab intervention 2: Erenumab intervention 3: Onabotulinumtoxin-A intervention 4: Fremanezumab intervention 5: Galcanezumab
Intervention descriptions: intervention 1: Concentrate for solution for IV infusion intervention 2: Solution for SC Injection intervention 3: Solution for IM Injection intervention 4: Solution for SC Injection intervention 5: Solution for SC Injection

Protocol documents:
Prot_000.pdf: 
H. Lundbeck A/S
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Study 19766N – Clinical Study Protocol
Page 1 of 73
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 
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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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References
1. Vypeti(TM) (eptinezumab-jjmr) Injection for Intravenous Use [package insert]. Bothell, WA : 
Lundbeck Seattle Biopharmaceuticals, 2020.  
2. New trends in migraine pharmacology: targeting gene-regulated peptide (CGRP) with monoclonal 
antibodies. Scuteri D, Adornetto A, Rombola L et al. 2019, Front Pharmacol, Vol. 10, p. 363.
3. The prevalence and impact of migraine and severe headache in the United States: figures and 
trends from government health studies. Burch R, Rizzoli P, Loder E. 4, 2018, Headache, Vol. 58, pp. 
496-505.
4 .Cumulative lifetime migraine incidence in women and men. Stewart WF, Wood C, Reed ML et 
al. 2008, Cephalagia, Vol. 28, pp. 1170-8.
5. Episodic and chronic migraine headache: breaking down barriers to optimal treatment and 
prevention. Lipton RB, Silberstein SD. Suppl 2, 2015, Headache, Vol. 55, pp. 103-22.
6. The international classification of headache disorders, 3rd edition. Headache Classification 
Committee of the International Headache Society. 1, 2018, Vol. 38, pp. 1-211.
7. KF, Thorpe. The Headache and Migraine Policy Forum. Prevalence, health care spending and 
comorbidities associated with chronic migraine patients (2017). [Online] [Cited: 3 February 2020.] 
https://static1.squarespace.com/static/5886319ba5790a66cf05d235/t/589dea22ebbd1a9c4386ae9a/1
486744100047/HMPF_Chronic_Migraine_Paper_Feb+2017.pdf.
8. Eptinezumab in episodic migraine: A randomized, double=blind, placebo-controlled study 
(PROMISE 1). Ashina M, Saper J, Cady R, et al. 3, 2020, Cephalalgia, Vol. 40, pp. 241-54.
9. Efficacy and safety of eptinezumab in patients with chronic migraine: Promise-2. Lipton RB, 
Goadsby PJ, Smith J, et al. 13, 2020, Neurology, Vol. 94, pp. e1365-e1377.
10. Lundbeck Seattle Biotherapeutics. Data on file. Bothell, WA : s.n.
11. Aimovig(R) (erenumab-aooe) Injection [package insert]. Amgen, Inc. Thousand Oaks, CA : 
Novartis Pharmaceuticals Corp. , 2019.
12. Ajovy(R) (fremanezumab-vfrm) Injection [package insert]. North Wales, PA : Teva 
Pharmaceuticals USA, Inc., 2020.
13. Emgality(R) (galcanezumab-gnlm) Injection [package insert]. Indianapolis, IN : Lilly and 
Company, 2019.
14. Botox(R) (onabotulinumtoxinA) Injection [package insert]. Allergan USA, Inc. Madison, NJ : 
Abbvie, 2019.
15. The American Headache Society position statement on intergrating new migraine treatments into 
clinical practice. American Headache Society. 2019, Headache, Vol. 59, pp. 1-18.
16. World Medical Association (WMA). Declaration of Helsinki: Ethical principals for medical 
research involving human subjects.
17. ICH. ICH Harmonized Guideline E6(R2): Integrated addendum to ICH E6(R1); Guideline for 
Good Clinical Practice. 2016.


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18. European Parliament and Council of the European Union. Regulation (EU) 016/679; Protection 
of natural persons with regards to the processing of personal data and on the free movement of such 
data, and repealing Directive 95/46/EC (General Data Protection Regulation) April 2016. s.l. : 
Official Journal of the European Union, 2016.
19. The International Headache Society. Medication Overuse Headache. International Classification 
of Headache Disorders, 3rd Edition. [Online] 2018. https://ichd-3.org/8-headache-attributed-to-a-
substance-or-its-withdrawal/8-2-medication-overuse-headache-moh/.
20. Development and first validation of the shared decision-making questionnaire (SDM-Q). Simon 
D, Schorr G, Wirtz M, et al. 2006, Patient Education and Counseling, Vol. 63, pp. 319-27.
21. Development of the patient activation measure (PAM) conceptualizing and measuring activation 
in patients and consumers. Hibbard JH, Stockard J, Mahoney ER, Tusler M. 4p1, 2004, Health 
Services Research, Vol. 39, pp. 1005-26.
22. When patient activation levels change, health outcomes, and costs change too. Greene J, HIbbard 
JH, Sacks R, et al. 3, 2015, Health Affairs, Vol. 34, pp. 431-7.
23. Development and testing of the Migraine Disability Assessment (MIDAS) Questionnaire to 
assess headache-related disability. Stewart WF, Lipton RB, Dowson AJ, Sawyer J. 6 Suppl 1, 2001, 
Neurology, Vol. 56, pp. 520-8.
24. Validation of the Headache Impact Test (HIT-6) across episodic and chronic migraine. Yang M, 
Rendas-Baum R, Varon SF, Koslinski M. 3, 2011, Cephalalgia, Vol. 31, pp. 357-67.
25. ICH. ICH Harmonized Tripartite Guideline E2A: Clinical safety data management definitions 
and standards for expedited reporting. October 1994.
26. International Committee of Medical Journal Editors (ICMJE). Recommendations for the 
conduct, reporting, editing, and publication of scholarly work in medical journals. 2014.

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Study 19766N - Statistical Analysis Plan                                                                                                                 Page 1 of 42
Statistical Analysis Plan
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
Sponsor:
Lundbeck LLC (Lundbeck)
Deerfield, Illinois 60015, United States
Global Health 
Economics and 
Outcomes Research:
 
SAP date:
4 October 2022
This document is the property of H. Lundbeck A/S and H. Lundbeck A/S 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 H. Lundbeck A/S.
PPD
NCT05284019


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Table of Contents
List of Panels and Tables...............................................................................................................5
List of Abbreviations and Definitions of Terms ..........................................................................6
1
Objectives and Endpoints....................................................................................................7
2
Study Design.........................................................................................................................7
2.1
Rationale for the Study Design..................................................................................10
2.2
Study design justification ..........................................................................................10
3
Definitions...........................................................................................................................11
3.1
Definition of Periods..................................................................................................11
3.2
Definition of Baseline................................................................................................12
3.3
Definition of Withdrawal...........................................................................................13
3.4
Definition of Planned versus Actual Treatment ........................................................13
3.5
Definition of Migraine and Headache Days ..............................................................14
3.5.1
Headache Day ............................................................................................14
3.5.2
Migraine Day..............................................................................................15
3.5.3
Clear Day....................................................................................................15
4
Analysis Sets .......................................................................................................................15
5
Descriptive Statistics..........................................................................................................16
6
Patient Disposition .............................................................................................................16
6.1
Summary of Patient Disposition................................................................................16
6.2
Withdrawals...............................................................................................................16
7
Demographics and Baseline Characteristics ...................................................................16
8
Recent and Concomitant Medication...............................................................................16
9
Exposure .............................................................................................................................17
10
eDiary Compliance.............................................................................................................17
11
Effectiveness Analysis........................................................................................................18
11.1
Overview ...................................................................................................................18
11.2
Analysis Methodology for the Exploratory Endpoints..............................................18
11.2.1
Estimand for the Number of Good Days (Week 1-4, 1-12, and 1-24) and 
Exploratory Endpoints................................................................................18
11.2.2
Analysis of the Exploratory Endpoints ......................................................20
11.2.3
Strategies for Addressing Intercurrent Events in the Exploratory Estimands
....................................................................................................................23
11.2.4
Rationale for Selected Analysis for the Exploratory Endpoints.................24
11.2.5
Evaluation of Model Assumptions for the Analysis of Exploratory 
Endpoints....................................................................................................24
11.2.6
Sensitivity Analyses of the Exploratory Endpoints....................................25
11.2.7
Supplementary Analyses of the Exploratory Endpoints.............................25
11.2.8
Covariate Investigation and Subgroup Analyses of the Exploratory 
Endpoints....................................................................................................25


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12
Safety Analyses...................................................................................................................26
13
Data Reviews ......................................................................................................................27
14
Interim Analyses ................................................................................................................28
15
Sample Size.........................................................................................................................28
15.1
Sample Size Rationale ...............................................................................................28
16
Statistical Software ............................................................................................................30
17
Changes to Analyses Specified in the Protocol................................................................30
18
Details on Data Handling ..................................................................................................30
18.1
Time from Scheduled Daily Report to Patient Reporting Time ................................30
18.2
eDiary ........................................................................................................................31
18.3
Good Day/Bad Day Scale (Week 1-4, 1-12, and 1-24) .............................................31
18.4
PI-MBS (weeks 1-4, 1-12, and 1-24).........................................................................31
18.5
EQ-5D-5L (weeks 1-4, 1-12, and 1-24).....................................................................31
18.6
HCRU (weeks 1-4, 1-12, and 1-24)...........................................................................31
18.6.1
Medical HCRU...........................................................................................32
18.6.2
Medication HCRU......................................................................................32
18.7
HIT-6 (week 4, 12, and 24) .......................................................................................33
18.8
MIDAS (weeks 12 and 24)........................................................................................33
18.9
Drug Switching..........................................................................................................33
18.10 TSQM (week 24).......................................................................................................33
18.11 SDMQ-9 (screening and week 24) ............................................................................34
18.12 SURE (screening)......................................................................................................34
18.13 PAM-10 (screening, week 12 and 24) .......................................................................34
18.14 PSS.............................................................................................................................35
18.15 ISS (screening, week 12 and 24) ...............................................................................35
18.15.1
Weekly Migraine Days...............................................................................35
References .....................................................................................................................................36


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Appendices
Appendix I
Covariate Definitions.........................................................................................37


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List of Panels and Tables
Panel 1
Objectives and Endpoints ................................................................................................... 7
Panel 2
Criteria for Chronic Migraine Diagnosis per International Headache Society (IHS) 
International Classification of Headache Disorders 3rd edition (ICHD-3). ....................... 8
Panel 3
Randomization Design........................................................................................................ 9
Panel 4
Patient Reported Outcomes Reporting Schedule.............................................................. 12
Panel 5
Effect Sizes Observed in Promise Trials .......................................................................... 29
Panel 6
Sample size and Power from PROMISE Trials Assumptions.......................................... 30
Table 1
Covariate Definitions........................................................................................................ 38


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List of Abbreviations and Definitions of Terms
AE
Adverse events
APRS
All-patients-randomized-set
APTS
All-patients-treated-set
aCGRP
Anti-calcitonin gene-related peptide
CM
Chronic migraine
eCRF
Electronic case report form 
EDC
Electronic data capture 
EM
Episodic migraine
EQ-5D-5L
Euroqol 5 Dimension – 5 Levels
FAS
Full analysis set
HIT-6
Headache impact test – 6
HCRU
Healthcare resource utilization 
ISS
Infusion Satisfaction Survey 
MHDs
Monthly headache days
MIDAS
Migraine Disability Assessment 
MMDs
Monthly migraine days
MMRM
Mixed model for repeated measures 
MOH
Medication overuse headache
OTC
Over the counter
PAM-10
Patient Activation Measure – 10
PI-MBS
Patient-Identified Most Bothersome Symptom
PRO
Patient reported outcome
PSS
Perceived Stress Scale 
QoL
Quality of life
SDM-Q-9
9-item Shared Decision-Making Questionnaire
SURE
Sure of myself; Understand information; Risk-benefit ratio; 
Encouragement
TEAE
Treatment-emergent adverse event 
TSQM
Treatment Satisfaction Questionnaire for Medication
US
United States


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1
Objectives and Endpoints 
The study objectives and endpoints are summarized below in Panel 1. 
Panel 1
Objectives and Endpoints
Objectives
Endpoints
Primary Objective

To explore the effectiveness of 
eptinezumab on patient-centered 
outcomes
Exploratory Endpoints
1.
Good Day/Bad Day scale at weeks 4, 12, and 24
2.
Euroqol 5 Dimension – 5 Levels (EQ-5D-5L) at weeks 
4, 12, and 24
3.
Patient-Identified Most Bothersome Symptom (PI-
MBS) at weeks 4, 12, and 24
4.
Healthcare resource utilization (HCRU) at weeks 4, 12, 
24
5.
Headache Impact Test – 6 (HIT-6) change from baseline 
at week 4, 12, and 24
6.
Migraine Disability Assessment (MIDAS) change from 
baseline at week 12 and 24
7.
Treatment Satisfaction Questionnaire for Medication 
(TSQM) at week 24
8.
Medication Switching at week 12 and 24
9.
Shared Decision-Making Qeustionnaire-9 (SDMQ-9) at 
screening and week 24
10. SURE test at screening
11. Patient Activation Measure – 10 (PAM-10) at screening, 
week 12 and 24
12. Infusion Satisfaction Survey (ISS) at baseline and at 
week 12
Safety objective

To evaluate the safety and 
tolerability of eptinezumab
Safety endpoints

Reported adverse effects
2
Study Design
This is an exploratory, prospective, randomized, pragmatic, open-label cohort study of 200 
participants receiving preventive treatment for episodic migraine (EM) or chronic migraine 
(CM) headache in the United States (US). Participants must have a history of > 8 migraine 
days in two of the past three months prior to enrolment and have documented failure to at 
least two previous oral preventive treatments per the American Headache Society (AHS) 
Consensus Statement. 


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Panel 2
Criteria for Chronic Migraine Diagnosis per International Headache Society 
(IHS) International Classification of Headache Disorders 3rd edition (ICHD-
3).
This study will be conducted in compliance with the protocol, Good Clinical Practice and 
applicable regulatory requirements.
Participants will be recruited from sites that can administer all therapies within the study in an 
outpatient setting.
After giving consent, participants will be classified as living with either EM or CM per 
International Classification of Headache Disorders 3rd edition (ICHD-3) guidelines (see Panel 
2) based upon their medical history. Within these strata, the participants living with EM will 
be randomized to eptinezumab or subcutaneous (SC) anti-calcitonin gene-related peptide 
(aCGRP) (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 aCGRP injectable of their choice (i.e., erenumab, fremanezumab or galcanezumab). 
Please see Panel 3 for further details on the randomization design.


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Panel 3
Randomization Design
Participants will be followed prospectively for 24 weeks; a follow-up phone call will then 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 (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, prescription medication, etc.). The site staff will also follow-up with 
participants at each study visit to record additional details of healthcare resource utilization 
(HCRU) recorded in the eDiary, record HCRU not reported in the eDiary, and record reasons 
for any changes in prescription or over-the-counter (OTC) medications. Quality of life (QOL)
data and HCRU data will be collected from participants via the smartphone application (app) 
and from the site staff via electronic data capture (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.


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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.  
2.1
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.  
2.2
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?” 
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. 
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 
principle 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 


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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.
3
Definitions
3.1
Definition of Periods
The study will have four periods:
• Screening (Visit #1) to Baseline (Visit #2)
At screening participants will complete the informed consent, review the patient decision aid 
describing the treatments, complete the SDMQ-9, SURE test, PAM-10, and receive training 
in use of the study eDiary app. During the period from Screening to Baseline, the participant 
will use the study app to report their daily experience. This will capture their compliance 
behavior to support the study analysis while also giving the participant training in use of the 
app. The site investigator will receive the treatment allocation and receive the participant’s 
first dose. 
• Baseline to Week 12 (Visit #5)
During this period, participants will complete the daily diary, and the weekly and monthly 
patient-reported outcomes (PROs) as prompted by the study app. This period is the primary 
reporting period for the study. Participants randomized to receive eptinezumab or 
onabotulinumtoxinA will receive that treatment at Visit #5 at the study site. Those 
randomized to receive a subcutaneously injected aCGRP may visit the study site at Visit #5 
for the follow-up visit or visit the study site. 
• Baseline to Week 24 (Visit #8)
For reporting purposes, the period for visits 6-8 will be pooled with the previous period, so 
that results for week #24 will include all data since the Baseline visit. From the patient
perspective there is no change in the required behavior. 
• Safety Follow-up period (Week 25-33, Visit #9)
This is the two-month follow-up period required by Lundbeck to assess safety. 


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The reporting schedule is defined in the table that follows:
Panel 4
Patient Reported Outcomes Reporting Schedule
Assessments
Reporting Schedule
Daily
Weekly(a)
Monthly(b)
Quarterly(c)
Early 
Termination
Healthcare Resource Utilization
X(d)
X
EQ-5D-5L
X
X
Good Day/Bad Day Scale
X
X
PSS
X
X
HIT-6
X
X
PAM-10
X
X
MIDAS
X
X
SDM-Q-9
X
X
TSQM
X(e)
X
(a) Weekly = every 7 days, Visit 2 date = Day 0
(b) Monthly = every 28 days, Visit 2 date = Day 0 
(c) Quarterly = every 84 days, Visit 2 date = Day 0
(d) Will be assessed 3 times per week
(e) Assessed at Day 168 only          
Participants will report daily whether they have had a headache in the previous 24 hours, any 
migraine related symptoms (concurrent with the migraine or interictal) and use of rescue 
medication. 
3.2
Definition of Baseline
The screening assessment (Visit 1) is to be conducted within 14 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 participant’s first treatment occurs as the Baseline Visit. The day of the visit, the 
participant will be notified by the study app to complete the Baseline PROs and prior to 
initiating treatment the site will confirm the completion. The participant will also complete 
the Daily Headache Status Report in their eDiary on this date. 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 aCGRP mAb. For participants in the 
subcutaneous aCGRP arm, the first dose should be self-administered by the participant under 
the supervision of the site staff.
Where a study endpoint is based upon the change from baseline, the report at this visit will 
serve as that baseline.


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3.3
Definition of Withdrawal
Withdrawal from the study is defined as termination of consent on or before Visit 8. 
Participants who withdraw from the study prior to Visit 8 will be asked to complete an Early 
Termination Visit. The visit must be scheduled as soon as possible after withdrawal. All 
information collected at an Early Termination Visit is to be recorded in the Visit 8 forms of 
the electronic case report form (eCRF). If the patient denies completing the Early Termination 
Visit, then no further data will be collected. 
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.
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.
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 might attend a Withdrawal Visit. If the participant:
o
Agrees to attend a Withdrawal Visit, all the data collected up to and including that 
visit will be used
o
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.
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.
3.4
Definition of Planned versus Actual Treatment 
As this is a pragmatic real-world study, there is no restriction on treatment pathways 
following randomization with the exceptions defined below. Note that all participants will be 
analyzed on an “intention to treat” basis, regardless of changes made to their treatment 
following the Baseline visit.


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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 aCGRP injectable (i.e., erenumab, 
fremanezumab or galcanezumab), they may not do so until week 12 (visit 5). 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 aCGRP 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 aCGRP 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.
3.5
Definition of Migraine and Headache Days
3.5.1
Headache Day
A headache day will be defined as a day in which the participant reports the following:
-
Reported “yes” to having a headache in the past 24 hours and who do NOT 
report criterion A nor B:
o Criterion A
Headache with ≥2 of the following features:
Moderate or severe pain intensity
Unilateral location
Pulsating quality
Aggravation by or causing avoidance of routine physical activity
During the headache, the patient reports ≥1 of the following symptoms:
Nausea and/or vomiting


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Photophobia  
Phonophobia 
o Criterion B
Reported acute medication use
3.5.2
Migraine Day
A migraine day will be defined as a day in which a patient reports the following features 
consistent with ICHD-3 criteria for migraine without aura (Panel 2):
-
Reported “yes” to having a headache in the past 24 hours and who also report 
either criterion A or B:
o Criterion A
Headache with ≥2 of the following features:
Moderate or severe pain intensity
Unilateral location
Pulsating quality
Aggravation by or causing avoidance of routine physical activity
During the headache, the patient reports ≥1 of the following symptoms:
Nausea and/or vomiting
Photophobia and 
Phonophobia 
o Criterion B
Reported acute medication use
3.5.3
Clear Day
A clear day will be defined as a day in which the patient reports:
-
Reported “No” to having a headache in the past 24 hours AND
o Reports no residual symptoms between headaches AND
o Reports no “warning” symptoms prior to a headache
4
Analysis Sets
The following analysis sets will be used for evaluation of the data:
• All patients randomized set (APRS) – all patients randomized to the eptinezumab and the 
other advanced migraine treatment arms
• All patients treated set (APTS) – all patients in the APRS who received at least one dose of 
eptinezumab or other advanced migraine therapy
• Full analysis set (FAS) – all patients in the APTS who completed at least one daily report 
after receiving eptinezumab or other advanced migraine therapy


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Effectiveness analyses over the 24-week period will be based on the FAS. We will also 
evaluate baseline characteristics based on the APRS to assess the validity of the 
randomization strategy. 
Safety analyses will be based on the APTS.
5
Descriptive Statistics
All assessment data, including demographics, will be summarised using descriptive 
techniques. Summary statistics (n, mean, standard deviation, median, lower and upper 
quartiles, minimum and maximum values) will be presented for continuous variables. Counts 
and percentages will be presented for categorical and binary variables.
6
Patient Disposition
6.1
Summary of Patient Disposition
Participant disposition will be reported overall and by treatment group. If needed, further 
tables summarizing disposition by site and treatment group can be added.
6.2
Withdrawals
For each period, the number of participants who withdrew from the study, will be summarized 
by treatment group, and primary reason for withdrawal, and by treatment group and all 
reasons for withdrawal.
If relevant, Kaplan-Meier failure plots of time to withdrawal in each period will be presented 
by treatment group. Participants who reach the end of follow-up without withdrawing from 
the study will be regarded as censored. 
7
Demographics and Baseline Characteristics
Demographics; baseline characteristics (including baseline eDiary compliance); baseline 
disease characteristics; and baseline efficacy (i.e., MMD) variables will be summarized at 
Baseline by randomization group and study site.
8
Recent and Concomitant Medication
Concomitant medication is any medication other than the investigational medicinal products 
(IMPs) that are taken during the study from Screening up until the participant completes the 
study at Visit 8. This includes all prescription and OTC medications, as well as vitamins and 


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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 enrolment in the study, 
the disorder must be recorded as an adverse event.
9
Exposure
For each period, the total number of infusions (for eptinezumab) or injections (for 
onabotulinumtoxinA) received and total number completed as planned will be summarized by 
treatment group.
For participants randomized to the subcutaneously injected aCGRPs, dispensing information 
will be obtained from the speciality pharmacy providing the medication. The date the 
participant reported injecting the medication will be captured in the eDiary. The information 
that the participant has been dispensed medication will be reported by medication group. 
Similarly, the information that the participant has injected the medication will be reported by 
medication group.
10 eDiary Compliance 
Participant compliance with eDiary use will be measured between the Screening and Baseline 
visits. This will be used in analysis as a model covariate to adjust for expected compliance. 
After Baseline, all data reported through the eDiary will be used in analysis as described in 
the section on Section 18 Details on Data Handling. 


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11 Effectiveness Analysis 
11.1
Overview
All effectiveness analyses will be based on the FAS, unless specified otherwise, and patients 
will be analyzed according to the randomized group. Details of calculating values for outcome 
variables and assumptions regarding handling of missing data is described in section 18.
11.2
Analysis Methodology for the Exploratory Endpoints
11.2.1
Estimand for the Number of Good Days (Week 1-4, 1-12, and 1-24) and 
Exploratory Endpoints
A summary of the intercurrent events that will be addressed and the estimand attributes can be 
found below. 
The estimand is the difference in the mean weekly number of good days within each specified 
time interval between eptinezumab compared to other advanced preventive therapies 
(erenumab, fremanezumab, galcanezumab, or onabotulinumtoxinA) in adults with migraine 
on concomitant acute migraine therapy who have failed ≥2 prior oral preventive therapies and 
who are naïve to advanced migraine therapy based on a treatment policy strategy in which 
patients are analyzed according to the randomized group and are included in the analysis 
regardless of discontinuation or switching of the index migraine therapy during the follow-up 
period.
Intercurrent events that will be addressed include:
• Discontinuing the index preventive migraine medication with or without initiation of a new 
preventive therapy (i.e., a treatment switch).
• Withdrawal from the study due to lack of efficacy, adverse event, participant request, 
physician request, or loss to follow-up.
• Interruption or termination of infusions.
Attributes of the estimand for the number of good days include:
• The index treatment of interest is eptinezumab (100 mg or 300 mg) compared to other 
advanced preventive therapies (erenumab 70 mg or 140 mg, fremanezumab 225 mg or 
675 mg, galcanezumab 120 mg, and onabotulinumtoxinA 155 units)
• The population is all patients with migraine who fulfil the inclusion and exclusion criteria.
• The primary endpoint of interest is the mean number of good days across weeks 1-12 after
randomization
• The population-level summary is the mean difference between eptinezumab and other 
advanced preventive therapies for the endpoint
Estimands for the remaining exploratory endpoints can be formulated similarly to the 
estimand for the number of good days described above.


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EQ-5D (weeks 1-4, 1-12, and 1-24)
• The endpoint to be obtained is the weekly EQ-5D score in each specified time interval
• The population level summary is the difference in mean weekly EQ-5D score in patients 
on eptinezumab relative to advanced migraine therapies in each time interval
PI-MBS (weeks 1-4, 1-12, and 1-24)
• The endpoint to be obtained is the weekly most bothersome symptom and associated 
severity
• The population level summary is the weekly proportion of most bothersome symptoms and 
average severity of each symptom in patients on eptinezumab and advanced migraine 
therapies in each time interval
Cumulative healthcare resource use (HCRU) (weeks 1-4, 1-12, and 1-24)
• The endpoint to be obtained is the cumulative HCRU (stratified by medical and 
pharmaceutical HCRU) in each specified time interval
• The population-level summary is the difference in mean HCRU in patients on eptinezumab 
relative to advanced migraine therapies in each time interval
HIT- 6 change from baseline score (week 4, 12, and 24)
• The endpoint to be obtained is the HIT-6 change from baseline score at each specified time 
point
• The population level summary is the difference in mean HIT-6 change from baseline score 
in patients on eptinezumab relative to advanced migraine therapies at each time point
MIDAS change from baseline score (weeks 12 and 24)
• The endpoint to be obtained is the MIDAS change from baseline score at each specified 
time point
• The population level summary is the difference in mean MIDAS change from baseline 
score in patients on eptinezumab relative to advanced migraine therapies at each time 
point
TSQM score (week 24)
• The endpoint to be obtained is the TSQM score at week 24 for each domain
• The population level summary is the difference in mean TSQM score in patients on 
eptinezumab relative to advanced migraine therapies for each domain
Switching of index medication (weeks 1-12 and 1-24)
• The endpoint to be obtained is a binary outcome indicating if a patient discontinued the 
index therapy and initiated a new therapy in the specified time intervals
• The population-level summary is the odds ratio of switching from the index medication in 
patients on eptinezumab relative to advanced migraine therapies in each time interval 


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SDMQ-9 (screening and week 24)
• The endpoint to be obtained is the SDMQ-9 score at each specified time point
• The population level summary is the mean SDMQ-9 in patients on eptinezumab and 
advanced migraine therapies in each time interval
SURE score at screening
• The endpoint to be obtained is the SURE test score at screening
• The population level summary is the mean SURE test score in patient on eptinezumab and 
advanced migraine therapies at screening
PAM-10 score (screening, week 12 and 24)
• The endpoint to be obtained is the PAM-10 score at each specified time point
• The population level summary is the mean PAM-10 score in patients on eptinezumab and 
advanced migraine therapies in each time interval
ISS score (screening, week 12 and 24)
• The endpoint to be obtained is the score or item response for each item in the ISS at each 
specified time point 
• The population level summary is the mean ISS score or proportion of responses for each 
item in patients on eptinezumab at each time point
11.2.2
Analysis of the Exploratory Endpoints 
The analysis of exploratory endpoints assumes that we have ≤10% of patients with at least 
one missing outcome value. A complete case analysis will be used as a preliminary approach 
to establish the “baseline” results prior to using a mixed model for repeated measures 
(MMRM) or multiple imputation to account for missing values.  
Number of good days (weeks 1-4, 1-12, and 1-24)
The weekly difference in mean number of good days will be estimated using a MMRM. The 
model will include the following independent variables:
• Week as a factor (week 1, week 2, week 3, week 4…week n) 
• Treatment indicator (eptinezumab vs other advanced therapies)
• Interaction of treatment and week (i.e., treatment*week 1…treatment*week 
2…treatment*week n)
• A vector of covariates identified to be significantly different between treatment groups 
after randomization.
We will assume that residuals are normally distributed, and we will also assume an 
unstructured covariance structure of the residuals. The Kenward-Roger approximation will be 
used to estimate standard errors. The hypothesis tested will be that the interaction term of 
treatment and week is significantly different from zero using a two-sided test at p<0.05. The 


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population level summary will be the difference in mean number of good days at weeks 1-4. 
The analysis will also be conducted for weeks 1-12 and 1-24. If the model fails to converge, 
then other covariance structures will be utilized. 
EQ-5D score (weeks 1-4, 1-12, and 1-24) 
The weekly difference in the EQ-5D score will be estimated using a MMRM. The model will 
include the following independent variables:
• Week as a factor (week 1, week 2, week 3, week 4…week n)
• Treatment indicator (eptinezumab vs other advanced therapies)
• Interaction of treatment and week (i.e., treatment*week 1…treatment*week 
2…treatment*week n)
• A vector of covariates identified to be significantly different between treatment groups 
after randomization.
We will assume that residuals are normally distributed, and we will also assume an 
unstructured covariance structure of the residuals. The Kenward-Roger approximation will be 
used to estimate standard errors. The hypothesis tested will be that the interaction term of 
treatment and week is significantly different from zero using a two-sided test at p<0.05. The 
population level summary will be the difference in mean EQ-5D score at weeks 1-4. The 
analysis will also be conducted for weeks 1-12 and 1-24. If the model fails to converge, then 
other covariance structures will be utilized.
HCRU (weeks 1-4, 1-12, and 1-24)
The difference in cumulative mean HCRU will be estimated using a negative binomial model. 
The analysis will be stratified by type of HCRU (i.e., outpatient, inpatient hospitalization, 
emergency department/urgent care visits, and migraine-specific medications such as triptans). 
Independent variables will include a treatment indicator (eptinezumab vs other advanced 
therapies) and a vector of covariates identified to be significantly different between treatment 
groups after randomization. The hypothesis tested will be that the treatment term is 
significantly different from zero using a two-sided test at p<0.05. The population level 
summary will be the relative difference in mean HCRU at weeks 1-4. The analysis will also 
be conducted for weeks 1-12 and 1-24. If there are a substantial number of observations with 
a value of zero HCRU, then a zero-inflated negative binomial model will be explored.
HIT-6 change from baseline score (month 1, 3, and 6)
The mean HIT-6 change from baseline score will be estimated using a mixed model for 
repeated measures (MMRM). The model will include the following independent variables:
• Month as a factor (Baseline month 0, month 1, month 3, and month n)
• Treatment indicator (eptinezumab vs other advanced therapies)
• Interaction of treatment and month (treatment*baseline…treatment*month 
1…treatment*month n)


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• A vector of covariates identified to be significantly different between treatment groups 
after randomization.
We will assume that residuals are normally distributed, and we will also assume an 
unstructured covariance structure of the residuals. The Kenward-Roger approximation will be 
used to estimate standard errors. The hypothesis tested will be that the interaction term of 
treatment and month is significantly different from zero using a two-sided test at p<0.05. The 
population level summary will be the difference in mean HIT-6 change from baseline score at 
month 1, month 3, and month 6. If the model fails to converge, then other covariance 
structures will be utilized.
MIDAS change from baseline score (month 3 and 6)
The mean MIDAS change from baseline score will be estimated using a MMRM. The model 
will include the following independent variables:
• Month as a factor (Baseline month 0, month 3 and month n)
• Treatment indicator (eptinezumab vs other advanced therapies)
• Interaction of treatment and month (treatment*baseline, treatment*month 3, 
treatment*month n)
• A vector of covariates identified to be significantly different between treatment groups 
after randomization.
We will assume that residuals are normally distributed, and we will also assume an 
unstructured covariance structure of the residuals. The Kenward-Roger approximation will be 
used to estimate standard errors. The hypothesis tested will be that the interaction term of 
treatment and month is significantly different from zero using a two-sided test at p<0.05. The 
population level summary will be the difference in mean MIDAS change from baseline score 
at month 3 and month 6. If the model fails to converge, then other covariance structures will 
be utilized.
PI-MBS (weeks 1-4, 1-12, and 1-24) 
Among daily headache reports, the weekly proportion of each most bothersome symptom 
(e.g., pain worsened by physical activity, throbbing head pain, nausea, vomiting, photophobia, 
phonophobia, difficulty concentrating, visual aura, other aura, or other) associated with a 
headache and proportions of reports with no headache will be calculated for the eptinezumab 
and advanced migraine therapy group. The average weekly severity associated with each most 
bothersome symptom will be calculated. The trend in the weekly proportion and severity of 
each most bothersome symptom will be descriptively compared between the eptinezumab and 
advanced migraine therapy group. 
TSQM score (week 24)
The difference in mean TSQM score for each domain (effectiveness, side effects, 
convenience, and overall satisfaction) at week 24 will be estimated using an ordinary least 


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square model. Independent variables will include a treatment indicator (eptinezumab vs other 
advanced therapies) and a vector of covariates identified to be significantly different between 
treatment groups after randomization. The hypothesis tested will be that the treatment term is 
significantly different from zero using a two-sided test at p<0.05. The population level 
summary will be the difference in mean TSQM score at week 24.
Index drug switching (weeks 1-12, and 1-24)
The difference in the odds of index drug switching will be estimated using a logistic 
regression model. Independent variables will include a treatment indicator (eptinezumab vs 
other advanced therapies) and a vector of covariates identified to be significantly different 
between treatment groups after randomization. The hypothesis tested will be that the 
treatment term is significantly different from zero using a two-sided test at p<0.05. The 
population level summary will be the odds ratio of index drug switching in the eptinezumab 
group relative to other advanced therapies. The analysis will be conducted weeks 12 and 24.
SDMQ-9 (screening and week 24)
The average SDMQ-9 score will be calculated for each treatment group and descriptively 
compared at screening and week 24. 
SURE score at screening
The average SURE score will be calculated for each treatment group and descriptively 
compared at screening.
PAM-10 score (screening, week 12 and 24)
The average PAM-10 score will be calculated for each treatment group and descriptively 
compared at screening, week 12, and week 24. 
ISS score (screening, week 12 and 24)
The ISS score or item responses will be analyzed descriptively using averages and proportions 
in the eptinezumab group at screening, week 12, and week 24. 
11.2.3
Strategies for Addressing Intercurrent Events in the Exploratory Estimands 
The goal of this pragmatic trial is to measure the effectiveness of migraine preventive 
treatments in “real-world” conditions regardless of the occurrence of intercurrent events 
during the follow-up period. Therefore, all intercurrent events will be addressed using a 
treatment policy strategy, in which all patients will be analysed despite the occurrence of an 
intercurrent event. This strategy reflects the intent-to-treat principle in which patients are 
analyzed regardless of protocol deviations. 


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Use of acute medication to treat a migraine headache
A treatment policy strategy will be used to address acute medication usage during the follow-
up period. Patients with available endpoint data will be analysed regardless of acute 
medication use during the follow-up period.
Discontinuing the preventive migraine medication with or without initiation of a new 
preventive therapy.
A treatment policy strategy will be used to address patients who switch or discontinue the 
index therapy. Patients with available endpoint data will be analysed according to their index 
therapy regardless of switch or discontinuing the index therapy.
Withdrawal from the study due to lack of efficacy, adverse event, participant request, 
physician request, or loss to follow-up.
A treatment policy strategy will be used to address patients who withdraw from the study for 
any reason. Imputation of missing data will aim to ensure that all observations with missing 
outcome values can be used in the analysis. 
Interruption or termination of infusions.
A treatment policy strategy will be used to address patients who experience an interruption or 
termination of infusions. Patients with available endpoint data will be analysed regardless of 
infusion interruption or termination.
11.2.4
Rationale for Selected Analysis for the Exploratory Endpoints
The number of good days, EQ-5D score, HIT-6, and MIDAS are continuous longitudinal data 
(i.e., correlated observations across time on the same individual) that are approximately 
normally distributed. Therefore, a MMRM is optimal for these outcomes. HCRU are counts, 
which follows a right skewed distribution and values are restricted >0, therefore, a negative 
binomial model is appropriate. The TSQM is approximately normally distributed and ordinary
least squares is appropriate. Index drug switching is a binary outcome measure, and a logistic 
regression is appropriate. Other patient reported outcomes such as the PI-MBS, SDMQ-9, 
SURE, PAM-10, and ISS are discrete or categorical variables and describing the endpoints by 
proportion, mean, or median is appropriate.
11.2.5
Evaluation of Model Assumptions for the Analysis of Exploratory Endpoints
The assumption of normality of the patient-reported outcomes will be evaluated by visual 
inspection of the distribution of the outcomes, residual Q-Q plots, and scatter plot of 
standardized residuals vs predicted values. 


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11.2.6
Sensitivity Analyses of the Exploratory Endpoints
Number of good days (weeks 1-4, 1-12, and 1-24), EQ-5D score (weeks 1-4, 1-12, and 1-
24), HIT-6 change from baseline score (month 1, 3, and 6), and MIDAS change from 
baseline score (month 3 and 6)
To test the robustness of the results with respect to missing data, the missing data will be 
imputed using multiple imputation by chained equation assuming data is missing at random.1
First, the proportion and pattern of missing outcome values will be evaluated, and descriptive 
statistics of variables with missing values will also be evaluated. Additionally, among 
outcome variables with missing data, the association of missingness with other variables will 
be measured. Missing values will be imputed using fully conditional specification imputation 
in which each variable with missing values is imputed using regression (type of regression 
dependent on the variable distribution). Imputation models will be specified to include all 
analytic variables and additional variables that are associated with missingness. A minimum 
of 20 imputed datasets will be generated.2 Trace plots for continuous variables and tabulations 
for categorical variables of the imputed datasets will be evaluated to assess the validity of 
imputations methods. Methods to “penalize” missing values will also be explored. Only 
observations in the eptinezumab group will be used to impute missing data in patients 
randomized to eptinezumab, and only observations in the comparator arm will be used to 
impute missing data in patients randomized to the comparator arm. 
A mixed model with repeated measures (MMRM) will be used to evaluate the association 
between treatment and patient reported outcomes and a generalized linear model (log link and 
gamma distribution) will be used to evaluate the association between treatment and HCRU 
across the imputed datasets. Coefficients and standard errors obtained from each imputed 
dataset will be pooled and combined for inference using PROC MIANALYZE in which 
regression coefficients are averaged across imputations and standard errors are estimated to 
incorporate uncertainty within imputations and between imputations.1 The hypothesis tested 
will be that the treatment term is significantly different from zero using a two-sided test at 
p<0.05. The population level summary will be the difference in means at each specified time 
interval.
11.2.7
Supplementary Analyses of the Exploratory Endpoints
The correlation between migraine days and patient reported outcomes will be evaluated 
visually by plotting the average number of weekly migraine days versus average weekly 
values of the PI-MBS severity, number of good days, and EQ-5D across the 24-week follow-
up period based on the entire cohort. Weekly correlation values will be calculated using 
Spearman’s rank correlation and plotted across time.   
11.2.8
Covariate Investigation and Subgroup Analyses of the Exploratory Endpoints
Although patients are randomized to eptinezumab and advanced therapies, randomization may 
not produce balanced groups. Baseline covariates listed below will be compared across the 
treatment groups using descriptive statistics. Significant differences will be tested using the t-


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test or the Mann-Whitney test for continuous variables and chi-square test for categorical 
variables (Appendix I). 
Baseline covariates include: 
• Demographic variables
o Age
o Sex
o Marital status
o Race/ethnicity 
o Zip code
o Highest education level attained
o Current employment status 
• Clinical variables
o eDiary compliance 
o Number of migraine days in each of the past three months (MMDs)
o Previous use of oral preventive medications
o Migraine symptoms experienced in the seven days prior to enrollment
o Migraine history (including age at time of first attack and classification of migraine as 
CM, EM, and MOH)
o Migraine related medication history
o Vital signs (height, weight, blood pressure, pulse, respiration)
o All current medications being taken (including prescription, OTC, 
vitamins/supplements, vaccinations)
o Medication allergies
o Medical and psychiatric history
o Cardiac history
o Family medical history of migraines (parents and siblings)
o Use of tobacco or vaping products, or any other nicotine product
o Perceived stress scale
No subgroup analyses are planned. 
12 Safety Analyses
Adverse events (AEs) will be collected throughout the 6-month study period. Analyses of 
adverse events will be based on the APTS, and events will be reported according to the 
therapy the patient received (i.e., not the randomized group). 
All AEs will be coded according to the MedDRA version 24.0 or higher. The incidence of 
AEs occurring in the 6-month study period will be analyzed using descriptive statistics by 
therapy received. Given sufficient sample size, AEs may also be evaluated by dose received 
to evaluate any AE trends by dose. 


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Adverse events will be recorded according to MedDRA system organ class and preferred term 
by therapy group and classified as pre-treatment adverse events (an adverse event that starts 
on or after the date the patient signed the Informed Consent Form and prior to the date and 
time of first dose of therapy) or treatment-emergent adverse events (TEAE; an adverse event 
that starts or increases in intensity on or after the date and time of first dose of therapy). Only 
TEAEs will be reported and will be tabulated as:
• Any AEs 
• AEs probably related to the therapy received stratified by AE
• Severe AEs stratified by AE 
• AE leading to treatment discontinuation stratified by AE 
• Serious AE stratified by AE  
• Serious AE probably related to the therapy received by AE 
• Serious AE leading to treatment discontinuation stratified by AE  
• Fatal AE
• Overall AEs 
o Any SAE
o Any AE probably related to the therapy received
o Any Severe AE
o Any AE leading to treatment discontinuation
o Any serious AE
o Any serious AE probably related to the therapy received
o Any serious AE leading to treatment discontinuation
o Fatal AE
13 Data Reviews
Data quality is controlled throughout the study by study-specific edit checks programmed 
within the software platforms used to collect data (eCaseLink and eCaseLinkMe). 
Edit checks are separated into the following categories:
• Programmed edit checks primarily checks programmed within the EDC system that allow 
for data to be checked in real time during the data entry process, and which assist sites 
during data entry. These checks may be divided into:
o Database Check: The corresponding data field limits the entry to a specific format (e.g. 
time in “HH:MM” [hours:minutes]).  
o Programmed Soft Check: This check category allows a confirmation of the discrepant 
information and subsequent manual closing of the discrepancy by Xcenda. 
o Programmed Hard Check: This check category requires a correction of the entered value 
to close the discrepancy. 
• Manual edit checks: Checks that are not pre-programmed within the EDC system and are 
performed by appropriate Lundbeck and/or Xcenda study personnel. Manual checks may 


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result in the need for manual queries to be recorded by Xcenda within the EDC system 
for site response and/or data correction.
It is the responsibility of Xcenda to check on a regular basis whether additional edit checks 
are necessary to achieve final clean database with an acceptable error rate. All additional 
checks following deployment of the EDC system to the LIVE environment have to be 
approved by Lundbeck prior to implementation. Subsequent changes to the edit checks after 
first version release are tracked within the data dictionary.
Data recorded within eCaseLinkMe will not be queried by Xcenda, however, site study 
personnel will be trained to review the ePRO data prior to their monthly touchpoint with the 
patient in order to address any data entry errors or missing data moving forward. Patients will 
not have the ability to modify data once it has been submitted within eCaseLinkMe. Data 
listings may be generated in order to inform the study team of erroneous, implausible, or 
missing data. Findings from data listings may be shared with study sites in order to retrain 
patients on the data entry process and requirements. Data will be checked in real time via pre-
programmed edit checks that will assist the patient during the data entry process. Edit checks 
will be detailed in the data dictionary.
Lundbeck will conduct manual data reviews based on weekly data transfers from Xcenda 
which include but are not limited to:
• eCaseLink
o Descriptive statistics to evaluate randomization group, baseline demographics, medical 
history, concomitant medications, adverse events, and treatment administration. Missing 
data will be flagged and monitored. Consistent missing data will be escalated to 
Xcenda. 
• eCaseLinkMe
o Descriptive statistics to evaluate daily headache status and associated symptoms, and 
trends in patient reported outcomes. Missing data will be flagged and monitored. 
Consistent missing data will be escalated to Xcenda.
14 Interim Analyses
No interim analyses are planned. 
15 Sample Size
15.1
Sample Size Rationale
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. In addition, we lack 
good preliminary data on the exploratory outcomes and PROs for assessing sample size. 
Therefore, for illustrative purposes we have limited our power analysis to an evaluation of 
monthly migraine days based upon the results observed in the PROMISE trials and Phase IIIa 


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studies of other medications to be evaluated in EVEC. In the Panel 5 below we describe the 
effect size observed in the PROMISE 1 and 2 trials:
Panel 5
Effect Sizes Observed in Promise Trials
Note that in EVEC, it is expected that most patients will initiate treatment on the 100 mg 
dose. 
The primary hypothesis will be tested using the following regression model:
Y = β0 + β1x1 + β2x2 + βzxz + ε
Where “Y” is the number of migraine days accumulated from treatment initiation to the final 
day of week 12 (and 24), This “area under the curve” (AUC) calculation will provide more 
power than the PROMISE calculations which were based upon the change between the 
baseline month and the final month of observation. β1 is the coefficient associated with the 
number of migraine days reported in the month proceeding screening, and β2 is the coefficient 
associated with treatment group assignment (i.e., eptinezumab or other advanced preventive 
medications). Βz is the coefficient associated with the vector of other covariates that might be 
considered for inclusion in the model to control other sources of variation (i.e., botox 
assignment, age, gender, etc.).  
The loss to follow-up in the Promise trials was less than 10%. As this is a pragmatic real-
world trial with patients receiving free medication and having the opportunity to change 
treatments without penalty, we expect to have a similarly modest loss to follow-up.  
Study
SD*
Epti dose vs placebo Effect Size (ES; 
MMDs)
Standardized Effect
Size (SES)
Promise 1 (episodic)
3.0
30mg
-0.82
0.27
100mg
-0.69
0.23
300mg
-1.11
0.37
Promise 2 (chronic)
5.7
100mg
-2.0
0.36
300mg
-2.6
0.45


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Panel 6
Sample size and Power from PROMISE Trials Assumptions
As would be expected in a pragmatic trial, the sample size of EVEC (100 persons per arm) is 
a function of the project budget and timeliness. In Panel 6 we illustrate the expected power 
based upon the assumptions developed from PROMISE 1 and 2. We have highlighted the 100 
per arm for the PROMISE 2 effect size. If, as expected, we meet the PROMISE 2 
assumptions, we will have at least 72% power to demonstrate a standardized effect of 0.45. 
Given that we believe that the effect size will be larger in EVEC than observed in PROMISE 
2, even as we pool patients with episodic and chronic migraine, we expect to have a practical 
power in excess of 80% to find a difference between eptinezumab and the other advanced 
preventive medications with an alpha of 0.05. 
16 Statistical Software
Analyses will be conducted using SAS®, Version 9.4 or later and R®, Version 4.2.1 or later.  
17 Changes to Analyses Specified in the Protocol 
N/A
18 Details on Data Handling
18.1
Time from Scheduled Daily Report to Patient Reporting Time
If the time from the scheduled daily report on the eDiary to the reporting time of the patient 
exceeds >24 hours, then the patient report will be considered invalid, and all relevant data are 
considered missing. 
Standardized Effect size (SES)
N per arm
Power
0.23 (Promise 1)
100
37%
150
51%
200
63%
0.30 (average)
100
56%
150
74%
200
85%
0.36 (Promise 2)
100
72%
150
88%
200
95%


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18.2
eDiary
Compliance to the eDiary between the Screening and Baseline visits will be measured as the 
proportion of days in which the patient accessed the eDiary and responded to the question “In 
the last 24 hours did you have a headache?” within the time interval between the Screening 
visit and Baseline visit (inclusive of the days of the Screening and Baseline visit). 
18.3
Good Day/Bad Day Scale (Week 1-4, 1-12, and 1-24)
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 (i.e, the 
sum of the number of good days and bad days must equal 7).
The Good Day/Bad Day scale is reported weekly. If the total number of days reported is <7 
for a given week, then the number of good days will be considered as missing. Missing values 
will be imputed using multiple imputation methods based on the amount and pattern of 
missing data.
18.4
PI-MBS (weeks 1-4, 1-12, and 1-24)
Patients will report their most bothersome symptom associated with a headache including 
pain worsened by physical activity, throbbing head pain, nausea, vomiting, photophobia, 
phonophobia, difficulty concentrating, visual aura, other aura, or the patient may specify other 
symptoms. For the most bothersome symptom, patients will be asked to rate its severity 
ranging from mild (1) to severe (3). The PI-MBS data will be captured daily via the 
smartphone app when participants are prompted to report if they had a headache. The PI-MBS 
and severity will be descriptively summarized, and missing data will not be imputed. 
18.5
EQ-5D-5L (weeks 1-4, 1-12, and 1-24)
The EQ-5D-5L is a patient-reported assessment designed to measure the patient’s well-being.3
It consists of 5 descriptive items (mobility, self-care, usual activities, pain/discomfort, and 
depression/anxiety) and a visual analogue scale (VAS) of the overall health state. Each 
descriptive item is rated on a 5-point index ranging from 1 (no problems) to 5 (extreme 
problems). The VAS is scored separately and ranges from 0 (worst imaginable health state) to 
100 (best imaginable health state). A single summary index (from 0 to 1) will be calculated
based on item responses using the Unites States value set (EuroQoL).
The EQ-5D will be reported weekly, and a missing weekly value for the EQ-5D score will be 
imputed using multiple imputation methods based on the amount and pattern of missing data.
18.6
HCRU (weeks 1-4, 1-12, and 1-24)
All-cause medical HCRU will include outpatient physician visits, inpatient hospitalizations, 
urgent care visits, and emergency department visits. Medications (over-the-counter and 


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prescription) used for the acute relief and prevention of migraine will also be included. HCRU 
is reported by patients using the ePRO application on a daily basis and on the HCRU follow-
up questionnaire, which is a comprehensive review of patient HCRU obtained by study 
coordinators during the monthly visits. Since the HCRU follow-up questionnaire contains 
more comprehensive information (i.e., patient reported HCRU and any that may not have 
been reported by the patient on the ePRO), the analysis will be based on the HCRU follow-up 
questionnaire. However, data reported in the ePRO and follow-up questionnaire will be 
compared to assess for inconsistencies. Missing values will not be imputed. 
18.6.1
Medical HCRU
Medical HCRU will be ascertained based on the HCRU follow-up questionnaire. Reported 
counts of HCRU will be summed across weeks 1-4, 1-12, and 1-24 based on the date of 
reported healthcare utilization.
Reported HCRU will be stratified as outpatient (physician office visit, outpatient service use, 
outpatient surgery), urgent care visit, emergency room visit, and inpatient service. 
18.6.2
Medication HCRU
Migraine medication HCRU (over-the-counter and prescription) will be ascertained based on 
the patient’s reported medication use during the monthly follow-up visits in which the study 
coordinator reviews all reported medication use in addition to any unreported utilization. 
Reported counts of medications will be summed across weeks 1-4, 1-12, and 1-24 based on 
the reported start and discontinuation dates of the medication. 
Medications will be classified as acute, or preventive stratified by drug class:
-
Acute
o Oral anti-CGRP
o Triptans 
o Analgesics (opioids, non-narcotic, anti-inflammatory)
o Barbiturate hypnotics
o Ergots 
o 5-HT agonist
o Isometheptene
o Antiemetics
-
Preventive
o Anticonvulsants
o Serotonin-norepinephrine reuptake inhibitor
o Selective serotonin reuptake inhibitors 
o Tricyclic antidepressants 
o Antihistamines
o Antihypertensives (angiotensin converting enzyme inhibitors, angiotensin 
receptor blockers, beta-blockers, alpha agonists, calcium channel blockers)


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o NMDA antagonists
o Monoamine oxidase inhibitors 
18.7
HIT-6 (week 4, 12, and 24)
The HIT-6 (v1.0) is a Likert-type, self-reporting questionnaire designed to assess the impact 
of an occurring headache and its effect on the ability to function normally in daily life.4 The 
HIT-6 contains 6 questions, each item is rated from “never” to “always” with the following 
response scores: never = 6, rarely = 8, sometimes = 10, very often = 11, and always = 13. The 
total score for the HIT-6 will be sum of each item score which ranges from 36 to 78.5  The life 
impact derived from the total score is described as followed: Severe (≥60), Substantial (56-
59), Some (50-55), Little to None (≤49).
The HIT-6 will be reported monthly and missing values will be imputed using multiple 
imputation methods based on the amount and pattern of missing data. 
18.8
MIDAS (weeks 12 and 24)
The MIDAS Questionnaire was developed to assess headache-related disability.6 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 migraine. The MIDAS score will be 
the sum of days reported from questions 1 through 5.7
The MIDAS score may be categorized according to the following:7
Score
Grade
Disability 
0-5
I
Little or no disability
6-10
II 
Mild disability
11-20
III
Moderate disability
≥21
IV
Severe disability
The MIDAS will be reported quarterly (weeks 12 and 24), and missing values will be imputed 
using multiple imputation methods based on the amount and pattern of missing data. 
18.9
Drug Switching
Drug switching will be based on monthly follow-up visits. In the case in which follow-up data 
is missing and it is unknown whether the patient received their treatment or switched, we will 
assume that the patient is still receiving their index therapy. 
18.10 TSQM (week 24)
The TSQM (version 1.4) measures the satisfaction of patients with their treatment with 
respect to side effects, effectiveness, convenience, and global satisfaction.8 The TSQM score 
ranges from 0 to 100 with high scores indicating greater satisfaction for each domain. Scores 
will for each domain will be calculated according to the following: 


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Effectiveness: ([(Item 1 + Item 2 + Item 3) − 3] divided by 18) × 100 If one item is missing: 
([(Sum of Item 1? + Item 2? + Item 3?)) − 2] divided by (12) × 100 
Side effects: ([Sum of Item 5 to Item 8) − 4] divided by 16) × 100 If one item is missing: 
([(Sum of Item 5? to Item 8?)) − 3] divided by 12) × 100
Convenience: ([Sum of Item 9 to Item 11) − 3] divided by 18) × 100 If one item is missing: 
([(Sum of Item9? to Item11?)) − 2] divided by (12) × 100 
Overall satisfaction, first recode Item14_recode = (Item14 − 1) × 5/6 , then: ([Sum of Item 12 
to Item 14) − 3] divided by (12) × 100 If any one Item is missing: ([Sum of Item 12? to Item 
14?) − 2] divided by (8) × 100
The TSQM will be reported at week 24, and missing values will not be imputed.
18.11 SDMQ-9 (screening and week 24)
The SDM-Q-9 measures the extent to which patients are involved in the process of decision-
making from the perspective of the patient.9  The questionnaire contains nine items, each 
describing one step of the SDM process. 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).10
Scores will be summed across the 9 items to calculate the raw total score ranging from 0 to 45 
with higher scores indicating higher shared decision making. 
The SDMQ-9 will be reported at screening and week 24, and missing values will not be 
imputed.
18.12 SURE (screening)
The SURE test is a brief 4-item screening questionnaire the patient uses to assess their 
readiness and capacity to decide or to determine whether they are comfortable with their 
decision.11 An answer of “yes” to an item yields a value of 1 and an answer of “no” yields a 
value of 0. Item values are summed to calculate the total score. A score of 4 indicates that a 
patient should not be experiencing a clinically significant decisional conflict, whereas a value 
of <4 indicates the presence of a clinically significant decisional conflict. 
The SURE score will be reported at screening, and missing values will not be imputed. 
18.13 PAM-10 (screening, week 12 and 24)
The Patient Activation Measure evaluates the knowledge, skills, and confidence a patient has 
in managing his or her health conditions.12 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 


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Study 19766N - Statistical Analysis Plan                                                                                                                 Page 35 of 42
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.13 Scores will be calculated based on item responses using a 
propriety algorithm. 
The PAM-10 score will be reported at screening, week 12, and week 24, and missing values 
will not be imputed. 
18.14 PSS
The Perceived Stress Scale (PSS) is a classic stress assessment instrument. The tool, measures 
how different situations affect feelings and perceived stress. The questions ask about feelings 
and thoughts during the last month.14 The 10 items use a 5-point Likert scale ranging from 0 
(never) to 4 (very often). Item scores are summed to arrive at a total score ranging from 0 to 
40, with higher scores indicating greater perceived stress. 
The PSS will be reported monthly, and missing values will be imputed using multiple 
imputation based on the amount and pattern of missing data. 
18.15 ISS (screening, week 12 and 24)
All participants receiving eptinezumab (regardless of initial treatment assignment) will 
complete an eptinezumab-specific survey describing their satisfaction with the infusion 
experience after each infusion while on site using a paper questionnaire.
The ISS item responses will be reported at screening, week 12, and week 24, and missing 
values will not be imputed. 
18.15.1 Weekly Migraine Days
For a 1-week period in which the eDiary is accessed (i.e., the patient reported the presence or 
absence of a headache) on at least 4 of the 7 days, the weekly number of migraine days will 
be prorated as follows:
7 eDiary Days*(Reported Migraine Days/Reported eDiary Days)
For a 1-week period in which the eDiary is accessed on less than 4 of the 7 days, then we will 
assume that the missing days are migraine days. The rationale is that patients will not fill out 
the eDiary while having a migraine, therefore, we assume that the missing days are migraine 
days. If the patient accesses the eDiary and does not report a headache, then we will assume 
that the patient did not have a migraine on that day. 


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References
1. Berglund, P. A. (2018, April). Using SAS for Multiple Imputation and Analysis of Longitudinal
Data. In Proceedings of the SAS® Global Forum 2018 Conference, Denver, CO, USA (pp. 8-11).
2. Sinharay, S., Stern, H. S., & Russell, D. (2001). The use of multiple imputation for the analysis of 
missing data. Psychological methods, 6(4), 317.
3. Herdman, M., Gudex, C., Lloyd, A., Janssen, M. F., Kind, P., Parkin, D., et al. (2011). Development 
and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). Quality of life 
research, 20, 1727-1736.
4. Kosinski, M., Bayliss, M. S., Bjorner, J. B., Ware, J. E., Garber, W. H., Batenhorst, A., et al. (2003). 
A six-item short-form survey for measuring headache impact: The HIT-6™. Quality of life 
research, 12, 963-974.
5. Shin, H. E., Park, J. W., Kim, Y. I., & Lee, K. S. (2008). Headache Impact Test-6 (HIT-6) scores 
for migraine patients: their relation to disability as measured from a headache diary. Journal of 
clinical neurology, 4(4), 158-163.
6. Stewart WF, Lipton RB, Dowson AJ, Sawyer J. Development and testing of the Migraine   
Disability Assessment (MIDAS) Questionnaire to assess headache-related disability. Neurology. 
2001.
7. Bigal, M. E., Rapoport, A. M., Lipton, R. B., Tepper, S. J, et al. (2003). Assessment of migraine 
disability using the migraine disability assessment (MIDAS) questionnaire: a comparison of 
chronic migraine with episodic migraine. Headache: The Journal of Head and Face Pain, 43(4), 
336-342.
8. Atkinson, M. J., Kumar, R., Cappelleri, J. C., & Hass, S. L. (2005). Hierarchical construct validity 
of the treatment satisfaction questionnaire for medication (TSQM version II) among outpatient 
pharmacy consumers. Value in Health, 8, S9-S24.
9. Kriston, L., Scholl, I., Hölzel, L., Simon, D., Loh, A., & Härter, M. (2010). The 9-item Shared 
Decision Making Questionnaire (SDM-Q-9). Development and psychometric properties in a 
primary care sample. Patient education and counseling, 80(1), 94-99.
10. Ballesteros, J., Moral, E., Brieva, L., Ruiz-Beato, E., Prefasi, D., & Maurino, J. (2017). 
Psychometric properties of the SDM-Q-9 questionnaire for shared decision-making in multiple 
sclerosis: item response theory modelling and confirmatory factor analysis. Health and quality of 
life outcomes, 15(1), 1-6.
11. Ferron Parayre, A., Labrecque, M., Rousseau, M., Turcotte, S., & Legare, F. (2014). Validation of 
SURE, a four-item clinical checklist for detecting decisional conflict in patients. Medical 
Decision Making, 34(1), 54-62.
12. Hibbard, J. H., Stockard, J., Mahoney, E. R., & Tusler, M. (2004). Development of the Patient 
Activation Measure (PAM): conceptualizing and measuring activation in patients and consumers. 
Health services research, 39(4p1), 1005-1026.
13. Greene, J., Hibbard, J. H., Sacks, R., Overton, V., & Parrotta, C. D. (2015). When patient 
activation levels change, health outcomes and costs change, too. Health affairs, 34(3), 431-437.
14. Roberti, J. W., Harrington, L. N., & Storch, E. A. (2006). Further psychometric support for the 10‐
item version of the perceived stress scale. Journal of College Counseling, 9(2), 135-147.


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Appendix I
Covariate Definitions


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Covariate Definitions
Table 1
Covariate Definitions
Variable
Time of 
measurement
Measurement
Definition
Treatment Group
Randomized group
Screening visit
Categorical
- Eptinezumab
- OnabotulinumtoxinA
- Self-injectible anti-CGRP
o Erenumab
o Fremanezumab
o galcanezumab
Eptinezumab dose
- 100 mg
- 200 mg
- 300 mg
Aimovig dose
Screening visit
Categorical
- 70 mg
- 140 mg
Ajovy Dose
Screening visit
Categorical
- 225 mg
- 675 mg
Emgality loading dose
- Yes
- No
Demographics
Age
Screening visit
Continuous 
Age of patient at time of enrolment
Sex
Screening visit
Categorical
- Female
- Male
Marital Status
Screening visit
Categorical
- Married,
- Divorced/separated/widow/widower
- Single
- Not reported 
Race
Screening visit
Categorical 
- White
- Asian
- Black/African American
- Native Hawaiian or Other Pacific 
Islander
- American Indian or Alaska Native
- Other or Unknown
Ethnicity 
Screening visit
Categorical
- Hispanic or Latino
- Not Hispanic or Latino
- Unknown 
Education
Screening visit
Categorical 
- Did not complete high school
- Highschool diploma or GED
- Some college or certificate
- College or university degree (2 year 
or 4 year)


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Variable
Time of 
measurement
Measurement
Definition
- Masters, doctorate, or other 
advanced professional degree
- Not reported 
Employment status
Screening visit
Categorical
- Full time employment
- Not reported or Other
- Homemaker 
- Part-time employment
- Retired 
- Student
- Unemployed 
- Volunteer 
- Disabled
Clinical Characteristics
eDiary compliance
Screening visit 
to baseline 
visit 
- A response to the question “In the 
last 24 hours did you have a 
headache?”
Age at onset of first migraine
Screening visit
Categorical 
- 18-33
- 34-48
- 49-64
- >64
- Unknown
Migraine classification 
Screening visit
Categorical
- Chronic
- Episodic 
- Medication overuse headache
MHDs in the past 3 months
Screening visit
Categorical
(How many headache days did the 
patient have… [IN THE LAST 
MONTH] +
How many headache days did the 
patient have… [IN THE MONTH 
BEFORE LAST] +
How many headache days did the 
patient have… [TWO MONTHS 
BEFORE LAST])/3 months
MMDs in the past 3 months 
Screening visit
Discrete 
(How many migraine days did the 
patient have… [IN THE LAST 
MONTH] +
How many migraine days did the 
patient have… [IN THE MONTH 
BEFORE LAST] +
How many migraine days did the 
patient have… [TWO MONTHS 
BEFORE LAST])/3 months 
Family history of migraine
Screening visit
Categorical
- Yes
- No
- Unknown 
1st preventive oral drug failure
Screening visit
Categorical
- Yes (if the patient does not respond 
with “none”)
- No (if the patient responds with 
“none”)


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Variable
Time of 
measurement
Measurement
Definition
2nd  preventive oral drug 
failure
Screening visit
Categorical
- Yes (if the patient does not respond 
with “none”)
- No (if the patient responds with 
“none”)
Migraine symptoms 
experienced in the last 7 days 
(patients may respond with 
more than one answer)
Screening visit 
Categorical
- Headpain that worsens with any 
movement or physical activity
- Throbbing head pain
- Nausea
- Vomiting
- Phonophobia
- Photophobia
- Difficulty concentrating or thinking 
clearly
- Visual aura
- Other aura
- Other  
1st preventive oral drug failure 
class
Screening visit
Categorical
- Advanced preventive
o Aimovig
o Ajovy
o Emgality 
o onabotulinumtoxinA
o Vyepti 
- Antihypertensive
o Atenolol
o Bisoprolol
o Candesartan
o Lisinopril
o Metoprolol
o Nadolol
o Nebivolol
o Pindolol
o Propranolol
o Timolol
o Verapamil
- Antidepressant
o Amitriptyline
o Desipramine
o Desvenlafaxine
o Doxepin 
o Duloxetine
o Milnacipran 
o Nortriptyline 
o Protriptyline
o Venlafaxine
- Antihistamine


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Variable
Time of 
measurement
Measurement
Definition
o Cyproheptadine
o Flunarizine 
- Anticonvulsant 
o Divalproex sodium
o Gabapentin
o Pregabalin 
o Sodium valproate
o Topiramate
o Zonisamide
- Other
o Memantine
o “other”
- None
2nd  preventive oral drug 
failure class
Screening visit
Categorical
Same as above
Acute medication use
Screening visit
Categorical
- Opioid analgesics (alone and in 
combination)
- Non-narcotic analgesics 
(acetaminophen, aspirin, 
caffeine, alone or in 
combination)
- Anti-inflammatory analgesics 
(NSAIDs)
- Barbiturate hypnotics
- 5-HT agonists
- Oral anti-CGRPs (Rimegepant, 
ubrogepant)
- Isometheptene containing products
- Antiemetics (chlorpromazine, 
droperidol, metoclopramide, 
prochlorperazine, promethazine)
All current medications
Screening visit
Categorical 
- TBD
Medical history (psychiatric, 
cardiac, and etc) 
Screening visit
Categorical 
- TBD
Smoking history 
Screening visit
Categorical
- Never
- Current 
- Former
Smokeless tobacco history 
Screening visit
Categorical
- Never
- Current 
- Former
Vaping history
Screening visit
Categorical
- Never
- Current 
- Former
Body mass index
Screening visit
Continuous 
- Calculated as BMI = weight (kg) ÷ 
height^2 (meters)
Perceived stress scale 
Baseline visit 
Categorical 
The total score will be defined as the 
sum of scores across all questions. 


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Variable
Time of 
measurement
Measurement
Definition
Total score will be categorized as (PSS 
Calculator):
- Low stress = 0-13
- Moderate stress = 14-26
- High stress = 27-40