Interventional, Randomized, Double-blind, Parallel-group, Placebo-controlled Study of add-on Eptinezumab Treatment to Brief Educational Intervention for the Preventive Treatment of Migraine in Patients With Dual Diagnosis of Migraine and Medication Overuse Headache
Phase: PHASE4
Conditions: Migraine, Medication Overuse Headache
Sponsor: H. Lundbeck A/S

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Final: Version 1.0
PLUTO ID: CLI_01719596
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Full Title
Interventional, randomized, double-blind, parallel-group, placebo-controlled study
of add-on eptinezumab treatment to brief educational intervention for the preventive
treatment of migraine in patients with dual diagnosis of migraine and medication
overuse headache
Short Title
20007A - Protocol - Edition 1.0
Study Number
20007A
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Study 20007A – Clinical Study Protocol
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Clinical Study Protocol
Interventional, randomized, double-blind, parallel-group,
placebo-controlled study of add-on eptinezumab treatment to
brief educational intervention for the preventive treatment of
migraine in patients with dual diagnosis of migraine and
medication overuse headache
Eptinezumab
Study No.:
20007A (RESOLUTION)
EudraCT/IND No.:
2021-003049-40 (EU) / 114647 (US)
Sponsor:
H. Lundbeck A/S (Lundbeck)
2500 Valby (Copenhagen), Denmark
Edition No.:
1.0
(the version No. in the footer is the system version No.)
Date of edition:
22 December 2021
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.
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Pluto ID: 
Status:  
Version: 1.0
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Synopsis – Study 20007A
Sponsor
H. Lundbeck A/S
Investigational Medicinal Product
Eptinezumab
Study Title
Interventional, randomized, double-blind, parallel-group, placebo-controlled study of add-on eptinezumab 
treatment to brief educational intervention for the preventive treatment of migraine in patients with a dual 
diagnosis of migraine and medication overuse headache
Objectives and Endpoints
Objectives
Endpoints
Primary Objective
To evaluate the efficacy 
of eptinezumab as add-
on to BI for the 
prevention of migraine 
and treatment of MOH
Primary endpoint:
Change from baseline in the number of MMDs (Weeks 1-4)
Key secondary endpoints:
Change from baseline in MMDs (Weeks 1-12)
Change from baseline in the number of MHDs (Weeks 1-4)
Change from baseline in MHDs (Weeks 1-12)
Not fulfilling the ICHD-3 diagnostic criteria for CM nor MOH (Week 4)
Not fulfilling the ICHD-3 diagnostic criteria for CM nor MOH (Week 12)
Change from baseline in average Daily Pain assessment score (Weeks 1-2)
Change from baseline in monthly days with acute medication use (Weeks 1-4)
Change from baseline in monthly days with acute medication use (Weeks 1-12)
Secondary endpoints:
Not fulfilling the ICHD-3 diagnostic criteria for CM (Week 4, Week 12)
Not fulfilling the ICHD-3 diagnostic criteria for MOH (Week 4, Week 12)
Change from baseline in MMDs with use of acute medication (Weeks 1-12)
Change from baseline in monthly days with triptan or ergotamine medication 
use (Weeks 1-12)
Change from baseline in monthly days with individual non-opioid analgesics or 
NSAID medication use (Weeks 1-12)
Change from baseline in monthly days with combination non-opioid analgesics 
medication use (Weeks 1-12)
Migraine on the day after dosing (Day 1)
Response: ≥50% reduction from baseline in MMDs (Weeks 1-4, Weeks 1-12)
Response: ≥75% reduction from baseline in MMDs (Weeks 1-4, Weeks 1-12)
Response: ≥50% reduction from baseline in MHDs (Weeks 1-4, Weeks 1-12)
Response: ≥75% reduction from baseline in MHDs (Weeks 1-4, Weeks 1-12)
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Objectives and Endpoints (continued)
Objectives
Endpoints
Secondary endpoints (continued):
Change from baseline in rate of migraines with severe pain 
intensity (Weeks 1-4, Weeks 1-12)
Change from baseline in rate of headaches with severe pain 
intensity (Weeks 1-4, Weeks 1-12)
PGIC score at Week 4 and Week 12
MBS score at Week 12
Exploratory endpoints:
Complete withdrawal of acute headache medication (Weeks 1-4, 
Weeks 5-8, Weeks 9-12)
Secondary Objectives
To evaluate the efficacy of 
eptinezumab as add-on to BI on health-
related quality of life and work 
productivity
Secondary endpoints
Change from baseline to Week 4, and from baseline to Week 12 
in the HIT-6 total score
Change from baseline to Week 4 and from baseline to Week 12 
in the mMIDAS total score
Change from baseline to Week 4, and from baseline to Week 12 
in the MSQ v2.1 sub-scores (Role Function-Restrictive, Role 
Function-Preventive, Emotional Function)
Change from baseline to Week 4, and from baseline to Week 12 
in the EQ-5D-5L VAS score
Migraine specific HCRU at Baseline and at Week 12
Change from baseline to Week 12 in the WPAI:M sub-scores 
(Absenteeism, Presenteeism, Work productivity loss, Activity 
impairment)
Change from baseline to Week 4, and from baseline to Week 12 
in HADS - depression, and anxiety subscale scores
Change from baseline to Week 4, and from baseline to Week 12 
in TSQM-9
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Objectives and Endpoints (continued)
Objectives
Endpoints
To evaluate the efficacy of 
eptinezumab during the 12-week 
open-label extension period
Change from baseline to Week 24 in the HIT-6 total score
Change from baseline to Week 24 in the mMIDAS total score
Change from baseline to Week 24 in the MSQ v2.1 sub-scores
Change from baseline to Week 24 in the EQ-5D-5L VAS score
Migraine specific HCRU at Week 24
Change from baseline to Week 24 in the WPAI:M sub-scores 
Change from baseline to Week 24 in HADS - depression and 
anxiety subscale scores 
PGIC score at Week 24
MBS score at Week 24
Change from baseline to Week 24 in TSQM-9
Change from baseline to Week 24 in MMDs
Change from baseline to Week 24 in MHDs
Not fulfilling the ICHD-3 diagnostic criteria for CM nor MOH 
(Week 24) 
Change from baseline to Week 24 in monthly days with acute 
medication use
Change from baseline to Week 24 in average Daily Pain 
assessment score 
Change from baseline to Week 24 in monthly days with triptan or 
ergotamine medication use
Change from baseline to Week 24 in monthly days with 
individual non-opioid analgesics or NSAID medication use
Exploratory Objectives
To investigate the efficacy of 
eptinezumab as add-on to BI on level 
of daily physical activity and sleep 
using a wearable digital device (subset)
Exploratory Endpoints
Change from baseline to Week 4 and Week 12 of passive 
registration of movement (actigraphy) (average per 28 days)
Minutes with light PA (11-50 a.U.) 
Minutes with moderate PA (51-100 a.U.)
Minutes with intense PA (101-200 a.U.)
Minutes in rest period (range 0-300, 101: rest epoch)
Change from baseline to Week 4 and Week 12 in sleep metrics 
assessment as assessed by actigraphy (average per 28 days)
Total Sleep Time (minutes per night)
Sleep Efficiency (percentage per night)
Wake After Sleep Onset (minutes per night) 
Sleep Onset Latency (minutes per night)
All analyses will also be done by week, for example change from 
baseline to Week 1, baseline to Week 2, and baseline to Week 12.
To investigate efficacy of eptinezumab 
as add-on to BI on the level of 
analgesic dependence 
Change from baseline to Week 12 in SDS:H score 
Safety Objective 
• To evaluate the safety and tolerability 
of eptinezumab
Safety Endpoints
Adverse events
Absolute values and changes from baseline in vital signs
Potentially clinically significant vital signs changes
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Study Methodology
This is a phase 4, interventional, multi-national, multi-site, randomized, double-blind, parallel-group, 
placebo-controlled study designed to demonstrate the efficacy and safety of add-on eptinezumab treatment to 
BI, performed at baseline, for the prevention of migraine and treatment of MOH in patients with a dual 
diagnosis of migraine and MOH.  The 12-week placebo-controlled period will be followed by a 12-week 
open-label period where all patients will receive eptinezumab to provide further relief and gain exploratory 
data on the durability of a potential remission of the MOH and CM. The safety and tolerability of 
eptinezumab will be also further assessed in this open-label period.
The target population for this study is defined as patients with a dual diagnosis of migraine and MOH and a 
level of disease activity matching the CM definition according to the IHS ICHD-3 guidelines. The  
medication overuse will be confirmed via prospectively collected information in the eDiary during the 
screening period.
Patients will be instructed to stop medication overuse during a semi-structured educational conversation.
Patients will be allowed use of medications (with restrictions for some of them) for acute and/or symptomatic 
treatment of headache (for example, paracetamol, NSAID, triptans, ergotamine, opioids, and/or combination
analgesics) throughout the study.  However, at the Baseline Visit they will be educated not to use acute 
medications.
Eligible patients will be randomly allocated via a randomization system to one of the two treatment groups: 
BI and eptinezumab 100 mg, or BI and placebo, in a ratio of 1:1.
Randomization will be stratified by country and number of previous preventive treatment failures (≤2; >2) 
occurring up to 5 years prior to Baseline Visit by using IRT system. Treatment failure is defined as treatment 
discontinuation due to lack of efficacy (no clinically meaningful improvement at the recommended or 
prescribed dose for at least 3 months), side effects, or general poor tolerability of the treatment.
The total study duration from Screening Visit to Safety Follow-up Visit is approximately 36 weeks and 
includes a screening period (4 weeks), a placebo-controlled period (12 weeks), an open-label period (12 
weeks), and a safety follow-up period (8 weeks).
Patients will attend on-site visits at the Screening Visit, visits with IMP intravenous (IV) infusions (Baseline 
Visit and Week 12 Visit), and EoS Visit at Week 24. All other visits will be conducted as telephone or 
telemedicine visits.
Patients will complete a daily headache eDiary from Screening Visit until EoS/Withdrawal Visit.
Patients will receive BI and IMP (eptinezumab or placebo) at Baseline Visit during the placebo-controlled 
period and IMP (eptinezumab) at Week 12 Visit during the open-label period. IMP is administered by 
intravenous infusion over 30 minutes (with possibility to extend the intravenous infusion by 15 minutes). 
During the visits with IMP infusion, safety assessments will be performed before and after the IV infusion. 
The ePROs must be completed prior to the intravenous infusion. Patients must ensure to complete eDiary 
recording of headaches prior to the intravenous infusion (that is, for headaches which are ongoing or not yet 
recorded in the eDiary).
The primary outcome visit is at Week 4 during the placebo-controlled period.
At designated sites, optional actigraphy assessments using a digital device will be performed on a consenting 
subset of patients. Patients can withdraw from these optional assessments without withdrawing from the main 
study.
Patients will be scheduled for a Safety Follow-up Contact (at Week 32), 8 weeks after EoS Visit. 
Patients who withdraw their consent for study participation should be withdrawn from the study. However, 
all efforts should be done to keep the patients who interrupted/terminated their IMP infusion in the study and 
all assessments should be performed as described in the protocol. If patients want to withdraw from the study 
and thus not willing to attend the remaining visits as scheduled, they will be asked to attend a Withdrawal 
Visit as soon as possible and a Safety Follow-Up Contact, 20 weeks after last administration of IMP.
The study design is presented in Panel 1 (including the study periods) and the scheduled study procedures and 
assessments are summarized in Panel 2.
Number of Patients Planned
570 patients, recruited from specialist setting, are planned for randomization: 285 in the BI + eptinezumab 
100 mg group and 285 in the BI + placebo group.
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Target Patient Population
Main Inclusion Criteria
The patient has a diagnosis of CM as defined by IHS ICHD-3 guidelines confirmed at the Screening Visit.
The patient has a history of migraine onset of at least 12 months prior to the Screening Visit.
The patient has ≥8 migraine days per month for each month within the past 3 months prior to the Screening 
Visit.
The patient has a diagnosis of MOH as defined by IHS ICHD-3 guidelines confirmed at the Screening Visit. 
The patient has ≥15 headache days per month for each month within the past 3 months prior to the 
Screening Visit.
The patient has regular overuse of one or more drugs that can be taken for acute treatment of headache, for 
>3 months prior to the Screening Visit.
The patient has ≥15 to ≤26 headache days, of which ≥8 days were assessed as migraine days during the 
screening period, based on prospectively collected information in the eDiary.
The patient overuses drugs that can be taken for acute treatment of headache during the screening period, 
based on prospectively collected information in the eDiary.
The patient has a history of treatment failure with at least 1 preventive treatment within the last 5 years prior 
to the Screening Visit due to lack of efficacy (no clinically meaningful improvement at the locally 
recommended dose for at least 3 months).
The patient has demonstrated compliance with the Headache eDiary by entry of data for at least 24 of the 
28 days following the Screening Visit.
The patient has had an onset of migraine diagnosis at <50 years of age. 
The patient is aged ≥18 and ≤75 years at the Screening Visit.
Main Exclusion Criteria
The patient has experienced failure on a previous preventive treatment targeting the CGRP pathway
including gepants for acute or preventive use. 
The patient has confounding and clinically significant pain syndromes (for example, fibromyalgia, chronic 
low back pain, and complex regional pain syndrome).
The patient has a diagnosis of acute or active temporomandibular disorders.
The patient has a history or diagnosis of chronic tension-type headache, hypnic headache, cluster headache, 
hemicrania continua, new daily persistent headache, or unusual migraine subtypes such as hemiplegic 
migraine (sporadic and familial), recurrent painful ophthalmoplegic neuropathy, migraine with brainstem 
aura and migraine with neurological accompaniments that are not typical of migraine aura (diplopia, altered 
consciousness, or long duration).
The patient has psychosis, bipolar mania, dementia, or any other psychiatric conditions whose symptoms 
are not controlled or who has not been adequately treated for a minimum of 6 months prior to the Screening 
Visit.
The patient has a history of clinically significant cardiovascular disease, including uncontrolled 
hypertension, vascular ischaemia, or thromboembolic events (for example, cerebrovascular accident, deep 
vein thrombosis, or pulmonary embolism).
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Target Patient Population (continued)
The following recent and concomitant medications are disallowed or allowed with restrictions with respect to 
their use prior to or during the study (the list is not exhaustive):
Disallowed: any investigational products within 30 days or 5 plasma half-lives (whichever is longer) before 
the Screening Visit. The following treatments are disallowed while the patient is under IMP (and can be 
prescribed after the patient has withdrawn the IMP treatment while still remaining in the study): 
eptinezumab or other mAb treatment targeting the CGRP pathway; oral CGRP antagonists for acute or 
preventive treatment; CNS- and migraine-related devices (neuromodulation, neurostimulation) or injectable 
therapy (trigger point injections, extracranial nerve blocks, or facet joint injections); botulinum toxin; 
monoamine oxidase inhibitors, ketamine, methysergide, methylergonovine, or nimesulide.
Allowed with restrictions: prescription or over-the-counter medication for preventive treatment of migraine 
prescribed or recommended by a health care professional; hormonal therapy (for example, contraceptives, 
hormone replacement therapy); anti-impotence agents; barbiturates (including Fiorinal®, Fioricet®, or any 
other combination containing butalbital); prescription opiates (including single-ingredient or combination 
medications containing opiates, opioids, tramadol, or tapentadol); and non-pharmacological interventions.
IMP, Dose and Mode of Administration, and Reference Therapy
Reference therapy: BI for MOH
BI is a semi-structured educational conversation with the purpose on helping the patients to reduce their 
MOH. The BI starts with five questions of the SDS:H (including an indication of the patient’s willingness 
and confidence to change his/her medication overuse). Then patient is shown a short-structured scheme 
bases presentation either on a flip-over or slides with information about MOH and the association between 
medication overuse and chronic headache. The interview will end with an agreed plan on how to stop or 
reduce the medication overuse. 
The intervention will take approximately 10 minutes to complete and is performed at Baseline Visit before IMP 
infusion.
IMP
Dosage form
Eptinezumab – 100 mg, Concentrate for Solution for Infusion 100 mg/mL added to 100 mL of 0.9% 
normal saline
Placebo – 100 mL of 0.9% normal saline
The IMP will be administered at Baseline Visit and Week 12 Visit (Visit 5), by intravenous infusion over 
30 minutes (+15 minutes).
Assessment Details 
The assessments are summarized in Panel 2. Details for assessments that are non-standard or require more 
description are provided below:
eDiary
Patients will complete a headache eDiary daily from the Screening Visit until the EoS/Withdrawal Visit. 
The eDiary consists of applications and reports which will be used to derive the migraine and headache 
endpoints, and medication use. The eDiary will be distributed to each patient at the Screening Visit after 
patient training on eDiary use by site staff. The eDiary data from the 28 days following the Screening Visit 
will be used to verify eligibility criteria, baseline migraine and headache values, and eDiary compliance. 
Ongoing evaluation of eDiary compliance will be performed by the study site based on eDiary reports.
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Assessment Details (continued)
HIT-6 (v1.0)
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.  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 is the sum of each 
response score and ranges from 36 to 78.  The life impact derived from the total score is described as 
followed: Severe (≥60), Substantial (56 59), Some (50-55), Little to None (≤49).  It takes less than 
5 minutes to complete the HIT 6 questionnaire.
mMIDAS
The mMIDAS is a self-reporting questionnaire designed to assess absenteeism (complete disability) and 
presenteeism (reduced participation) in several domains, including work, school, family, social, and leisure 
activities.  The total number of days with disability is rated on a 4-point scale, from the lower total score 
that indicates a Little or No Disability; Mild Disability; Moderate Disability to the higher total score that 
indicates a Severe Disability.  It takes approximately 5 to 10 minutes to complete the mMIDAS.
MSQ (v2.1)
The MSQ v2.1 is a patient-reported outcome designed to assess the quality of life in patients with migraine.  
It consists of 14 items covering three domains: role function restrictive (7 items); role function preventive 
(4 items); and emotional function (3 items).  Each item is scored on a 6-point scale ranging from 1 (none of 
the time) to 6 (all of the time).  Raw domain scores are summed and transformed to a 0-to-100-point scale.  
Higher scores indicate better quality of life.  It takes approximately 5 to 10 minutes to complete the MSQ 
v2.1.
PGIC
The PGIC is a single patient-reported item reflecting the patient’s impression of change in their disease 
status since the Baseline Visit (that is, in relation to activity limitations, symptoms, emotions, and overall 
quality of life). The item is rated on a 7-point scale, where a high score indicate improvement (very much 
improved; much improved; minimally improved; no change; minimally worse; much worse; very much 
worse). It takes approximate 1 minute to complete the scale.
MBS
The Investigator will verbally obtain the most bothersome symptom associated with the patient’s migraines 
during the Screening Visit. The selected most bothersome symptom will be incorporated in the electronic 
version of the MBS (ePRO). Patients will be asked to rate the improvement in this symptom from 
screening on a 7-point scale identical to the scale used for the PGIC. The MBS areas include nausea, 
vomiting, sensitivity to light, sensitivity to sound, mental cloudiness, fatigue, pain with activity, mood 
changes, and other. It takes less than 5 minutes to complete the MBS.
HCRU
Migraine-specific health care resource utilization information will be collected in terms of outpatient health 
care professional visits, emergency room visits, hospital admissions, as well as duration of hospital stays. 
Clinical site personnel and patients will be instructed to capture utilization that takes place outside of visits 
associated with their participation in the clinical study. It takes approximately 5 minutes to complete the 
HCRU.
WPAI:M
The WPAI is a patient self-rated scale designed to provide a quantitative measure of the work productivity 
and activity impairment due to a specific health problem (WPAI:M). The WPAI:M assesses activities over 
the preceding 7 days and consists of 6 items: 1 item assess employment status, 3 items assess the number of 
hours worked, the number of hours missed from work due to the patient’s condition, or due to other reasons, 
and 2 visual numerical scales to assess how much the patient’s condition affects their productivity at work 
and their ability to complete normal daily activities. It takes approximately 5 minutes to complete the 
WPAI:M.
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Assessment Details (continued)
HADS
The HADS is a patient-rated scale designed to screen for anxiety and depressive states in non-psychiatric 
patients. The HADS consists of two sub-scales: the D-scale measures depression and the A-scale measures 
anxiety. Each sub-scale contains 7 items, and each item is rated from 0 (absent) to 3 (maximum severity). 
The score of each sub-scale ranges from 0 to 21 and are analysed separately. It takes approximately 5 to 
10 minutes to complete the HADS.
TSQM-9
The TSQM-9 is a generic questionnaire assessing the patient’s satisfaction with the medication (IMP). The 
tool consists of 9 items addressing effectiveness, side effects, convenience, and overall satisfaction of the 
IMP.  It takes approximately 5 minutes to complete the TSQM-9.
Digital device, actigraphy (optional)
Actigraphy is a non-invasive way of monitoring activity and sleep. Actigraphy will be recorded using a 
wrist-worn device which continuously records physiological data. The device (actigraphy) assessment is a 
voluntary option for this study.
SDS:H
The SDS:H is a patient reported scale, designed to assess dependency-like behaviour in patients with 
headache. The SDS:H is performed as a semi-structured interview, where the following questions will be 
addressed: 1) Do you think your use of headache medication was out of control? 2) Did the prospect of 
missing a dose make you anxious or worried? 3) Did you worry about your use of your headache 
medication? 4) Did you wish you could stop? 5) How difficult would you find it to stop or go without your 
headache medication? Each item is scored on a 4-point scale ranging from 0 (never/almost never, question 
1-4, and not difficult, question 5) to 3 (always/nearly always, question 1-4, and impossible, question 5). It 
takes less than 5 minutes to complete the SDS:H.
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Primary Estimand
Key elements of the primary estimand: the analyses of the primary endpoint aim to estimate “the treatment 
effect that is seen in the population, regardless of use of preventive migraine medication, assuming other 
anti-CGRP treatment is not available.”  
Estimands for the key secondary endpoints will be described in the SAP.
Complete set of attributes of the primary estimand:
Intercurrent Events and Strategies
Initiation of a new preventive migraine medication other than anti-CGRP treatment, during the study period 
(Strategy: Treatment policy)
Use of disallowed anti-CGRP medication other than eptinezumab as preventive migraine medication 
(Strategy: Hypothetical) 
Interruption/termination of infusions (Strategy: Treatment policy)
Treatment condition of interest 
The treatment condition of interest is eptinezumab 100 mg compared to placebo provided as add-on to the 
BI 
Population 
The population is the entire study population, that is, patients who suffer from migraine and MOH and who 
fulfil the inclusion and exclusion criteria.
Variable
Change from baseline in MMDs (Weeks 1-4)
Population-level summary
The population-level summary for the primary endpoint is the mean difference in the change from baseline 
in MMDs (Weeks 1-4) between patients on eptinezumab and placebo.
Statistical Methodology
The following analysis sets will be used for the analyses:
APRS – all randomized patients
APTS – all patients in the APRS who received an infusion of the IMP in the placebo-controlled period
FAS – all patients in the APTS who had a valid baseline assessment and at least one valid post-baseline 
4-week assessment of MMDs in Weeks 1-12
APTS-OL – all patients in the APRS who received an infusion of the IMP in the open-label period
The FAS will be used for all efficacy analyses in the placebo-controlled period, and the APTS will be used for 
all safety analyses in the placebo-controlled period, while the APTS-OL will be used for the safety and efficacy 
analysis of the open-label period.
The main estimator for the primary estimand is defined as the estimated effect from the MMRM model 
described below:
The primary endpoint will be analysed using MMRM with the number of MMDs at baseline as a 
continuous covariate and including treatment group, month (Month 1: Weeks 1-4; Month 2: Weeks 5-8; 
Month 3: Weeks 9-12), country, and previous treatment failures (≤2; >2), as categorical variables. An 
interaction term between month and treatment as well as between month and number of MMDs at baseline 
will be included. The model will assume an unstructured covariance matrix to model the within patient 
variance. The statistical test will be based on the treatment contrast for change from baseline in MMDs 
(Weeks 1-4).
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The main estimator for each of the key secondary estimands is defined as the estimated effect from the 
analysis models described below:
All continuous key secondary endpoints addressing changes from baseline to Weeks 1 to 4 will be analysed
using the same methodology as that described for the primary analysis.
All continuous key secondary endpoints addressing changes from baseline to Weeks 1 to 12 will be 
analysed using the same methodology as that described for the primary analysis, except that the test will be 
based on the estimated mean MMDs averaged over Weeks 1 to 4, Weeks 5 to 8, and Weeks 9 to 12.
Change from baseline in average Daily Pain will be analysed using ANCOVA with the average Daily Pain 
at baseline as a covariate and including treatment group, country, and previous treatment failures as 
categorical variables.
The binary key secondary endpoints will be analysed using logistic regression with baseline MMDs as a 
covariate and treatment and previous treatment failures (≤2, >2) as categorical variables.
Sensitivity analyses of the primary endpoint will be described in the SAP.
Sensitivity analyses of the key secondary endpoints will be described in the SAP.
All statistical testing will be done two-sided, based on a 5% significance level.
Testing Strategy
For the primary endpoint (change from baseline in MMDs [Weeks 1-4]), test the hypothesis of no difference 
between the eptinezumab and placebo groups using a two-sided test on 5% significance level. If rejected and if 
the test shows a numerical advantage to eptinezumab, then continue to the first key secondary endpoint (change 
from baseline in MMDs [Weeks 1-12]). 
On the first key secondary endpoint, test the hypothesis of no difference between the eptinezumab and placebo 
groups. If rejected and if the test shows a numerical advantage to eptinezumab, then continue to the second key 
secondary endpoint (change from baseline in MHDs [Weeks 1-4]). This continues through the list of key 
secondary endpoints (change from baseline in MHD [Weeks 1-12], not fulfilling the ICHD-3 diagnostic criteria 
for CM nor MOH [Week 4], not fulfilling the ICHD-3 diagnostic criteria for CM nor MOH [Week12], change 
from baseline in average Daily Pain assessment score [Weeks 1-2], change from baseline in monthly days with 
acute medication use [Weeks 1-4], change from baseline in monthly days with acute medication use [Weeks 1-
12]), until an endpoint fails to reach significance.
Sample Size Considerations
It is assumed that the treatment effect of eptinezumab 100 mg compared to placebo in change from baseline in 
MMDs (Weeks 1-4) will be -1.5 MMDs. The difference between eptinezumab 100 mg and placebo was -2.0 in 
Study 011, a study that did not include education on MOH, after 4 weeks and –3.1 in the subgroup of patients 
with CM and MOH. The difference between withdrawal from treatment with and without preventive treatment 
was –1.7 and –1.4 days after 2 and 4 months.
The SD is assumed to be 6.2, based on the averaged SD across treatment groups in the MOH subgroup of 
Study 011 on the change from baseline in MMDs (Weeks 1-4).
Based on the assumed effect size and SD, using a two-sided test on the 5% significance level, 270 patients per 
treatment group will provide 80% power for showing an effect on the primary endpoint. Assuming 5% of 
patients will not contribute data to the analysis, 285 patients randomized per treatment group or 570 patients 
randomized in total will be needed. 
Sample size re-assessment will be conducted on blinded data when approximately 70% of the patients have
been randomized.
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Panel 1
Study Design
IMP = investigational medicinal product
Panel 2
Study Procedures and Assessments
Visit Name
Screening
Placebo-controlled 
Period
Open-label 
Period
Safety Follow-up
Decentralizedc
Withdrawald
Baseline + IMP
PO Visit, 
Decentralizedc
Decentralizedc
IMP
Decentralizedc
EoS Visit
Visit Number
1
2
3
4
5
6
7
8
WD
End of Weeka
-4
0
4
8
12
16
24
32
Visit Windowb (days relative to nominal visit)
-2
2
2
2
2
2
5
Screening and Baseline Procedures and Assessments
Signed informed consent (including digital 
wearables)

Demographics (age, sex, and race)

Diagnosis (migraine and MOH)

Disease-specific historye

Relevant history (social, medical, psychiatric, 
neurological)

Previous migraine and preventive medication usee
including treatment failures

Recent medication (prescription and non-
prescription: traditional herbal medicines, non-
pharmacological interventions, vitamins and mineral 
supplements)

Height and weight

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Visit Name
Screening
Placebo-controlled 
Period
Open-label 
Period
Safety Follow-up
Decentralizedc
Withdrawald
Baseline + IMP
PO Visit, 
Decentralizedc
Decentralizedc
IMP
Decentralizedc
EoS Visit
Visit Number
1
2
3
4
5
6
7
8
WD
End of Weeka
-4
0
4
8
12
16
24
32
Visit Windowb (days relative to nominal visit)
-2
2
2
2
2
2
5
Examinations (physical, neurological)

Blood sampling for eligibility (including serology 
and other screening, for example β-HCG)

Urine drug and alcohol screen

ECG

C-SSRSf

Inclusion/exclusion criteria


Signs and symptoms present at Screening and/or 
Baseline (before IMP intake) (recorded on an 
Adverse Event Form)


Randomization

Efficacy Assessments (eDiary and ePROsg)h
eDiary recordingi

j


j

k
k
eDiary compliance checkl







PGIC

j


MBS

j

j


HADS

j

j


Digital device (optional)m




n

n
Pharmacoeconomic Assessments (ePROsg)h
HIT-6
j

j


mMIDAS





MSQ v2.1
j

j


EQ-5D-5L
j

j


HCRU
j

j


WPAI:M
j

j


TSQM-9
j


j


Safety Assessments
Adverse events
o,p,q


o,p,q




Vital signs (including body temperature)

p,q
p,q


Other Study Procedures and Assessments
Brief educational interventionr, including SDS:H


SDS:H


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Visit Name
Screening
Placebo-controlled 
Period
Open-label 
Period
Safety Follow-up
Decentralizedc
Withdrawald
Baseline + IMP
PO Visit, 
Decentralizedc
Decentralizedc
IMP
Decentralizedc
EoS Visit
Visit Number
1
2
3
4
5
6
7
8
WD
End of Weeka
-4
0
4
8
12
16
24
32
Visit Windowb (days relative to nominal visit)
-2
2
2
2
2
2
5
IMP administered (intravenous infusion)s
o,t
o,t
IMP accountabilityu


Concomitant medication (prescription and non-
prescription: traditional herbal medicines, non-
pharmacological interventions, vitamins, and mineral 
supplements)
q


q




Substance use (alcohol, tobacco, caffeine, marijuana)





v
eDiary trainingh

ePRO trainingh

eDiary closeoutk


Pregnancy testw





β-HCG = human chorionic gonadotropin; C-SSRS = Columbia-Suicide Severity Rating Scale; ECG = 
electrocardiogram; EoS = end of study; eDiary = electronic diary; ePRO = electronic patient-reported outcome; 
EQ-5D-5L = Euroqol 5 Dimensions; HADS = Hospital Anxiety and Depression Scale; HCRU = Health Care 
Resource Utilization; HIT-6 = Headache Impact Test; IMP = investigational medicinal product; MBS = Most 
Bothersome Symptom; mMIDAS = modified Migraine Disability Assessment; MOH = medication overuse 
headache; MSQ v2.1 = Migraine-Specific Quality of Life Questionnaire Version 2.1; PGIC = Patient Global 
Impression of Change; PO = primary outcome; SDS: H = Severity of Dependence Scale Adapted for Headache;
TSQM-9 = Treatment Satisfaction Questionnaire for Medicine – 9 items; WD = withdrawal; WPAI:M = Work 
Productivity and Activity Impairment questionnaire, Migraine version
a. All assessments may be completed over a maximum of 2 consecutive days with the exception of ePROs (see 
footnote g below); if so, the first day is considered the “visit” day according to the schedule.
b. If the date of an on-site visit or decentralized contact does not conform to the schedule, subsequent visits 
should be planned to maintain the visit schedule relative to the Baseline Visit. In exceptional cases, the 
screening period (visit interval between Screening and Baseline Visits) may be extended by an extra period 
of seven days with approval from the sponsor (the medical expert at H. Lundbeck A/S or the CRO’s medical 
monitor) based on the provided rationale.
c. For decentralized visits, the patient will be contacted for eDiary compliance check, to ensure that the selected 
assessments have been completed and for collection of relevant information such as adverse events and 
concomitant medications.
d. Patients who withdraw their consent for study participation should be withdrawn from the study. However, 
all efforts should be done to keep the patients who interrupted/terminated their IMP infusion in the study and 
all assessments should be performed as described in the protocol. If patients want to withdraw from the 
study and thus not willing to attend the remaining visits as scheduled, they will be asked to attend a 
Withdrawal Visit as soon as possible and a further Safety Follow-up Visit at 20 weeks after administration of 
IMP. 
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e. Patients’ available adequately documented records of migraine and MOH history and previous migraine
preventive medication use (including treatment failures) within the 5 years prior to the Screening Visit. See 
chapter 12 for definition of adequately documented records.
f.
The C-SSRS at Screening Visit will be administered by the authorized rater at the clinical site.
g. ePROs scheduled at Baseline Visit (Visit 2) and Week 12 Visit (Visit 5) must be completed in the clinical 
site on the visit date and before the infusion. ePROs which are scheduled in alignment with the Withdrawal 
Visit can be completed in the clinical site or in a remote setting within 3 days prior to the scheduled on-site
visit date. ePROs which are scheduled in alignment with a decentralized contact must be completed in a
remote setting and can be completed on the day or within 3 days prior to the scheduled decentralized contact 
date.
h. At the Screening Visit, the patient must be assisted with the provisioning and training of the eDiary and 
ePROs. Details will be provided in a separate user manual.
i.
The eDiary assessments will be completed in the remote setting on a daily basis from Screening to EoS.
j.
On the Baseline Visit and Week 12 Visit day, patients must complete the ePRO entries prior to infusion. 
Patients must ensure to complete eDiary recording of headaches that ended prior to infusion (that is, for 
headaches which are ongoing or not yet recorded in the eDiary).
k. The eDiary closeout will take place at EoS Visit/Withdrawal Visit while the patient is at the clinical site.
Details will be provided in a separate user manual.
l.
In addition to the eDiary compliance checks performed at the defined on-site visits and decentralized 
contacts, ongoing evaluation of eDiary compliance will be performed by the site (based on eDiary reporting) 
and more frequent contact with patients may be needed in case of non-compliance.
m. At designated sites, the patients undergoing the additional actigraphy assessments must provide a signed 
digital device Informed Consent Form.
n. Hand in of Digital device. Patients undergoing the additional actigraphy assessments who drop out from the 
study before Visit 5 must hand in the device at the Withdrawal Visit.
o. Infusion Related Reactions must be checked as part of the overall adverse event collection, during/after 
infusion and before the patient is discharged from the site.
p. Infusion must be preceded by the assessment of vital signs including body temperature, concomitant 
medications, and adverse events.
q. Vital signs including body temperature and adverse events must be checked after infusion.
r.
The brief educational intervention must take place prior to IMP infusion.
s. An unblinded pharmacist or designee is responsible for receiving, storing and preparing IMP. The pharmacist 
or designee will not be responsible for other aspects of the clinical trial where blinding is necessary.
t.
Patients must be monitored during and after the infusion in accordance with usual clinical practice. 
u. A designated unblinded CRA is responsible for the IMP accountability.
v. Substance use will only be collected if the patient withdraws during the placebo-controlled period.
w. For women of childbearing potential, pregnancy test at the Screening Visit is to be conducted using serum 
β-HCG. At all other visits, where this is applicable the urine pregnancy testing will be performed using a 
urine stick test and in case of a positive finding, further confirmatory testing will be performed via serum 
β-HCG.
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Table of Contents
List of Panels........................................................................................................................... 21
List of Abbreviations and Definitions of Terms..................................................................... 22
1
Introduction.................................................................................................................... 24
1.1
Background........................................................................................................... 24
1.1.1
Overview ............................................................................................... 24
1.1.2
Nonclinical Data .................................................................................... 26
1.1.3
Clinical Data.......................................................................................... 27
1.2
Rationale for the Study.......................................................................................... 29
2
Objectives, Endpoints, and Estimands........................................................................... 29
3
Study Design................................................................................................................... 33
3.1
Overview of the Study Design............................................................................... 33
3.2
Rationale for the Study Design.............................................................................. 34
4
Ethics .............................................................................................................................. 36
4.1
Ethical Rationale................................................................................................... 36
4.2
Informed Consent.................................................................................................. 37
4.3
Personal Data Protection ....................................................................................... 38
4.4
Ethics Committees and Institutional Review Boards.............................................. 39
4.5
European Medicines Agency Treatment Policy...................................................... 39
5
Study Population ............................................................................................................ 39
5.1
Number of Patients and Sites................................................................................. 39
5.2
Patient Recruitment............................................................................................... 39
5.3
Selection Criteria .................................................................................................. 40
5.4
Withdrawal Criteria from the Study and IMP......................................................... 43
6
Investigational Medicinal Product................................................................................. 43
6.1
Treatment Regimen............................................................................................... 43
6.2
IMP, Formulation, and Strength ............................................................................ 44
6.3
Manufacturing, Packaging, Labelling, and Storage of IMP .................................... 44
6.4
Method of Assigning Patients to Treatment ........................................................... 45
6.5
IMP Accountability............................................................................................... 45
6.6
Unblinding Procedures.......................................................................................... 45
6.7
Post-study Access to IMP(s).................................................................................. 45
7
Concomitant Medication................................................................................................ 46
7.1
Interaction with Coronavirus Disease 2019 Vaccine .............................................. 46
8
Study Visit Plan.............................................................................................................. 47
8.1
Overview .............................................................................................................. 47
8.2
Screening Visit (Visit 1)........................................................................................ 48
8.2.1
Pre-screening ......................................................................................... 48
8.2.2
Patient Identification Card...................................................................... 48
8.2.3
Re-screening .......................................................................................... 48
8.3
Baseline Visit + IMP (Visit 2)............................................................................... 48
8.4
Decentralized Contacts (Visits 3, 4, and 6) ............................................................ 50
8.5
Week 12 Visit + IMP (Visit 5)............................................................................... 50
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8.6
End of Study Visit (Visit 7)................................................................................... 51
8.7
Withdrawal Visit................................................................................................... 52
8.8
Safety Follow-up Contact (Visit 8)........................................................................ 53
8.9
Unscheduled Visits ............................................................................................... 53
8.10
End-of-study Definition ........................................................................................ 53
9
Assessments .................................................................................................................... 54
9.1
Screening and Baseline Procedures and Assessments............................................. 54
9.1.1
Demographics and Baseline Characteristics............................................ 54
9.1.2
Diagnostic Assessments ......................................................................... 55
9.1.3
Classifications for Eligibility.................................................................. 56
9.1.4
Urine Drug and Alcohol Screen.............................................................. 57
9.1.5
Reference Therapy ................................................................................. 58
9.2
Efficacy Assessments............................................................................................ 58
9.2.1
Clinical Outcome Assessments............................................................... 59
9.2.1.1
Use of eCOA Tools ................................................................ 59
9.2.1.2
Electronic Diary ..................................................................... 59
9.2.1.3
Patient Global Impression of Change...................................... 60
9.2.1.4
Most Bothersome Symptom.................................................... 60
9.2.1.5
Hospital Anxiety and Depression Scale................................... 61
9.2.1.6
Severity of Dependence Scale Adapted for Headache ............. 61
9.2.1.7
External eCOA Monitoring Oversight..................................... 61
9.2.1.8
eCOA Tool Training............................................................... 61
9.2.2
Optional Digital Device (Actigraphy) Assessments................................. 61
9.3
Pharmacoeconomic Assessments........................................................................... 62
9.3.1
Clinical Outcome Assessments............................................................... 63
9.3.1.1
Use of eCOA Tools ................................................................ 63
9.3.1.2
Headache Impact Test............................................................. 63
9.3.1.3
Migraine Disability Assessment, Modified Version................. 63
9.3.1.4
Migraine-Specific Quality of Life Questionnaire, Version 2.1. 64
9.3.1.5
Euroqol 5 Dimension – 5 Levels............................................. 64
9.3.1.6
Health Care Resource Utilization............................................ 64
9.3.1.7
Work Productivity and Activity Impairment: Migraine ........... 64
9.3.1.8
Treatment Satisfaction Questionnaire for Medicine – 9 Items.. 64
9.3.1.9
External eCOA Monitoring Oversight..................................... 65
9.3.1.10
eCOA Tool Training............................................................... 65
9.4
Safety Assessments............................................................................................... 65
9.4.1
Adverse Events ...................................................................................... 65
9.4.2
Clinical Safety Laboratory Tests............................................................. 65
9.4.3
Vital Signs Including Body Temperature................................................ 67
9.4.4
Height and Weight ................................................................................. 67
9.4.5
Electrocardiograms................................................................................. 68
9.4.6
Physical and Neurological Examinations................................................ 68
9.4.7
Columbia-Suicide Severity Rating Scale................................................. 69
9.5
Order of Assessments............................................................................................ 69
9.6
Total Volume of Blood Drawn and Destruction of Biological Material.................. 70
9.7
Treatment Compliance .......................................................................................... 71
10
Adverse Events ............................................................................................................... 71
10.1
Definitions............................................................................................................ 71
10.1.1
Adverse Event Definitions...................................................................... 71
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10.1.2
Adverse Event Assessment Definitions................................................... 72
10.2
Management of Reactions to Study Drug............................................................... 73
10.3
Pregnancy ............................................................................................................. 74
10.4
Recording Adverse Events .................................................................................... 74
10.5
Reporting Serious Adverse Events......................................................................... 75
10.6
Treatment and Follow-up of Adverse Events......................................................... 75
11
Data Handling and Record Keeping.............................................................................. 76
11.1
Data Collection ..................................................................................................... 76
11.1.1
Electronic Case Report Forms ................................................................ 76
11.1.2
Patient Binders....................................................................................... 76
11.1.2.1
Use of Patient Binders ............................................................ 76
11.1.2.2
Serious Adverse Event Fallback Forms................................... 76
11.1.3
External Data ......................................................................................... 76
11.2
Retention of Study Documents at the Site.............................................................. 77
11.2.1
eCRF Data ............................................................................................. 77
11.2.2
Other Study Documents.......................................................................... 77
12
Monitoring Procedures................................................................................................... 78
13
Audits and Inspections ................................................................................................... 79
14
Protocol Compliance ...................................................................................................... 79
15
Study Termination.......................................................................................................... 79
16
Statistical Methodology.................................................................................................. 80
16.1
Responsibilities..................................................................................................... 80
16.2
Analysis Sets......................................................................................................... 80
16.3
Descriptive Statistics............................................................................................. 80
16.4
Patient Disposition................................................................................................ 80
16.5
Demographics and Baseline Characteristics........................................................... 81
16.6
Recent and Concomitant Medication..................................................................... 81
16.7
Exposure............................................................................................................... 81
16.8
Efficacy Analyses ................................................................................................. 81
16.8.1
General Efficacy Analysis Methodology................................................. 81
16.8.2
Primary Analysis of the Primary Endpoint.............................................. 82
16.8.3
Sensitivity Analyses of the Primary Endpoint ......................................... 82
16.8.4
Analysis of the Key Secondary Endpoints............................................... 82
16.8.5
Sensitivity Analyses of the Key Secondary Endpoints............................. 83
16.8.6
Testing Strategy ..................................................................................... 84
16.8.7
Analysis of the Secondary Endpoints...................................................... 84
16.8.8
Analysis of the Exploratory Endpoints.................................................... 85
16.8.9
Analysis of Subgroups............................................................................ 85
16.9
Safety Analyses..................................................................................................... 85
16.9.1
Analysis of Adverse Events.................................................................... 85
16.9.2
Analysis of Other Safety Endpoints........................................................ 85
16.10 Handling of Missing Data...................................................................................... 85
16.11 Interim Analyses................................................................................................... 86
16.12 Sample Size and Power......................................................................................... 86
16.13 Statistical Analysis Plan ........................................................................................ 87
17
Clinical Study Report and Publications......................................................................... 87
17.1
Data Ownership .................................................................................................... 87
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17.2
Clinical Study Report............................................................................................ 87
17.3
Summary of Clinical Study Results ....................................................................... 87
17.4
Publications .......................................................................................................... 87
18
Indemnity and Insurance ............................................................................................... 87
19
Finance............................................................................................................................ 88
19.1
Site Agreements.................................................................................................... 88
19.2
Financial Disclosure.............................................................................................. 88
19.3
Equipment............................................................................................................. 88
References ............................................................................................................................... 89
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Appendices
Appendix I
Clinical Study Protocol Authentication and Authorization.............................. 93
Appendix II
Recent and Concomitant Medication Disallowed or Allowed with Restrictions
...................................................................................................................... 95
Appendix III
Interpretation of Hepatitis B Serologic Test Results ....................................... 98
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List of Panels
Panel 1
Study Design.........................................................................................................12
Panel 2
Study Procedures and Assessments........................................................................12
Panel 3
Objectives, Endpoints, and Estimands ...................................................................30
Panel 4
IHS ICHD-3 Guidelines for Migraine....................................................................55
Panel 5
IHS ICHD-3 Guidelines for MOH.........................................................................56
Panel 6
Clinical Safety Laboratory Tests............................................................................66
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List of Abbreviations and Definitions of Terms
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
Anti-HCV
hepatitis C virus antibody
APRS
all-patients-randomized set
APTS
all-patients-treated set
APTS-OL
all-patients-treated set Open-Label
AST
aspartate aminotransferase
a.U.
arbitrary unit
AUC
area under the concentration-time curve
BI
brief educational intervention
CGRP
calcitonin gene-related peptide
CI
confidence interval
CM
chronic migraine
Cmax
maximum observed concentration
CNS
central nervous system
COVID-19
Coronavirus Disease 2019
CRA
clinical research associate
CRO
Contract Research Organization
C-SSRS
Columbia-Suicide Severity Rating Scale
DSM-5®
Diagnostic and Statistical Manual of Mental Disorders, 5th edition
ECG
electrocardiogram
eCRF
electronic case report form
eDiary
electronic diary
EC
ethics committee
eCOA
electronic clinical outcome assessment
EM
episodic migraine
EMA
European Medicines Agency
EoS
End-of-Study
FAS
full-analysis set
ePRO
electronic patient-reported outcome
EQ-5D-5L
Euroqol 5 Dimension – 5 Levels
US FDA
United States Food and Drug Agency
HADS
Hospital Anxiety and Depression Scale
HCG
human chorionic gonadotropin
HCRU
Health Care Resources Utilization
HIT-6
Headache Impact Test
HIV
human immunodeficiency virus
ICHD
International Classification of Headache Disorders
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IHS
International Headache Society
IMP
investigational medicinal product
IRB
institutional review board
IRT
interactive response technology
IRR
infusion related reaction
mAb
monoclonal antibody
MBS
Most Bothersome Symptom
MHD
monthly headache day
MMD
monthly migraine day
mMIDAS
modified Migraine Disability Assessment
MMRM
Mixed Models Repeated Measurements
MOH
medication overuse headache
MSQ v2.1
Migraine-Specific Quality of Life Questionnaire, Version 2.1
NSAID
nonsteroidal anti-inflammatory drug
OTC
over-the-counter
PA
physical activity
PGIC
Patient Global Impression of Change
QP
qualified person
QTcF
heart-rate corrected QT interval using Fridericia’s correction formula
SAE
serious adverse event
SAP
Statistical Analysis Plan
SD
standard deviation
SDS:H
Severity Dependence Scale adapted for headache
SUSAR
suspected unexpected serious adverse reaction
TMF
trial master file
TSQM-9
Treatment Satisfaction Questionnaire for Medicine – 9 items
VAS
Visual Analogue Scale
WPAI:M
Work Productivity and Activity Impairment Questionnaire, Migraine version
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1
Introduction
1.1
Background
1.1.1
Overview
Migraine is a disabling disorder characterised by headache and often accompanied by nausea, 
vomiting, photophobia, and phonophobia.1 Migraine is one of the most prevalent 
neurological disease for which medical treatment is sought, and worldwide, is considered the 
leading cause of disability for people under the age of 50 and second leading cause of 
disability worldwide.2,3
MOH is the development of a new type of headache, or significant worsening of pre-existing 
headache, resulting from frequent and excessive intake of medications for the acute treatment 
of headache1. MOH prevalence is estimated at 1% to 2% worldwide but varies from country 
to country (range 0.5% to 7%). Acute medications (for treatment of a migraine / headache 
once it begins) involved in MOH vary with country and over time.4,5 MOH is defined as the 
combination of chronic headache and overuse of analgesics and/or acute migraine medication 
(use of paracetamol and NSAID ≥15 days a month, or triptans, ergotamine, opioids, 
combination-analgesics, or any combination of drug classes ≥10 days a month). In fact, 
medication overuse is considered the most central factor for chronification of migraine, and 
40% to 70% of patients with CM also fulfil the diagnostic criteria for MOH.
The condition of MOH with underlying migraine may be treated by education of patients to 
stop/reduce acute medication or institute an acute medication withdrawal for 8 weeks or 
combine education or withdrawal with other preventive medication targeting the underlying 
migraine. However, these treatment strategies often lead to initial severe discomfort in terms 
of worsening in headache (the so-called rebound headache), and withdrawal symptoms (such 
as, nausea, vomiting, hypotension, tachycardia, sleep disturbance, restlessness, anxiety, and 
nervousness). These symptoms, lasting approximately 2 to 3 weeks6, may be attenuated by 
rescue medication and anti-emetics, but there is no consensus on rescue medication. Thus, 
potentially avoiding this initial period of discomfort for the patients could ensure a successful 
stop of acute medication overuse.  Furthermore, in many clinics there is immense resistance 
from health care providers against this medication withdrawal because it often leads to a need 
for hospitalization for a number of weeks, due to severity of the rebound headaches and the 
related anxiety from the patients. After successful medication withdrawal, patients will still 
suffer from their primary headache and although some patients get relief and transform from 
their CM into an EM, they still need treatment for their migraine.
Several clinical studies have been conducted to provide evidence that combination of 
preventive medication and withdrawal of overused medication is the most optimal treatment;
however, no significant results have been obtained.7,8 Thus, this evidence is lacking and in 
current guidelines, no clear advice is given. The previous studies that have investigated oral 
preventive medications or botox were limited in sample size and were mostly single-centre 
studies.9 None of the new CGRP mAbs have been investigated as add-on treatment to 
education of treatment management or of medication withdrawal.  Therefore, it is of high 
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clinical relevance to explore if education about the cause of MOH aiming to eliminate the
medication overuse would benefit from combination with a preventive treatment that has 
rapid onset of action and long-lasting effect. For this purpose, the intravenously administered 
CGRP mAb, eptinezumab, with an early onset may be a strong candidate due to its
pharmacokinetic profile (specifically, its immediate high bioavailability and its ability to
reach steady state within 30 minutes of administration), potentially offering patients an
effective preventive treatment that in combination with motivational education could secure a 
successful and lasting relief from MOH by terminating the acute medication overuse.
There is no gold standard for this type of patient education of treatment management or of 
medication withdrawal. While current guidelines recommend that patients with MOH should 
be managed by a multidisciplinary team of neurologists or pain specialists and behavioural 
psychologists, these resources are not available in most headache clinics and only few clinics 
are able to provide inpatient care for the patients to the often-necessary level of intervention to 
ensure a successful outcome. BI as a patient education tool have been investigated in a study 
with general practitioners in Norway with promising results7. As it only takes on average 10
minutes to conduct, it would be feasible to provide BI at most headache clinics when 
combined with a fast--onset modern preventive therapy.
CGRP is known to play an important role in migraine by facilitating the transmission of 
migraine pain, thereby contributing to the induction of the pronociceptive stage through 
modulation of the CNS.10,11 Studies in animals and humans indicate that the trigeminal 
ganglion and its nucleus caudalis are likely to be sites of action of CGRP in migraine. In 
addition, CGRP is expressed at low level in many locations within the CNS, including regions 
that may be relevant to migraine pain.12,13  During migraine attacks, there is an increase in the 
plasma levels of CGRP in the external jugular vein.14  In addition, intravenous infusion of 
CGRP has caused migraine and headache in patients with migraine, suggesting that the 
increase in CGRP observed during spontaneous migraine attacks plays a causative role.15  
CGRP dilates intracranial and extracranial blood vessels, and regulates mast cell 
degranulation, which during migraine, leads to the secretion of vasoactive, proinflammatory, 
and neurosensitizing mediators, thereby contributing to migraine pathogenesis.16,17
A large body of evidence has established the CGRP pathway as a target for the treatment of 
migraine.  Studies with mAbs targeting CGRP or the CGRP receptor have shown that 
inhibition of CGRP is efficacious in the treatment of chronic and episodic migraine.18,19,20
Eptinezumab is a humanised mAb that binds and blocks the action of CGRP and is approved 
by several medical agencies, including the US FDA and EMA, as the first and only 
intravenous preventive treatment for migraine.  Eptinezumab addresses an unmet medical 
need of patients who require preventive treatment of migraine with an early onset of effect.  
Eptinezumab is administered by intravenous infusion every 12 weeks offering a route of drug 
administration with 100% bioavailability that allows for rapid CGRP inhibition, which has 
been associated with a clinically meaningful migraine preventive effect as soon as the day 
following the first infusion and pain relief from ongoing attacks within hours
(CSR ALD403-CLIN-015/18903A).  Eptinezumab intravenous infusion administered every 
12 weeks by a health care professional helps to ensure treatment adherence and delivery of a 
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known quantity of drug with each dose.  Results from two placebo--controlled, phase 3
studies showed that eptinezumab led to significant reductions in the number of MMDs in 
patients with EM (ALD403 CLIN-006)21 and CM (ALD403-CLIN-011).22 Furthermore , 
treatment with eptinezumab has been associated with a sustained efficacy throughout the 
treatment period and an acceptable tolerability profile with low incidences of study drug 
withdrawal due to adverse events.
The following sections provide a brief overview of the nonclinical and clinical data currently 
available for eptinezumab.  Refer to the current version of the Investigator’s Brochure23 for 
more detailed information.
1.1.2
Nonclinical Data
Data from the comprehensive program of nonclinical studies support the clinical mechanism 
of action and safety of eptinezumab.
To demonstrate the ability of eptinezumab to block CGRP-driven vasodilation in vivo, several 
primary pharmacodynamic animal studies were conducted in rat, cynomolgus monkey, and 
rabbit. The administration of eptinezumab was well tolerated at doses up to 100 mg/kg, the 
highest dose administered, and inhibited increases in dermal blood perfusion induced by 
either topical capsaicin (rats and monkey) or intradermal β-CGRP challenge (rabbit). The 
pharmacodynamic effects were dose-dependent and occurred from 0.1 mg/kg. The 
appropriateness of the nonclinical species has been established in vitro (rat and rabbit). 
Across species (including human), eptinezumab has a binding affinity in the low picomolar 
range for α- and β-CGRP and has been shown to functionally inhibit α- and β-CGRP with 
high specificity.
Intravenous administration of eptinezumab, either as a single- or multiple-dose for 1-month 
duration up to 100 mg/kg/dose in rats or monkeys, or multiple-dose for 6 months duration up 
to 150 mg/kg/dose in monkeys, was well tolerated. No mortality or adverse findings 
attributed to the pharmacological activity of eptinezumab were observed in the single- or 
repeat-dose studies in rats or cynomolgus monkeys.  As determined during a 6-month chronic 
toxicity in cynomolgus monkeys, the no observed adverse effect level of 150 mg/kg/dose 
supports a 103-fold or 123-fold safety margin by Cmax or AUC for the highest dose, 300 mg, 
of eptinezumab administered by intravenous infusion every 12 weeks in humans.
Overall, following intravenous administration in the nonclinical studies, eptinezumab 
exposure was generally dose proportional, and the plasma-concentration profiles were 
consistent for intravenous administration with the rapid achievement of Cmax followed by a 
mono-exponential decline.  The volume of distribution for eptinezumab is generally limited to 
the vascular compartment.23
Eptinezumab is unlikely to interact directly with deoxyribonucleic acid or other chromosomal 
material, and under ICH S6(R1) guidance, evaluations for potential genotoxicity were 
considered unnecessary and were not performed for eptinezumab. Based on extensive 
evaluation of the literature related to inhibition of CGRP, angiogenesis, and tumour growth as 
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well as the absence of eptinezumab-related proliferative findings from long-term studies in 
monkeys, no further nonclinical studies addressing the carcinogenic risk are considered 
necessary.
Eptinezumab is being developed for the prevention of migraine, and a significant proportion 
of migraineurs are women of childbearing potential.24  Given the patient population, and in 
conformance with applicable guidance documents, a complete package of 
reproductive/development toxicity studies was conducted. In these studies, administration of 
eptinezumab by intravenous injection to pregnant female rats or rabbits at 75 or 150 
mg/kg/dose was well tolerated. No effects on male or female reproductive function or 
performance, fertility, or early embryonic development in rats were observed. No parental 
effects or evidence of embryo-lethality, fetotoxicity, or teratogenicity in rats or rabbits were 
observed. There were no effects on the survival, physical development, behaviour, or 
reproductive performance of the first filial generation in the pre- and postnatal development 
study in rats.
The local tolerance of eptinezumab was assessed following multiple dose studies in rats and 
cynomolgus monkeys utilizing eptinezumab administered intravenously.  No gross 
observations including erythema and oedema, or toxicologically significant histological 
changes at the injection site(s) were noted in either species for any dose route at 
concentrations up to 100 mg/mL eptinezumab.
Biologics in general have minimal risks regarding drug-drug interactions;25 therefore, drug 
interactions with eptinezumab and concomitant medications are not expected, and nonclinical 
studies evaluating the potential for interactions with drugs that may be co-administered with 
eptinezumab were not performed.
1.1.3
Clinical Data
The clinical program of eptinezumab is composed of six completed studies to date; 4 studies 
are placebo-controlled (phase 1b study in frequent EM (ALD403-CLIN-002),26 phase 2 study 
in CM (ALD403-CLIN-005),27 phase 3 study in frequent EM (ALD403-CLIN 006),21 phase 3
study in CM (ALD403-CLIN-011)22, one study is open-label (phase 3 study in CM (ALD403-
CLIN-013))28,29, and a Phase 3 study (18903A)30 to assess treatment of eptinezumab in 
patients experiencing an acute attack of migraine.
Eptinezumab is administered by 30-minute intravenous infusion, which bypasses 
extravascular absorption routes and renders 100% bioavailability.  The time required to 
achieve therapeutic concentrations for eptinezumab is rapid and Cmax is typically observed at 
the end of infusion. The low plasma clearance (0.15 L/d) and protracted terminal-elimination 
half-life of 27 days for eptinezumab support a sustained duration of effect and infrequent, 
once every 12 weeks dosing.  The mean accumulation ratios based on Cmax and AUC during 
the first dosing interval are 1.08 and 1.15, respectively.
Eptinezumab is not metabolized by cytochrome P450 enzymes. Therefore, interactions by
eptinezumab with concomitant medications that are substrates, inducers, or inhibitors of 
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cytochrome P450 enzymes are considered unlikely.31  Nevertheless, the co-administration of 
eptinezumab in combination with sumatriptan was investigated in Study ALD403-CLIN-
001.23  The co-administration of sumatriptan did not appear to alter the single dose PK of 
eptinezumab.  Similarly, the PK of sumatriptan was not impacted upon by the 
co-administration of eptinezumab.
Results from the two pivotal, placebo-controlled, phase 3 studies showed that eptinezumab at 
doses of 100 mg or 300 mg administered by intravenous infusion every 12 weeks 
(2 infusions) led to significant reductions in MMDs in patients with EM or CM
(ALD403-CLIN-006 and ALD403-CLIN-011).21,22  Both eptinezumab 300 mg and 100 mg 
groups achieved the primary efficacy endpoint and all key secondary endpoints in the 
prespecified statistical hierarchy. The therapeutic benefit resulting from administration of 
eptinezumab for the preventive treatment of migraine in adults is robust and clinically 
meaningful, as demonstrated by the results of the 75% and 50% migraine responder analyses. 
Administration of eptinezumab 100 or 300 mg resulted in a rapid, migraine preventive effect 
that was established on the day after the first infusion and maintained over the 12-week 
dosing cycle. Both eptinezumab doses were associated with a consistent pattern of 
statistically significant and clinically meaningful efficacy across these endpoints compared 
with placebo. Furthermore, subgroup analyses showed that the reduction in MMDs seen with 
eptinezumab compared to placebo was also present in the distinct subpopulation of patients 
with the dual diagnosis of migraine and MOH. Post-hoc analyses indicated that in the 
subgroup of patients with MOH, eptinezumab also had advantages over placebo in the 50% 
and 75% response rates for Weeks 1 to 12, for both doses (p<0.05).  The early onset of 
eptinezumab 100 mg has been further established by the results from the recently completed 
Study 18903A (CSR ALD403-CLIN-015/18903A). The results, evaluated within 48 hours 
after start of infusion, demonstrated that patients receiving an intravenous infusion of 
eptinezumab 100 mg during an ongoing migraine attack achieved statistically significant 
shorter time to freedom from headache pain (p = 0.0006). The median time to freedom from 
headache pain was 4 hours for patients receiving eptinezumab 100 mg and 9 hours for patients 
receiving placebo. Similarly, the results also showed that patients receiving eptinezumab had 
a statistically significantly shorter time to absence of their MBS (p <0.0001) compared to 
patients receiving placebo, a median time of 2 hours versus 3 hours. The key secondary 
endpoints, headache pain freedom and absence of MBS 2 hours post-dose, were also 
statistically significantly in favour of eptinezumab (23.5% versus 12% [p = 0.0009] and 
55.5% versus 35.8% [p <0.0001], respectively). Furthermore, eptinezumab 100 mg was also 
statistically significantly (p <0.001) better than placebo on all the secondary endpoints 
included in the testing hierarchy in Study 18903A (headache pain freedom and absence of 
MBS 4 hours post-dose as well as on the use of acute medication within 24 hours). Median 
time to next migraine was 10 days with eptinezumab versus 5 days with placebo (p <0.001).
The safety of eptinezumab has been evaluated in more than 2500 patients with migraine.
Nasopharyngitis and hypersensitivity reactions, including anaphylactic reactions and fatigue
are considered adverse drug reactions for eptinezumab. In the pivotal phase 3 studies 
(ALD403-CLIN-006 and ALD403-CLIN-011) hypersensitivity reactions were reported with 
multiple related adverse event terms, such as hypersensitivity, angioedema, urticaria, 
flushing/hot flush, rash, and pruritus. These events were reported in approximately 4% of 
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patients on 300 mg eptinezumab, 3% of patients on 100 mg eptinezumab, and 1% of patients 
on placebo. Furthermore, approximately 3% of patients on eptinezumab and 2% of patients 
on placebo in the placebo-controlled clinical trials experienced fatigue. Fatigue was most 
frequent on the day of the first infusion. Following the first week and with subsequent 
infusions, fatigue was reported in lower incidences and the incidences were comparable to 
placebo.  The majority of these adverse events were categorized as mild to moderate, and 
most hypersensitivity reactions occurred during the infusion. Serious hypersensitivity 
reactions have been reported, including anaphylactic reactions on rare occasions. In most 
cases, the events developed during or within minutes of the infusion and patients recovered 
following drug discontinuation and adequate treatment.
Long-term safety data with eptinezumab is limited; however, 128 patients have been treated 
with up to 2 years of exposure and no new significant findings have been identified during the 
long-term follow-up.
The safety findings to date indicate that eptinezumab is well tolerated and demonstrates a 
favourable risk-benefit profile based on review of nonclinical, clinical, and scientific literature 
data.
1.2
Rationale for the Study
Eptinezumab is approved for migraine prevention and s substantial proportion of migraine 
patients have a dual diagnosis of migraine and MOH. These patients generally constitute the 
most burdensome population, accounting for approximately 80% of all health care costs 
generated by the patients with CM.32
MOH is a global health problem with a prevalence in the general adult population of different 
countries ranging from 0.5% to 7.6%. Robust data from Scandinavia indicate a prevalence of 
1% to 2%, representing around 50% of all patients with chronic daily headache.6  There is a 
substantial proportion of patients with a dual diagnosis of migraine and MOH worldwide5,33
who do not respond to, or cannot tolerate, existing treatments.  None of the new CGRP mAbs 
have been investigated as add-on treatment to education or medication withdrawal.  
Therefore, it is of high clinical relevance to explore if BI would benefit from combination 
with a preventive treatment that has rapid onset of action and long-lasting effect.  
This study is a placebo-controlled study in patients with a dual diagnosis of migraine and 
MOH.  The study is intended to evaluate the effect on MMDs, of eptinezumab as add-on 
treatment to BI, for the prevention of migraine and treatment of MOH in patients with a dual 
diagnosis of migraine and MOH.
2
Objectives, Endpoints, and Estimands
The study objectives, endpoints, and estimands are summarized in Panel 3.
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Panel 3
Objectives, Endpoints, and Estimands
Objectives
Endpoints
Primary Objective
To evaluate the efficacy of 
eptinezumab as add-on to 
BI for the prevention of 
migraine and treatment of 
MOH
Primary Endpoint:
Change from baseline in the number of MMDs (Weeks 1-4)
Key Secondary Endpoints:
Change from baseline in MMDs (Weeks 1-12)
Change from baseline in the number of MHDs (Weeks 1-4)
Change from baseline in MHDs (Weeks 1-12)
Not fulfilling the ICHD-3 diagnostic criteria for CM nor MOH (Week 4)
Not fulfilling the ICHD-3 diagnostic criteria for CM nor MOH (Week 12)
Change from baseline in average Daily Pain assessment score (Weeks 1-2)
Change from baseline in monthly days with acute medication use
(Weeks 1-4)
Change from baseline in monthly days with acute medication use
(Weeks 1-12)
Secondary Endpoints:
Not fulfilling the ICHD-3 diagnostic criteria for CM (Week 4, Week 12)
Not fulfilling the ICHD-3 diagnostic criteria for MOH (Week 4, Week 12)
Change from baseline in MMDs with use of acute medication (Weeks 1-12)
Change from baseline in monthly days with triptan or ergotamine medication 
use (Weeks 1-12)
Change from baseline in monthly days with individual non-opioid analgesics 
or NSAID medication use (Weeks 1-12)
Change from baseline in monthly days with combination non-opioid
analgesics medication use (Weeks 1-12)
Migraine on the day after dosing (Day 1)
Response: ≥50% reduction from baseline in MMDs (Weeks 1-4, Weeks 1-12)
Response: ≥75% reduction from baseline in MMDs (Weeks 1-4, Weeks 1-12)
Response: ≥50% reduction from baseline in MHDs (Weeks 1-4, Weeks 1-12)
Response: ≥75% reduction from baseline in MHDs (Weeks 1-4, Weeks 1-12)
Change from baseline in rate of migraines with severe pain intensity 
(Weeks 1-4, Weeks 1-12)
Change from baseline in rate of headaches with severe pain intensity 
(Weeks 1-4, Weeks 1-12)
PGIC score at Week 4 and Week 12
MBS score at Week 12
Exploratory Endpoint:
Complete withdrawal of acute headache medication (Weeks 1-4, Weeks 5-8, 
Weeks 9-12)
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Objectives
Endpoints
Primary Estimand
Key elements to the primary estimand: the analyses of the primary endpoint aim to estimate “the treatment 
effect that is seen in the population, regardless of the use of preventive migraine medication, assuming other 
anti-CGRP treatment is not available.”  
Estimands for the key secondary endpoints will be described in the SAP.
Complete set of attributes of the primary estimand:
Intercurrent Events and Strategies
Initiation of a new preventive migraine medication other than anti-CGRP treatment, during the study period 
(Strategy: Treatment policy)
Use of disallowed anti-CGRP medication other than eptinezumab as preventive migraine medication
(Strategy: Hypothetical)
Interruption/termination of infusions (Strategy: Treatment policy)
Treatment condition of interest
The treatment condition of interest is eptinezumab 100 mg compared to placebo provided as add-on to the 
BI.
Population
The population is the entire study population, that is, patients who suffer from migraine and MOH and who
fulfil the inclusion and exclusion criteria.
Variable
Change from baseline in MMDs (Weeks 1-4)
Population-level summary
The population-level summary for the primary endpoint is the mean difference in the change from baseline 
in MMDs (Weeks 1-4) between patients on eptinezumab and placebo.
Secondary Objectives:
To evaluate the efficacy of 
eptinezumab as add-on to 
BI on health-related
quality of life and work
productivity
Secondary Endpoints:
Change from baseline to Week 4 and from baseline to Week 12 in the HIT-6 
total score
Change from baseline to Week 4 and from baseline to Week 12 in the 
mMIDAS total score
Change from baseline to Week 4 and from baseline to Week 12 in the MSQ 
v2.1 sub-scores (Role Function-Restrictive, Role Function-Preventive, 
Emotional Function)
Change from baseline to Week 4,andfrom baseline to Week 12 in the 
EQ-5D-5L VAS score
Migraine specific HCRU at Baseline and at Week 12
Change from baseline to Week 12 in the WPAI:M sub-scores (Absenteeism, 
Presenteeism, Work productivity loss, Activity impairment)
Change from baseline to Week 4, and from baseline to Week 12 in HADS -
depression, and anxiety subscale scores
Change from baseline to Week 4 and from baseline to Week 12 in TSQM-9
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Objectives
Endpoints
To evaluate the efficacy of 
eptinezumab during the 
12-week open-label 
extension period
Change from baseline to Week 24 in the HIT-6 total score
Change from baseline to Week 24 in the mMIDAS total score
Change from baseline to Week 24 in the MSQ v2.1 sub-scores
Change from baseline Week 24 in the EQ-5D-5L VAS score 
Migraine specific HCRU at Week 24
Change from baseline to Week 24 in the WPAI:M sub-scores 
Change from baseline to Week 24 in HADS - depression and anxiety 
subscale scores 
PGIC score at Week 24
MBS score at Week 24
Change from baseline to Week 24 in TSQM-9
Change from baseline to Week 24 in MMDs 
Change from baseline to Week 24 in MHDs
Not fulfilling the ICHD-3 diagnostic criteria for CM nor MOH (Week 24) 
Change from baseline to Week 24 in monthly days with acute medication use
Change from baseline to Week 24 in average Daily Pain assessment 
Change from baseline to Week 24 in monthly days with triptan or ergotamine 
medication use
Change from baseline to Week 24 in monthly days with individual non-
opioid analgesics or NSAID medication use
Exploratory Objectives:
To investigate the efficacy 
of eptinezumab as add-on 
to BI on level of daily 
physical activity and sleep 
using a wearable digital 
device (subset)
Exploratory Endpoints:
Change from baseline to Week 4 and Week 12 of passive registration of 
movement (actigraphy) (average per 28 days)
-
Minutes with light PA (11-50 a.U.) 
-
Minutes with moderate PA (51-100 a.U.)
-
Minutes with intense PA (101-200 a.U.)
-
Minutes in rest period (range 0-300, 101: rest epoch)
Change from baseline to Week 4 and Week 12 in sleep metrics assessment as 
assessed by actigraphy (average per 28 days)
-
Total Sleep Time (minutes per night)
-
Sleep Efficiency (percentage per night)
-
Wake After Sleep Onset (minutes per night) 
-
Sleep Onset Latency (minutes per night)
All analyses will also be done by week, for example change from baseline to 
Week 1, from baseline to Week 2, and from baseline to Week 12.
To investigate efficacy of 
eptinezumab as add-on to 
BI on the level of 
analgesic dependence
Change from baseline to Week 12 in SDS:H score
Safety Objective:
To evaluate the safety and 
tolerability of 
eptinezumab
Safety Endpoints:
Adverse Events
Absolute values and changes from baseline in vital signs
Potentially clinically significant vital signs changes
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3
Study Design
3.1
Overview of the Study Design
This study has been designed in accordance with the Declaration of Helsinki.34
This is a phase 4, interventional, multi-national, multi-site, randomized, double-blind, 
parallel-group, placebo-controlled study designed to demonstrate the efficacy and safety of 
add-on eptinezumab treatment to BI, performed at baseline, for the prevention of migraine 
and treatment of MOH in patients with a dual diagnosis of migraine and MOH.
The 12-week placebo-controlled period will be followed by a 12-week open-label period 
where all patients will receive eptinezumab to provide further relief and gain exploratory data 
on the durability of a potential remission of the MOH and CM. The safety and tolerability of 
eptinezumab will be also further assessed in this open-label period.
This study will be conducted in compliance with the protocol, Good Clinical Practice,35 and 
applicable regulatory requirements.
An overview of the study is presented in Panel 1.
The target population for this study is defined as patients with a dual diagnosis of migraine
and MOH and a level of disease activity matching the CM definition, according to the IHS
ICHD-3 guidelines.1 The medication overuse will be confirmed via prospectively collected 
information in the eDiary during the screening period.
Patients will be instructed to stop medication overuse during a semi-structured educational 
conversation.
Patients will be allowed use of medications (with restrictions for some of them) for acute 
and/or symptomatic treatment of headache (for example, paracetamol, NSAID, triptans, 
ergotamine, opioids, and/or combination analgesics) throughout the study.  However, at the 
Baseline Visit they will be educated not to use acute medications.
Eligible patients will be randomly allocated via a randomization system to one of the two 
treatment groups: BI and eptinezumab 100 mg, or BI and placebo, in a ratio of 1:1.
Randomization will be stratified by country and number of previous preventive treatment 
failures (≤2; >2) occurring up to 5 years prior to Baseline Visit by using the IRT system. 
Treatment failure is defined as treatment discontinuation due to lack of efficacy (no clinically
meaningful improvement at the recommended or prescribed dose for at least 3 months), side 
effects, or general poor tolerability of the treatment.
The total study duration from Screening Visit to Safety Follow-up Contact is approximately 
36 weeks and includes a screening period (4 weeks), a placebo-controlled period (12 weeks), 
an open-label period (12 weeks), and a safety follow-up period (8 weeks).
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Patients will attend on-site visits at Screening Visit, visits with IMP intravenous infusions 
(Baseline Visit and Week 12 Visit), and EoS Visit at Week 24.  All other visits will be 
conducted as telephone or telemedicine visits.
Patients will complete a daily headache eDiary from Screening Visit until EoS/Withdrawal 
Visit.
Patients will receive BI and IMP (eptinezumab or placebo) at Baseline Visit during the 
placebo-controlled period and IMP (eptinezumab) at Week 12 Visit during the open-label 
period. IMP is administered by intravenous infusion over 30 minutes (with possibility to 
extend the intravenous infusion by15 minutes).
During the visits with IMP infusion, safety assessments will be performed before and after the 
infusion. The ePROs must be completed prior to the intravenous infusion. Patients must 
ensure to complete eDiary recording of headaches prior to the intravenous infusion (that is, 
for headaches which are ongoing or not yet recorded in the eDiary).
The primary outcome visit is at Week 4 during the placebo-controlled period. 
At designated sites, optional actigraphy assessments using a digital device will be performed 
on a consenting subset of patients. Patients can withdraw from these optional assessments 
without withdrawing from the main study.
Patients will be scheduled for a Safety Follow-up Contact (at Week 32), 8 weeks after EoS
Visit.
Patients who withdraw their consent should be withdrawn from the study. However, all 
efforts should be done to keep the patients who interrupted/terminated their IMP in the study 
and all assessments should be performed as described in the protocol. If patients want to 
withdraw from the study and thus not willing to attend the remaining visits as scheduled, they
will be asked to attend a Withdrawal Visit as soon as possible and a Safety Follow-Up 
Contact, 20 weeks after the last administration of IMP.
Patients in the study will have access to appropriate medical care in accordance with usual
clinical practice after they complete or withdraw from the study.
3.2
Rationale for the Study Design
This study is a placebo-controlled study in patients with a dual diagnosis of migraine and 
MOH.  The sample size for the primary endpoint is chosen based on the phase 3 data with 
eptinezumab in the sub-population of patients with migraine and MOH, a study that did not 
include systematic education36, and on a study of combining preventive therapy chosen 
according to current guidelines and a withdrawal programme.9
The primary endpoint is to evaluate the efficacy of eptinezumab as add-on to BI for the 
prevention of migraine and treatment of MOH.
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Fulfilment of criteria for migraine, according to the eligibility criteria in this protocol, will be 
confirmed via prospectively collected information in the eDiary during the screening period, 
that is, migraine occurring on ≥8 days and headache occurring on <26 days. The proposed 
study population comprises patients who have at least 8 migraine days per month.  Based on 
prior studies in migraine, this target population is justified based on a lower heterogeneity of 
the data and an optimized chance of getting a conclusive result. The rationale for an upper 
limit on the number of headache days is to exclude patients with chronic daily headaches (for 
example, hemicrania continua, new daily persistent headache). Prior to randomization, the 
investigator will review the data in the eDiary Eligibility Report to determine if eligibility 
criteria are fulfilled.
The definition of a migraine day in the protocol is based on the IHS guidelines1 for controlled 
studies of preventive treatment of migraine in adults. Patients will be asked, based on daily 
questions in the eDiary, if they took any medications to treat a headache and, if so, did at least 
one medication successfully treat the headache. Furthermore, the patients will be asked to 
register the medication used. The master medication list will be classified into migraine-
specific and non-migraine-specific medication to ensure that a migraine day is classified 
correctly as a day that is successfully treated with migraine-specific acute medication.
Fulfilment of criteria for MOH based on the investigators interview with the patient according 
to the ICHD-3 criteria, will be confirmed via  prospectively collected information in the 
eDiary during the screening period, that is, headache occurring on ≥15 days and have regular 
overuse of one or more drugs that can be taken for acute and/or symptomatic treatment of 
headache
Secondary endpoints evaluating health-related quality of life, such as MBS, as well as work 
productivity, are included in the study to evaluate the impact of preventive treatment beyond 
the reduction in number of MMDs and medication overuse.
A study duration of 12 weeks for the placebo-controlled period is in line with the Guidelines 
of the IHS for controlled studies of preventive treatment of CM in adults37 and with the
previous completed phase 3 studies that showed a persistence of a robust migraine preventive 
effect of eptinezumab across 12 weeks with administration every 12 weeks. In addition, 
treatment of MOH with withdrawal of acute medication is normally evaluated after 8 to 12 
weeks in the headache clinics, thus a 12-week study duration for evaluation of the combined 
effect of BI with eptinezumab for treatment of MOH is justified.
A further 12-week open-label period with eptinezumab treatment is included to provide 
further relief and gain exploratory data on the durability of a potential remission of the MOH. 
The open-label part will also ensure all participating patients administered with an active 
preventive migraine medication and further develop clinical experience with eptinezumab.  
One dose of eptinezumab (100 mg) is recommended, based on the US FDA and EMA 
approved labels and the results in the completed phase 3 program, showing similar efficacy on 
the reduction of MMDs and overall good tolerability of eptinezumab 100 mg and 300 mg in a 
population of patients with migraine and MOH.
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Patients will be randomly allocated to one of two treatment arms of either 100 mg 
eptinezumab or placebo, with a randomization ratio of 1:1. Inclusion of a placebo group is 
justified since the group is representative of the best supportive care and there is no current 
evidence showing that preventive medication and education is better than education alone. 
Thus, the study will compare the efficacy of eptinezumab and BI versus BI alone and no 
patient will be denied access to acute migraine treatments in this study.
The current study includes the use of digital tools (electronic data collection systems, tele- and 
phone visits) combined with site visits. Digitalisation and decentralisation of assessments and 
visits will provide the patient with the possibility of conducting study visits in a remote 
setting and reduce the burden of attending physical appointments at the clinic.  Furthermore, 
decentralisation will help to ensure a wider representation of trial participants, which is likely 
to facilitate the recruitment and retention of patients.
The safety assessments will be limited to adverse events and vital signs monitoring including 
body temperature as this is a phase 4 post-approval study, and the safety and tolerability have 
been evaluated and established in the extensive clinical programme in the target patient 
population.
In clinical studies it is not uncommon that events that occur after treatment initiation have the 
potential to either preclude observation of the study endpoints or affect their interpretation. 
Such events are termed intercurrent events, and strategies how to address these in order to 
describe the treatment effect of interest have to be defined. The identified intercurrent events 
in this study, and the strategies to address them are stated in chapter 2.
4
Ethics
4.1
Ethical Rationale
Eptinezumab 100mg is a recently approved in several countries (including USA, Canada, 
Australia, and European Union) as a preventive treatment of migraine in adults.
This study will evaluate eptinezumab as a potential treatment candidate add-on to BI for a 
target patient population with a dual diagnosis of migraine and MOH. Patients will be 
instructed at Baseline Visit to stop medication overuse during a semi-structured educational 
conversation.
Inclusion of a placebo group is justified as the group is representative of the best supportive 
care allowing acute treatment of migraine when prior preventive treatment have not worked.  
Thus, no patient will be denied access to acute migraine treatment in this study. Furthermore, 
all patients will receive eptinezumab in the open-label period. No patient will be denied 
access to active treatment with eptinezumab. 
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One dose group (100 mg) is considered for the current study as this dose has shown to be 
efficacious, is generally well tolerated in the treatment of migraine in the phase 3 studies and 
is approved recommended dose.
The patients will be fully informed about the study, including the risks and benefits of their 
participation in the study.
The patient may withdraw from the study at any time, for any reason, specified or unspecified 
and without penalty or loss of benefits to which the patient is otherwise entitled. Unscheduled 
visits can be made, and immediate withdrawal is possible if considered as necessary by the 
investigator and/or the patient. However, to comply with the EMA treatment policy 
strategies, the patient will be encouraged to stay in study for adequate follow up except if 
she/he withdraws her/his consent.
In accordance with Good Clinical Practice,35 qualified medical personnel at H. Lundbeck A/S 
or the clinical CRO will be readily available to advise on study-related medical questions.  
Medical monitoring will be performed throughout the study.  Safety data will be reviewed 
regularly by the Safety Committee at H. Lundbeck A/S to ensure that prompt action is taken, 
if needed.
In accordance with Good Clinical Practice,35 the investigator will be responsible for all study-
related medical decisions.
Based on data from the nonclinical and clinical studies, and in combination with the 
cautionary measures implemented in the study design, the risks for the patients are considered 
well controlled and balanced with the potential benefits of the treatment.
4.2
Informed Consent
No study-related procedures, including any screening procedures, may be performed before 
the investigator has obtained written informed consent from the patient.
Changing (for example, discontinuing or down-tapering) a patient’s concomitant medications 
prior to the Screening Visit to ensure that the patient 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 patient.  If the informed consent process may be delegated, 
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 patients, that is, patients 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 from senior 
members of a hierarchy in case of refusal to participate.  Patients thus identified must be 
excluded from participation in the study.
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Prior to obtaining written informed consent, the investigator or a designee must explain to the 
patients the aims and methods of the study and any reasonably expected benefits and 
foreseeable risks or inconveniences to the patients.
The patients 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 the possibility of withdrawing consent (section 8.7)
of their right to request a copy of their personal data from the study via the investigator
of their right to be informed by the investigator, after the study has been reported, about 
which treatment they received
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 patients must be informed that persons authorized by H. Lundbeck A/S and authorized 
personnel from certain authorities (domestic, foreign, data protection agencies, or ECs or 
IRBs) may view their medical records.  The patients 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 ECs or 
IRBs) for verification of study procedures and/or data.  The confidentiality of the patients will 
in all cases be respected.
The patients 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 patients. Prior to allowing a patient to participate in the 
study, an Informed Consent Form must be signed and dated by the patient and signed and 
dated by the investigator or a designee on the same day.  The patients must be given a copy of 
the written information (Patient Information Sheet) as well as a copy of the signed Informed 
Consent Form.
The consent procedures described above will only be implemented if allowed by local law 
and regulations and will only be initiated after approval by the relevant ECs or IRBs.
The actigraphy assessments using a digital device is optional, and a subset-specific Informed 
Consent Form is provided for participating in the assessments.
4.3
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 legislation38 to ensure that 
requirements regarding personal data protection are met. If an external organization will 
process data on behalf of H. Lundbeck A/S, a contractual procedure will be signed between 
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H. Lundbeck A/S or delegate and the external organization to ensure compliance with the 
above-mentioned legislation.
4.4
Ethics Committees and Institutional Review Boards 
This study will be conducted only after H. Lundbeck A/S 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 EC or IRB.
The investigator must not allow any patients to participate in the study before receiving 
confirmation from H. Lundbeck A/S or the CRO that the required approvals and/or 
notifications have been received.
The EC or 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 
EC or IRB by the investigator at intervals stipulated in its guidelines.
4.5
European Medicines Agency Treatment Policy
The patients are encouraged to stay in the study even if they interrupt/terminate their IMP 
infusion to allow for EMA treatment policy strategies to be applied. Patients who withdraw 
the informed consent or who are not compliant with the study procedures should be 
withdrawn from the study (see section 5.4).
5
Study Population
5.1
Number of Patients and Sites
Planned regions: Approximately 70 sites in select countries across North America, Australia,
and Europe.
Planned number of screened patients:
1140
Planned number of randomized patients:
570
5.2
Patient Recruitment
Competitive patient recruitment between countries and sites will be used during the entire 
recruitment period to ensure that the required number of patients are randomized within the 
planned recruitment period.
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The investigators will be notified immediately when the recruitment period comes to an end.
5.3
Selection Criteria
Patient selection is based on the inclusion and exclusion criteria listed below.
Patients who meet each of the inclusion criteria and none of the exclusion criteria are eligible 
to participate in this study.
Inclusion Criteria
1.
The patient is able to read and understand the Informed Consent Form.
2.
The patient has signed the Informed Consent Form.
3.
The patient is an outpatient.
4.
The patient has adequate venous access for administration of IMP.
5.
The patient has a diagnosis of CM as defined by IHS ICHD-3 guidelines1 confirmed at 
the Screening Visit.
6.
The patient has a history of migraine onset of at least 12 months prior to the Screening 
Visit. 
7.
The patient has ≥8 migraine days per month for each month within the past 3 months 
prior to the Screening Visit. 
8.
The patient has a diagnosis of MOH as defined by IHS ICHD-3 guidelines1 confirmed at 
the Screening Visit.
9.
The patient has ≥15 headache days per month for each month within the past 3 months 
prior to the Screening Visit.
10. The patient has regular overuse of one or more drugs (section 9.1.1) that can be taken for 
acute treatment of headache, for >3 months prior to the Screening Visit.
11. The patient has ≥15 to ≤26 headache days, of which ≥8 days were assessed as migraine 
days during the screening period, based on prospectively collected information in the 
eDiary.
12. The patient overuses drugs that can be taken for acute treatment of headache during the 
screening period, based on prospectively collected information in the eDiary.
13. The patient has a history of treatment failure with at least 1 preventive treatment within 
the last 5 years prior to the Screening Visit due to lack of efficacy (no clinically 
meaningful improvement at the locally recommended dose for at least 3 months) as 
defined in section 9.1.1.
14. The patient has demonstrated compliance with the headache eDiary by entry of data for at 
least 24 of the 28 days following the Screening Visit.
15. The patient has had an onset of migraine diagnosis at ≤50 years of age.
16. The patient is aged ≥18 and ≤75 years at the Screening Visit.
17. The patient, if a woman, must:

have had her last natural menstruation ≥12 months prior to the Screening Visit and had 
a high FSH level in the postmenopausal range as per local thresholds to confirm a 
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postmenopausal state in women not using hormonal contraception or hormonal 
replacement therapy, OR

have been surgically sterilized (including tubal ligation, tubal occlusion, and 
oophorectomy) prior to the Screening Visit, OR

have had a hysterectomy prior to the Screening Visit, OR

remain sexually abstinent, when this is in line with her preferred and usual lifestyle, 
OR

engage exclusively in same-sex relationships, OR

agree not to try to become pregnant during the study AND use at least one of the 
below adequate contraception:
o
combined oral, intravaginal, or transdermal hormonal contraception
o
progestogen-only oral, injectable, or implantable hormonal contraception
o
intrauterine devices
o
intrauterine hormone-releasing system
o
male or female condom with or without spermicide
o
cap, diaphragm or sponge with spermicide
o
vasectomized partner
The contraception must be used from the Screening Visit to ≥6 months after the last 
dose of IMP (if hormonal contraceptives are used, see Appendix II for stability 
requirement for hormonal contraceptives 12 weeks prior to Screening Visit)
18. The patient has provided a signed optional subset-specific Informed Consent Form for
actigraphy assessments, if applicable.
Exclusion Criteria
1.
The patient has previously been enrolled in this study.
2.
The patient has experienced failure on a previous preventive treatment targeting the 
CGRP pathway including gepants for acute or preventive use.
3.
The patient has participated in a clinical study <30 days or has taken any investigational 
products within 5 plasma half-lives (whichever is longer) prior to the Screening Visit.
4.
The patient 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.
5.
The patient is pregnant, planning to become pregnant, or breastfeeding.
6.
The patient has a history of severe drug allergy or hypersensitivity or known 
hypersensitivity or intolerance to any of the IMPs or its/their excipients.
7.
The patient has confounding and clinically significant pain syndromes (for example, 
fibromyalgia, chronic low back pain, and complex regional pain syndrome).
8.
The patient has a diagnosis of acute or active temporomandibular disorders.
9.
The patient has a history or diagnosis of chronic tension-type headache, hypnic headache, 
cluster headache, hemicrania continua, new daily persistent headache, or unusual 
migraine subtypes such as hemiplegic migraine (sporadic and familial), recurrent painful 
ophthalmoplegic neuropathy, migraine with brainstem aura, and migraine with 
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neurological accompaniments that are not typical of migraine aura (diplopia, altered 
consciousness, or long duration).
10. The patient has psychosis, bipolar mania, dementia, or any other psychiatric conditions 
whose symptoms are not controlled or who has not been adequately treated for a 
minimum of 6 months prior to the Screening Visit.
11. The patient has a current diagnosis or history of substance or alcohol use disorder 
(DSM-5® criteria) <24 months prior to the Screening Visit.
12. The patient has any other disorder for which the treatment takes priority over treatment of 
migraine or is likely to interfere with study treatment or impair treatment compliance. 
13. The patient has a history of moderate or severe head trauma or other neurological 
disorder or systemic medical disease that is, in the investigator’s opinion, likely to affect 
CNS functioning. 
14. The patient has a history of cancer, other than basal cell or Stage 1 squamous cell 
carcinoma of the skin, that has not been in remission for >5 years prior to the first dose of 
IMP. 
15. The patient has a history of clinically significant cardiovascular disease including 
uncontrolled hypertension, vascular ischaemia, or thromboembolic events (for example, 
cerebrovascular accident, deep vein thrombosis, or pulmonary embolism).
16. The patient has or has had one or more of the following conditions that is/are considered 
clinically relevant in the context of the study: other neurological, pulmonary, hepatic, 
endocrinological, gastrointestinal, haematological, infectious, immunological, or ocular 
disorder.
17. The patient takes or has taken recent or concomitant medication that is disallowed or 
allowed with restrictions (specified in Appendix II) or it is anticipated that the patient will 
require treatment with at least one of these medications during the study.
18. The patient has one or more clinically significant out-of-range vital signs at the Screening 
Visit.
19. The patient has a BMI ≥39 kg/m2 at the Screening Visit.
20. The patient has tested positive for HIV, anti-HCV, or hepatitis B serology that is 
confirmed to have acute or chronic infection (Appendix III for interpretation).
21. The patient has one or more clinical laboratory test values outside the reference range, 
based on the blood and urine samples taken at the Screening Visit, that are of potential 
risk to the patient’s safety, or the patient has, at the Screening Visit:

a serum creatinine value >1.5 times the upper limit of the reference range

a serum total bilirubin value >1.5 times the upper limit of the reference range

an ALT or AST value >2 times the upper limit of the reference range
22. The patient has, at the Screening Visit, an abnormal ECG that is, in the investigator’s 
opinion, clinically significant.
23. The patient has a QTcF >450 ms (for men) or >470 ms (for women) at the Screening 
Visit, as calculated by the ECG equipment and evaluated by the investigator.  The ECG 
may be repeated if any of the values are out of range or abnormal.
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24. The patient is, at the Screening Visit, at significant risk of suicide (defined, using the C-
SSRS, as the patient answering: "yes" to suicidal ideation questions 4 or 5 or answering: 
"yes" to suicidal behaviour within the past 12 months).
25. The patient 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.
26. The patient is, in the investigator’s opinion, unlikely to comply with the protocol or is 
unsuitable for any reason.
5.4
Withdrawal Criteria from the Study and IMP
A patient must be withdrawn from the study if:
the patient withdraws consent (defined as a patient who takes back consent); section 8.7
states how the patient’s data will be handled
the patient fails to comply with study procedures
the patient is lost to follow-up (defined as a patient who fails to comply with scheduled 
study visits or contact, who has not actively withdrawn from the study, and for whom no 
alternative contact information is available [this implies that at least two documented 
attempts have been made to contact the patient])
A patient must be withdrawn from further treatment with IMP if:
the patient has been randomized in error and has not received IMP
any site personnel break the randomization code for that patient before the patient has 
entered in the open-label period
the investigator considers it, for safety, lack of efficacy, and/or study compliance reasons, 
in the best interests of the patient that he or she be withdrawn from treatment
the patient experiences an anaphylactic reaction or another serious and/or severe 
hypersensitivity reaction to the IMP infusion, as assessed by the investigator. If the event 
occurs during the infusion, the infusion must be discontinued immediately.
Patients who interrupt/terminate their IMP infusion are encouraged to complete the study to 
allow for application of treatment policy strategies (see section 4.5).  Patients who withdraw 
from treatment with IMP will not be replaced.
6
Investigational Medicinal Product
6.1
Treatment Regimen
Patients will be randomly allocated via a centralized randomization system to one of two 
treatment groups: eptinezumab 100 mg, or placebo, in a ratio of 1:1.
The patient will receive IMP at the Baseline Visit with either eptinezumab or placebo by 
intravenous infusion.
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At the Visit 5 all patients who were assigned to either eptinezumab or placebo will enter the 
open-label period and receive an intravenous infusion with eptinezumab 100 mg.
6.2
IMP, Formulation, and Strength
The IMP supplied by H. Lundbeck A/S in this study is:

Eptinezumab 100 mg/mL (1 mL/vial) as Concentrate for Solution for Infusion.
100 mg eptinezumab will be dispensed as 1 vial of 100 mg/mL (1 mL/ vial), Concentrate for 
Solution for Infusion. 1 mL of 100 mg/mL Concentrate for solution for Infusion is added to 
100 mL of 0.9% normal saline, administered intravenously. 

Placebo will be dispensed as 100 mL of 0.9% normal saline, administered intravenously.
The pharmacist or designee responsible for receiving, storing, preparing, and dispensing 
eptinezumab and placebo intravenous infusions will be unblinded and will not be responsible 
for other aspects of the clinical study where blinding is necessary.
Doses will be administered intravenously over a period of 30 minutes (+15 minutes) by the 
blinded investigator or designee.
Further instructions on preparation and procedures associated with administering 
intravenously can be found in the Pharmacy Manual and Infusion Guidelines.
6.3
Manufacturing, Packaging, Labelling, and Storage of IMP
The IMP(s) will be manufactured, packaged, labelled, released (by a qualified person [QP]), 
and distributed in accordance with the principles of Good Manufacturing Practice, under the 
responsibility of H. Lundbeck A/S.
The IMP will be provided in single-use vials (as a concentrate for solution for infusion).
The wording on the labels will be in accordance with Good Manufacturing Practice regarding 
labelling and national and/or local regulatory requirements.  If additional information is to be 
added when the IMP is dispensed to the patients, this will be clearly stated on the labels, and 
the investigator will be instructed to do so.
No manipulation, repackaging, or relabelling of IMP is permitted after QP release by 
H. Lundbeck A/S, unless a repackaging/relabelling agreement exists, and the documentation 
is available to Clinical Supply, H. Lundbeck A/S, and, where necessary, new QP releases are 
made.
The IMPs will be identified using a unique Medication number.
The IMPs must be stored in a safe and secure location, and in accordance with the storage 
conditions specified on the labels.
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6.4
Method of Assigning Patients to Treatment
IRT will be used in this study. Each patient will be assigned a screening number, and that 
number will be used to identify the patient throughout the study.  Randomization of the 
patient will be performed by using the IRT system and stratified by country and number of 
previous preventive treatment failures (≤2; >2) occurring up to 5 years prior to Baseline Visit.  
The IRT will allocate the patient to a treatment group during the call and assign the patient a 
randomization number in accordance with the specifications from Biostatistics, 
H. Lundbeck A/S.
6.5
IMP Accountability
IMP accountability will be documented in the IRT by the unblinded CRA.
The investigator and the pharmacist must agree to only dispense IMP to patients enrolled in 
the study.  The unblinded pharmacist or designee must maintain an adequate record of the 
receipt and distribution of the IMP(s).  This record must be available for inspection by the 
unblinded CRA at any time.
6.6
Unblinding Procedures
Global Patient Safety, H. Lundbeck A/S, and the investigator or the pharmacist (if applicable), 
will have access to the unblinded information for the double-blind treatment for each patient.  
Access to these details will be via IRT.
The IRT unblinding procedure is described in the IRT User Guide.
The investigator may only break the code for a patient if knowledge of the IMP is necessary 
to provide optimal treatment to the patient in an emergency situation.  If possible, the 
investigator should consult the CRA (in some cases it may be the medical monitor) before 
breaking the code.  The investigator must record the date and reason for breaking the code on 
the IMP Code Break Form.  If the emergency situation was an adverse event, it must be 
recorded on an Adverse Event Form.  The CRA (in some cases it may be the medical monitor) 
must be notified immediately.  The IRT will capture the date and time of the code break call.  
Information on the allocated treatment will be provided during the call and by fax or email, 
depending on availability/preference.  If this occurs during a visit, the investigator must 
complete the visit as a Withdrawal Visit; otherwise, the patient will be asked to attend a 
Withdrawal Visit.
6.7
Post-study Access to IMP(s)
Patients in the study will have access to appropriate medical care after they complete or 
withdraw from the study.
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7
Concomitant Medication
Concomitant medication is any medication other than the IMP and that is taken during the 
study, up until the Safety Follow-up Contact, including during the screening period.
The concomitant medications that are disallowed or allowed with restrictions during the study 
are summarized in Appendix II.  Some of the restrictions apply up until the EoS Visit 
(Week 24) after which the investigator should continue to treat the patient as required by the 
patient’s clinical condition. The restriction for use of mAb targeting the CGRP pathway must 
also be applied during the safety follow-up period.
Acute medication for treatment of migraine (triptans, ergotamine, combination of non-opioid 
analgesics, individual non-opioid analgesics, opioid analgesics, and NSAIDs) is allowed for 
the entire duration of the study and will be collected in the eCRF and the eDiary. 
Investigators must ensure the patients are informed to which class of medication(s) their acute 
treatment(s) belong to.
Details of all concomitant medication (prescription and OTC), traditional herbal medicines, 
non-pharmacological interventions, and vitamin and mineral supplements for the treatment of 
migraine taken <3 months prior to the Screening Visit must be recorded in the eCRF at the 
Screening Visit.  Any changes (including reason for changes) in these therapies must be 
recorded at each subsequent visit.
Details of all migraine preventive medications including treatment failures (prescription and 
OTC) taken within 5 years prior to the Screening Visit must be recorded in the eCRF at the 
Screening Visit.
For any concomitant medication, traditional herbal medicines, non-pharmacological 
interventions, and vitamin and mineral supplements for which the dose has been increased 
due to worsening of a concurrent disorder after enrolment in the study, the worsening of the 
disorder must be recorded as an adverse event.  For any of these therapies initiated due to a 
new disorder after enrolment in the study, the disorder must be recorded as an adverse event.
7.1
Interaction with Coronavirus Disease 2019 Vaccine
There is currently no data indicating that eptinezumab may interact with or impair the body’s 
immunological response to the COVID-19 vaccines. Hence, there are no indications for 
safety concerns of concomitant use of the COVID-19 vaccines with eptinezumab. As such, 
COVID-19 vaccination is allowed during the eptinezumab studies with the guidance measures 
as described in Appendix II. All adverse events, including those judged by the investigator to 
be related to the COVID-19 vaccine, must be recorded on an Adverse Event Form. A 
causality assessment, including an alternative causality as relevant, must be provided on the 
Adverse Event Form.
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8
Study Visit Plan
8.1
Overview
An overview of the procedures and assessments to be conducted during the study and their 
timing is presented in Panel 2.  Further details are in chapter 9.
The Screening Visit (Visit 1) is performed 28 to 30 days before the Baseline Visit (Visit 2). 
Thereafter, study visits during the placebo-controlled period consist of two decentralized
contacts (Visit 3 and Visit 4) including the Primary Outcome Visit at Visit 3. During the 
open-label period, IMP will be administered at Visit 5 followed by a decentralized contact
(Visit 6) and an EoS Visit (Visit 7).
IMP will be administered at the Baseline Visit (Visit 2) and Week 12 Visit (Visit 5) which is 
performed 12 weeks after the Baseline Visit.
The EoS Visit (Visit 7) will be performed at Week 24, 12 weeks after the second IMP 
administration. A Safety Follow-up Contact (Visit 8) will be performed 8 weeks after the 
EoS Visit. Patients who withdraw, except for those who withdraw their consent, will be
asked to attend a Withdrawal Visit as soon as possible and a Safety Follow-Up Contact at 
20 weeks after last administration of IMP.
At the on-site visits all assessments may be completed over a maximum of 2 consecutive days 
(with the exception of ePROs); if so, the first day is considered the “visit” day according to 
the schedule. If the date of an on-site visit or decentralized contact does not conform to the 
schedule, subsequent visits should be planned to maintain the visit schedule relative to the 
Baseline Visit.
Patients will record headache data daily in eDiary from the Screening Visit until the 
EoS/Withdrawal Visit.  Throughout the double-blind and open-label periods compliance 
check of eDiary data will be conducted at each on-site visit and decentralized contact.
ePROs scheduled at Baseline Visit (Visit 2) and Week 12 Visit (Visit 5) must be completed in 
the clinical site at the visit date and before the infusion. ePROs which are scheduled in 
alignment with the Withdrawal Visit can be completed in the clinical site or in the remote 
setting within 3 days prior to the scheduled on-site visit date. ePROs which are scheduled in 
alignment with a decentralized contact must be completed in the remote setting and can be 
completed on the day or within 3 days prior to the scheduled decentralized contact date.
After completing or withdrawing from the study, the patient must be treated in accordance 
with usual clinical practice.
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8.2
Screening Visit (Visit 1)
The Screening Visit must be conducted as an on-site visit. Signed informed consent must be 
in place before any study-related assessments are performed and may be obtained prior to the 
Screening Visit. Further details on screening assessments are provided in section 9.1.
At the Screening Visit, the patient must be assisted with the provisioning and training of the 
eDiary and ePROs (efficacy and pharmacoeconomic assessments). Details will be provided 
in a separate eDiary and ePRO Training Module.  Further details on eDiary are provided in 
section 9.2.1.2. 
In exceptional cases, the screening period (visit interval between Screening and Baseline 
Visits) may be extended by an extra period of seven days with approval from the sponsor 
provided the medical expert at H. Lundbeck A/S (or the CRO’s medical monitor) accepts the 
rationale provided for the extension.
Prior to the Baseline Visit, study-specific eligibility must be reviewed by the CRO’s medical 
monitor before randomization, to advise if the patient appears eligible according to the 
selection criteria of the protocol.
8.2.1
Pre-screening
Each site must record in a pre-screening log which patients attended the Screening Visit.
8.2.2
Patient Identification Card
Each patient will be provided with a patient identification card that states, at a minimum, the 
name of the IMP, the study number, the patient identification number, the investigator’s 
name, and an emergency telephone number providing 24-hour service.
The patient identification card should be returned to the investigator upon completion of the 
patient’s participation in the study.
8.2.3
Re-screening
Re-screening is not allowed in this study.
8.3
Baseline Visit + IMP (Visit 2)
The Baseline Visit must be conducted as an on-site visit and will occur 28 to 30 days after the 
Screening Visit. In exceptional cases, the screening period (visit interval between Screening 
and Baseline Visits) may be extended with approval from the sponsor provided the medical 
expert at H. Lundbeck A/S accepts the rationale provided for the extension.
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Prior to the Baseline Visit, study-specific eligibility must be reviewed by the CRO’s medical 
monitor before randomization, to advise if the patient appears eligible or not according to the 
selection criteria of the protocol.
At the Baseline Visit, inclusion and exclusion criteria review must be done prior to dosing 
(see section 5.3 for further details on selection criteria). A compliance check of eDiary, based 
on the 28-day screening period, will be conducted and the patient must be assisted with 
re-training if necessary.
On the Baseline Visit day, patients must ensure to complete eDiary recording of headaches 
that ended prior to infusion (that is, for headaches which are ongoing or not yet recorded in 
the eDiary). Further details on eDiary are provided in section 9.2.1.2. 
ePROs which are scheduled in alignment with the Baseline Visit must be completed in the 
clinical site. The ePROs should preferably be completed in the following order: HIT-6, 
mMIDAS, MBS, MSQ v2.1, HADS, EQ-5D-5L, WPAI:M, TSQM-9, and HCRU. It is 
preferable that the same order of assessments is used per patient and the scheduled time of the 
day for the assessments is as consistent as possible across all the study visits. Further details 
on ePROs are provided in sections 9.2 and 9.3.
At the Baseline Visit the patients will receive a dose of IMP. Further instructions on 
procedures associated with administering the IMP are provided in section 6.2 and Infusion 
Guidelines.
Before IMP infusion:
Patients must complete the ePROs.  ePROs can be completed at the patient’s convenience 
before  the pre-infusion blood and urine sampling.
The following assessments must be conducted: vital signs including body temperature, 
concomitant medications, adverse events, substance use, urine sampling for pregnancy test, 
and optional digital device assessment (for patients on a consenting subset). Vital signs 
must be assessed prior to blood sampling. 
On the Baseline Visit day, patients will follow semi-structured interview based on BI
including SDS:H which must take place prior to IMP infusion. 
During IMP infusion: 
Patients must be monitored during the infusion in accordance with usual clinical practice. 
Adverse events, including IRRs, must be checked during the infusion. 
After end-of-IMP-infusion and before the patient is discharged from the site:
Patients must be monitored according to usual clinical practice.
The following assessments must be conducted: vital signs including body temperature, and 
adverse events, including IRRs.
Patients will be requested to stay for as long as the investigator or designee determine this 
is clinically warranted. After the infusion, the patients will be under observation, but not 
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confined to bed, unless the investigator or designee decides, based on the patient’s 
condition, that it is in the best interest of the patient to be confined to bed.
8.4
Decentralized Contacts (Visits 3, 4, and 6)
Decentralized contacts will be conducted as telephone or telemedicine visits for an eDiary 
compliance check, to ensure that selected ePROs have been completed (Visit 3) and for 
collection of relevant information such as adverse events and concomitant medication 
(Visits 3, 4, and 6) and substance use (Visits 3 and 4). Decentralized contacts should be 
planned to maintain the visit schedule relative to the Baseline Visit.
At Visits 3, 4, and 6, a review and compliance check of eDiary data will be conducted and the 
patient must be assisted with re-training if necessary. Further details on eDiary are provided 
in section 9.2.1.2
Additionally, at Visit 3, ePROs assessment which are scheduled in alignment with a 
decentralized contact must be completed in the remote setting and can be completed on the 
day or within 3 days prior to the scheduled contact date. The ePROs should preferably be 
completed in the following order: HIT-6, mMIDAS, PGIC, MSQ v2.1, HADS, EQ-5D-5L, 
WPAI:M, TSQM-9, and HCRU. It is preferable that the same order of assessments is used 
per patient and the scheduled time of the day for the assessments is as consistent as possible 
across all the study visits. Further details on ePROs are provided in sections 9.2 and 9.3.
Only site staff trained and listed in the delegation log will conduct decentralized contacts and 
hence be allowed to contact the patient. Each decentralized contact must be documented in 
medical notes and used for source data verification when completing the eCRF and for 
subsequent monitoring.
8.5
Week 12 Visit + IMP (Visit 5)
The Week 12 Visit must be conducted as an on-site visit and should be planned to maintain 
the visit schedule relative to the Baseline Visit.
Patients will receive an IMP infusion with eptinezumab 100 mg at Week 12 Visit.
Before IMP infusion: 
Patients must complete the ePROs. ePROs can be completed at the patient’s convenience 
before the pre-infusion blood and urine sampling. 
The following assessments must be conducted: vital signs including body temperature, 
concomitant medications, adverse events, substance use, urine sampling for pregnancy test, 
and optional digital device (actigraphy) assessment (for patients on a consenting subset).  
On the Week 12 Visit day, the SDS:H must take place prior to IMP infusion.
During IMP infusion: 
Patients must be monitored during the infusion in accordance with usual clinical practice. 
Adverse events, including IRRs, must be checked during the infusion.
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After end-of-IMP-infusion and before the patient is discharged from the site: 
Patients must be monitored according to usual clinical practice. 
The following assessments must be conducted: vital signs including body temperature, 
IRRs, and adverse events including IRRs.
Patients will be requested to stay for as long as the investigator or designee determine this 
is clinically warranted. After the infusion, the patients will be under observation, but not 
confined to bed, unless the investigator or designee decides, based on the patient’s 
condition, that it is in the best interest of the patient to be confined to bed. 
A compliance check of eDiary will be conducted.  Patients will be reminded to continue the 
daily eDiary assessments until the EoS/Withdrawal Visit. Details will be provided in a 
separate eDiary and ePRO Training Module. Further details on eDiary are provided in 
section 9.2.1.2. 
Patients undergoing the optional digital device (actigraphy) assessments will hand in the 
device, or who withdraw from the study before the Week 12 Visit must hand in the device at 
the Withdrawal Visit.
ePROs which are scheduled in alignment with the Week 12 Visit must be completed in the 
clinical site on the visit date and prior to infusion. The ePROs should preferably be 
completed in the following order: HIT-6, mMIDAS, PGIC, MBS, MSQ v2.1, HADS, EQ-5D-
5L, WPAI:M, TSQM-9, and HCRU. It is preferable that the same order of assessments is 
used per patient and if the scheduled time of the day for the assessments is as consistent as 
possible across all the study visits.  Further details on ePROs are provided in sections 9.2 and 
9.3.
8.6
End of Study Visit (Visit 7)
The EoS Visit (Visit 7) must be conducted as an on-site visit and is performed 12 weeks after 
the Week 12 Visit. The EoS Visit should be planned to maintain the visit schedule relative to 
the Baseline Visit.
At the EoS Visit assessments of safety and information collection of concomitant medication 
will be performed.
A compliance check of eDiary will be conducted.  The eDiary closeout will take place at the 
EoS Visit or Withdrawal Visit (for patients who withdraw from the study prior to the EoS 
Visit) while the patient is at the site. Details will be provided in a separate eDiary and ePRO 
Training Module.  Further details on eDiary are provided in section 9.2.1.2. 
ePROs which are scheduled in alignment with the EoS Visit can be completed either in the 
clinical site or in the remote setting within 3 days prior to the scheduled on-site visit date.  
The ePROs should preferably be completed in the following order: HIT-6, mMIDAS, PGIC,
MBS, MSQ v2.1, HADS, EQ-5D-5L, WPAI:M, TSQM-9, and HCRU.  It is preferable that 
the same order of assessments is used per patient and if the scheduled time of the day for the 
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assessments is as consistent as possible across all the study visits.  Further details on ePROs 
are provided in sections 9.2 and 9.3.
8.7
Withdrawal Visit
Interruption/termination of IMP infusion does not imply that the patient will be withdrawn 
from study (refer to section 5.4 for further details). The patient should be withdrawn from the 
study only if he/she withdrew the informed consent or not compliant with study procedures. 
All efforts should be done to keep the patient in the study until the end of the study period and 
all assessments should be done as specified in the protocol.
Patients who withdraw from the study will be asked to attend a Withdrawal Visit. The visit 
must be scheduled as soon as possible after withdrawal, and further a Safety Follow-Up 
Contact at 20 weeks after last administration of IMP (except for the patient who withdraw the 
inform consent).  
The eDiary closeout will take place at the Withdrawal Visit (for patients who withdraw from 
the study prior to the EoS Visit) while the patient is at the site.  Details will be provided in a 
separate eDiary and ePRO Training Module.  Further details on eDiary are provided in 
section 9.2.1.2. 
If the patient withdraws during the placebo-controlled period, substance use will also be 
collected.  If the patient withdraws from the study, ePROs should also be completed. 
ePROs which are scheduled in alignment with the Withdrawal Visit can be completed either 
in the clinical site or in the remote setting within 3 days prior to the scheduled on-site visit 
date.  The ePROs should preferably be completed in the following order: HIT-6, mMIDAS, 
PGIC, MBS, MSQ v2.1, HADS, EQ-5D-5L, WPAI:M, TSQM-9, and HCRU.  It is preferable 
that the same order of assessments is used per patient and if the scheduled time of the day for 
the assessments is as consistent as possible across all the study visits.  Further details on 
ePROs are provided in sections 9.2 and 9.3.
No new information will be collected from patients 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 10.6).
The reason for withdrawal must be recorded in the eCRF.
For a patient who withdraws consent:
if the patient 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 patient withdraws consent during a decentralized contact, the investigator will ask the 
patient if he or she will attend a Withdrawal Visit.  If the patient:
agrees to attend a Withdrawal Visit, all the data collected up to and including that visit 
will be used.
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refuses to attend a Withdrawal Visit, the investigator should attempt to follow the 
patient’s safety and future treatment; any information collected will only be recorded in 
the patient’s medical records.
if the patient explicitly requests that the patient’s data collected from the time of 
withdrawal of consent onwards not be used, this will be respected.
8.8
Safety Follow-up Contact (Visit 8)
The Safety Follow-up Contact will be conducted as a telephone or telemedicine visit 8 weeks 
after the EoS Visit (20 weeks after the last administration of IMP).  
A safety follow-up is conducted to capture adverse events 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 
EoS/Withdrawal Visit.  For patients who withdraw from the study, except for those who 
withdraw their consent, the Safety Follow-up Contact should be scheduled after the 
Withdrawal Visit and 20 weeks after the last administration of IMP. 
For adverse events that were ongoing at the end of the EoS/Withdrawal Visit 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 Contact, the Ongoing Adverse Event 
checkbox on the Adverse Event Form must be ticked.  SAEs must be followed until resolution 
or the outcome is known.
The safety follow-up for patients who withdraw consent must be performed, if at all possible; 
any information collected will only be recorded in the patients’ medical records.
8.9
Unscheduled Visits
An unscheduled visit may occur throughout this study if needed. Unscheduled visits can be 
completed if required as either site visit or decentralized contacts.  At these visits, any needed 
clinical investigations can be performed, and the results can be reported in connection with an 
adverse event reporting (chapter 10) or documented in the medical records, as applicable.
8.10
End-of-study Definition
The end of the study for an individual patient 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
9.1
Screening and Baseline Procedures and Assessments
9.1.1
Demographics and Baseline Characteristics
Prior to enrolling a patient in the study, the investigator must ascertain that the patient meets 
the selection criteria.
The following assessments will be performed after the Informed Consent Form has been 
signed:
demographics (age, sex, and race)
migraine history (including diagnosis of MOH)
relevant history (social, medical, psychiatric, neurological)
previous migraine preventive medication use including treatment failures (see below for 
definition)* within the 5 years prior to the Screening Visit (see chapter 12 for adequately 
documented records for migraine and MOH history)
other recent medication (including migraine medications)
height and weight without shoes
examinations (physical and neurological) 
blood sample for eligibility (β-HCG, HIV, anti-HCV, hepatitis B serology) and other 
clinical safety laboratory tests (as listed in Panel 6) 
urine sample for eligibility (drug screen, alcohol screen) and other clinical safety 
laboratory tests
Vital signs (including body temperature) and ECGs
Signs and symptoms present at screening and/or baseline before IMP administration 
(recorded on an Adverse Event Form)
Substance use (alcohol, tobacco, caffeine, marijuana consumption) **
C-SSRS 
optional digital device (actigraphy) assessment
  *
Treatment failure could have been due to inadequate efficacy (that is, no clinically meaningful 
improvement at the locally recommended dose for at least 3 months) and/or safety/tolerability 
reasons (that is, discontinuation due to adverse event) and/or contraindications (that is, 
ineligibility due to medical reasons). 
  ** Substance use during the screening period will be collected at the Baseline Visit. Substance use 
throughout the study will be collected at all visits until the Week 12 Visit/Withdrawal Visit (if the 
patient withdraws during the placebo-controlled period).
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9.1.2
Diagnostic Assessments
IHS ICHD-3 guidelines1 section 1.3 for migraine listed in Panel 4 are the diagnostic criteria to 
be used by the investigator when assessing patient eligibility.
Panel 4
IHS ICHD-3 Guidelines for Migraine
1.1 Migraine without aura
A. At least five attacks fulfilling criteria B to D
B. Headache attacks lasting 4 to 72 hours (when 
untreated or unsuccessfully treated)
C. Headache has at least two of the following 
four characteristics:
1. unilateral location
2. pulsating quality
3. moderate or severe pain intensity
4. aggravation by or causing avoidance of 
routine physical activity (for example
walking or climbing stairs)
D. During headache at least one of the 
following:
1. nausea and/or vomiting
2. photophobia and phonophobia
E. Not better accounted for by another ICHD-3 
diagnosis.
1.2 Migraine with aura
A. At least two attacks fulfilling criteria B and C
B. One or more of the following fully reversible aura 
symptoms:
1. visual
2. sensory
3. speech and/or language
4. motor
5. brainstem
6. retinal
C. At least three of the following six characteristics:
1. at least one aura symptom spreads gradually over ≥5 
minutes
2. two or more aura symptoms occur in succession
3. each individual aura symptom lasts 5–60 minutes
4. at least one aura symptom is unilateral
5. at least one aura symptom is positive
6. the aura is accompanied, or followed within 60 
minutes, by headache
D. Not better accounted for by another ICHD-3 diagnosis.
1.3 Chronic migraine
A. Headache (migraine-like or tension-type-like) on >15 days/month for >3 months, and fulfilling criteria B 
and C
B. Occurring in a patient who has had at least five attacks fulfilling criteria B to D for 1.1 Migraine without 
aura and/or criteria B and C for 1.2 Migraine with aura
C. On >8 days/month for >3 months, fulfilling any of the following:
1. criteria C and D for 1.1 Migraine without aura
2. criteria B and C for 1.2 Migraine with aura
3. believed by the patient to be migraine at onset and relieved by a triptan or ergot derivative
D. Not better accounted for by another ICHD-3 diagnosis.
For the diagnosis of MOH, the investigator will make the diagnosis by using the IHS ICHD-3 
guidelines1 listed in Panel 5.
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Panel 5
IHS ICHD-3 Guidelines for MOH
A. Headache occurring on ≥15 days/month in a patient with a pre-existing headache disorder
B. Regular overuse for >3 months of one or more drugs that can be taken for acute and/or symptomatic 
treatment of headache 
C. Not better accounted for by another ICHD-3 diagnosis
Regular overuse is defined either on:

10 days of use/month for >3 months of ergotamine, triptan, opioid (butalbital in US), or combination of 
analgesics

15 days of use/month for >3 months of non-opioid analgesics (paracetamol [acetaminophen], 
acetylsalicylic acid, NSAIDs)
In order to meet the eligibility with regards to MOH for the study, a patient has to have 
headache on ≥15 days/month for each month within the past 3 months prior to the Screening 
Visit and have regular overuse of one or more drugs that can be taken for acute and/or 
symptomatic treatment of headache, for >3 months.
9.1.3
Classifications for Eligibility
Fulfilment of criteria for migraine, according to the eligibility criteria in this protocol, will be
confirmed via prospectively collected information in the eDiary during the screening period, 
that is, migraine occurring on ≥8 days and headache occurring on ≥15 to ≤26 days. Prior to 
randomization, the investigator will review the data in the eDiary Eligibility Report to 
determine if eligibility criteria are fulfilled.
Definition of a Migraine Day: The migraine day definition is based on the IHS guidelines1
for controlled studies of preventive treatment of migraine in adults and here defined as a day 
with a headache that: 
lasts at least 30 minutes and meets ICHD-3 criteria C and D for migraine without aura 
(1.1) (following HIS corporate round table meeting held on 17th December 2021, 
consensus on changing the duration to 30 minutes for both EM and CM)
or lasts at least 30 minutes and where the patient had an aura with the headache (migraine 
with aura)*
or lasts ≥30 minutes and meets two of the three ICHD-3 criteria B (without the condition 
on 72 hours), C and D for migraine without aura (1.1) (probable migraine**)
or is a day with a headache that is successfully treated with a triptan, ergotamine, or other 
migraine-specific acute medication (for this purpose the master medication list will be
classified into migraine-specific and non-migraine-specific medication) ***
Data on characteristics of a headache will be collected in the eDiary for each headache, and 
for each headache it will be determined if it qualifies as a migraine day. 
If a headache lasts ≥72 hours, the days will still be counted as headache days or migraine 
days as aligned with the IHS guidelines. 1
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A day where the symptoms are not recorded for an ongoing headache (missed data entry) will 
be classified as a headache day.
Further details on the definitions:
*
At the Screening Visit, the patient’s usual aura is described. The patient will be asked about 
occurrence of aura based on questions in the eDiary as follows: “Did you experience an aura with 
this headache?”
**
For probable migraine, the definition in the protocol is based on ICHD-3 criteria for probable 
migraine (1.5) with the exception of criterion A in 1.1 Migraine without aura (at least five 
attacks fulfilling criteria B-D). The definition does not include probable migraine with aura, as 
detailed aura criteria are not collected in the eDiary and hence it is not possible to check if one 
criterion is missing. 
*** If patients are taking acute migraine medication, the following questions are captured in the 
eDiary: “Did you take any medications to treat this headache today?” and “Did at least one of the 
medications you took today successfully treat your headache??” Only if both are affirmed, and 
the medication reported by the patient is classified as migraine-specific, will the headache be 
classified as a migraine.
Definition of a Headache Day: A headache day is defined as a day with a headache that lasts 
≥30 minutes or that meets the definition of a migraine day.
Definition of a Migraine Attack: A migraine that fulfils the criteria for a migraine, is also 
referred to as a migraine attack. A migraine attack can last for a single day or for multiple 
days. 
Definition of a Headache Episode: A headache that either lasts ≥30 minutes or qualifies as a 
migraine, is also referred to as a headache episode. A headache episode can last for a single 
day or for multiple days. 
Definition of an eDiary Compliant Day: A compliant day is defined as any day where the 
following information is available:
headache diary is completed: a headache event is reported to take place and the patient has 
recorded the daily symptoms
headache diary is completed: confirming that the patient did not have any new headache to 
report
9.1.4
Urine Drug and Alcohol Screen
A urine drug screen will be performed at the central laboratory at the Screening Visit only. If 
the patient has tested positive for drugs of abuse (cocaine, amphetamines, phencyclidine, 
propoxyphene), then the patient should be excluded.  Note: positive result for 
benzodiazepines or cannabinoids is not an exclusion criterion.
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9.1.5
Reference Therapy
Reference therapy is BI for MOH, which is a semi-structured educational conversation with 
the purpose on helping the patients to reduce their MOH.  The BI starts with five questions of 
the SDS:H (including an indication of the patient’s willingness and confidence to change 
his/her medication overuse). Then patient is shown a short-structured scheme bases 
presentation either on a flip-over or slides with information about MOH and the association 
between medication overuse and chronic headache. The interview will end with an agreed 
plan on how to stop or reduce the medication overuse. 
The consultation is done in an empathic and collaborative manner aiming at achieving a 
decision by the patient that he/she would cut down the offending medication. Explicit 
recommendations are to stop or to reduce headache medications towards safe levels and 
information about possible difficulties and gains including that MOH usually “gets worse 
before it improves. 
The BI will take approximately 10 minutes to complete and is performed at Baseline Visit 
before IMP infusion.
The investigators and the study staff will be trained during the investigator meeting on the 
administration of the BI.  A demonstration video on how to conduct the BI will be mandatory
training for study personnel involved in submitting this intervention to the study population. 
9.2
Efficacy Assessments
Efficacy assessments include the eDiary to record daily headache data and ePROs (PGIC, 
MBS, and HADS). 
Patients will record eDiary headache data on daily basis from the time of screening until the 
EoS/Withdrawal Visit. At each on-site visit and decentralized contact during the placebo-
controlled period (that is, every 4 weeks), a compliance check of eDiary will be conducted 
(based on eDiary reporting). Additionally, ongoing evaluation of eDiary compliance will be 
performed by the site and more frequent contact with patients may be needed in case of non-
compliance. On on-site visit days, patients must complete the daily eDiary entries prior to 
infusion.
Patients will complete the PGIC, MBS, and HADS along with the pharmacoeconomic 
assessment ePROs (see section 9.3). The ePROs should preferably be completed in the 
following order: HIT-6, mMIDAS, PGIC, MBS, MSQ v2.1, HADS, EQ-5D-5L, WPAI:M, 
TSQM-9, and HCRU. It is preferable that the same order of assessments is used per patient 
and if the scheduled time of the day for the assessments is as consistent as possible across all 
the study visits.
ePROs will be completed in alignment with on-site visits and decentralized contacts:
ePROs which are scheduled in alignment with an on-site visit (see Panel 2): can be 
completed in the clinical site or in the remote setting within 3 days prior to the scheduled 
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on-site visit date. On the Baseline Visit day and Week 12 Visit day, patients must 
complete the ePROs on the visit date and prior to infusion. 
ePROs which are scheduled in alignment with a decentralized contact (see Panel 2): must 
be completed in the remote setting and can be completed on the day or within 3 days prior 
to the scheduled decentralized contact date.
9.2.1
Clinical Outcome Assessments 
9.2.1.1
Use of eCOA Tools
The eCOA tools are the eDiary and ePROs, and guidance will be given on how to complete 
them to the patients by designated site staff (see section 9.2.1.8). Detailed instructions will be 
provided to the site in a separate eDiary and ePRO Training Module and Site Information 
Guide. Site staff will be given access to review the eDiary data.
The eCOA tools will be administered electronically in the local language. Only those 
provided by H. Lundbeck A/S that have been validated in the language to which they have 
been translated will be used in this study. 
The following eCOA tools will be used for efficacy assessments:
eDiary – to assess daily headache and migraine variables, that is, the number of hours with 
headache, presence of associated symptoms, use of acute migraine medications start and 
stop dates, and headache severity.
PGIC - to assess overall change in the severity of illness following treatment.
MBS - to assess a migraine-related symptom that is most bothersome for the patient.
HADS - to assess psychological distress in non-psychiatric patients.
SDS:H - to assess dependency-like behaviour in patients with headache.
9.2.1.2
Electronic Diary
At the Screening Visit, the patient must be assisted with the provisioning of the eDiary and 
must be trained in eDiary use and compliance requirements by designated site staff.  Patients 
will be instructed to complete the eDiary on a daily basis, from the time of screening until the 
EoS/Withdrawal Visit.  During the EoS/Withdrawal Visit, eDiary close-out must be 
performed while the patient is at the site. Details will be provided in a separate eDiary and 
ePRO Training Module. 
The content of the headache eDiary is developed on key symptoms and characteristics as 
mentioned in the definition of migraine (see sections 9.1.2 and 9.1.3). The eDiary consists of 
applications and reports which will be used to derive the headache and migraine endpoints, 
and medication use.  For each day, the patient will record if they experienced any headaches. 
For each experienced headache, the start and stop date and time will be collected. The patient 
will record further daily information regarding headache characteristics (for instance, 
headache severity, additional symptoms) and intake of headache/migraine acute medication.
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Headache items will be assessed with a yes/no response; and severity will be rated as mild, 
moderate, or severe. Additional details regarding the questions that patients will answer can 
be found in the eDiary and ePRO Training Module.
The Screening Visit will correspond to the day of eDiary distribution and will start the 28-day 
eDiary screening period. Any patient found to be ineligible for the study during the screening 
period will not be randomized. An eDiary Eligibility Report will be used to review headache 
eDiary data (including baseline headache and migraine days and eDiary compliance) during 
the 28-day screening period for the eligibility assessment of:
migraine occurring on ≥8 days and headache occurring on ≤26 days.
compliance by entry of headache data for at least 24 of the 28 days following the Screening 
Visit.
On the Baseline Visit day and Week 12 Visit day, patients must ensure to complete eDiary 
recording of headaches that ended prior to infusion (that is, for headaches which are ongoing 
or not yet recorded in the eDiary).
Site staff will be given access to the eDiary data. Compliance data (based on eDiary 
reporting) will be made available until the EoS/Withdrawal Visit to site staff for review on a 
regular basis. At each on-site visit and decentralized contact (that is, every 4 weeks), a 
compliance check of eDiary will be conducted. Additionally, ongoing evaluation of eDiary 
compliance will be performed by the site and more frequent contact with patients may be 
needed in case of non-compliance. All follow-up with patients regarding eDiary compliance 
should be documented in the source records.
9.2.1.3
Patient Global Impression of Change
The PGIC is a single patient-reported item reflecting the patient’s impression of change in 
their disease status since the Baseline Visit (that is, in relation to activity limitations, 
symptoms, emotions, and overall quality of life). The item is rated on a 7-point scale, where a 
high score indicate improvement (very much improved; much improved; minimally 
improved; no change; minimally worse; much worse; very much worse). It takes approximate 
1 minute to complete the scale.
9.2.1.4
Most Bothersome Symptom
The investigator will verbally obtain the most bothersome symptom associated with the 
patient’s migraines during the Screening Visit. The selected most bothersome symptom will 
be incorporated in the electronic version of the MBS (ePRO). Patients will be asked to rate 
the improvement in this symptom from screening on a 7-point scale identical to the scale used 
for the PGIC. The MBS areas include nausea, vomiting, sensitivity to light, sensitivity to 
sound, mental cloudiness, fatigue, pain with activity, mood changes, and other. It takes less 
than 5 minutes to complete the MBS.
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9.2.1.5
Hospital Anxiety and Depression Scale
The HADS is a patient-rated scale designed to assess psychological distress in non-psychiatric 
patients. The HADS consists of two sub-scales: The D-scale measures depression and the 
A-scale measures anxiety. Each sub-scale contains 7 items, and each item is rated from 
0 (absent) to 3 (maximum severity). The score of each sub-scale ranges from 0 to 21 and are 
analysed separately. It takes approximately 5 to 10 minutes to complete the HADS.
9.2.1.6
Severity of Dependence Scale Adapted for Headache
The SDS:H is a patient reported scale, designed to assess dependency-like behaviour in 
patients with headache. The SDS:H is performed as a semi-structured interview, where the 
following questions will be addressed: 1) Do you think your use of headache medication was 
out of control? 2) Did the prospect of missing a dose make you anxious or worried? 3) Did 
you worry about your use of your headache medication? 4) Did you wish you could stop?
5) How difficult would you find it to stop or go without your headache medication? Each 
item is scored on a 4-point scale ranging from 0 (never/almost never, question 1-4, and not 
difficult, question 5) to 3 (always/nearly always, question 1-4, and impossible, question 5). It 
takes less than 5 minutes to complete the SDS:H.
9.2.1.7
External eCOA Monitoring Oversight
H. Lundbeck A/S reserves the right to use external quality oversight methods to ensure the 
eDiary compliance and data quality, as well as ensure accurate completion of eCOAs.  For 
this study, the CRO agreed with H. Lundbeck A/S will conduct the external data monitoring. 
9.2.1.8
eCOA Tool Training
eCOA training will be conducted by the CRO as agreed with H. Lundbeck A/S.  Site staff will 
complete their designated training curriculum based on their initial qualification status and 
assigned role. The training program will also include general eCOA quality assurance and 
management guidance.
Only site staff who have adequate experience with migraine and who have received adequate 
training on good standards in completion of the eDiary and ePROs will be authorized to train 
the patients on completion of eDiary and ePROs in the study.  Documentation of training will 
be provided to site staff for archiving in the investigator TMF. New eDiary and ePRO 
trainers joining the study must be trained similarly.
9.2.2
Optional Digital Device (Actigraphy) Assessments
Actigraphy is a non-invasive way of monitoring activity and sleep via an actimetry sensor 
picking up accelerations in three dimensions. Actigraphy is recorded using a wrist-worn 
device (EmbracePlus; Empatica, Boston, MA, US) which continuously records physiological 
data using an accelerometer, an electrodermal activity sensor, and a peripheral temperature 
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sensor. The data is recorded on the internal memory of the wearable wristband and sent to a 
paired application via Bluetooth (Care App). Data from the application is transferred to a 
research portal (Care Portal) via Internet connection. A guide with details on how to use the 
device will be provided to the patient. The actigraphy device is a voluntary option for this 
study.
The following actigraphy parameters will be derived to capture physical activity and sleep:
Movement intensity (activity counts): Time in light PA (11-50 a.U.), moderate PA (51-
100 a.U.) and intense PA (101-200 a.U.), minutes per 24 hours. 
Rest: Time in rest period: measured as minutes per 24 hours in the rest epoch state (range 
0-300: 0=wake epoch; 101=rest epoch; 102=turn and toss epoch; 300=rest interruption 
epoch).
Total Sleep Time: corresponding to the total time identified as sleep, per night in minutes.
Wake After Sleep Onset: corresponding to the amount of time spent awake after the Sleep 
Onset Latency, in minutes.
Sleep Efficiency: corresponding to the percentage of time asleep within the time-in-bed 
period.
Sleep Onset Latency: corresponding to the time from the start of the time in bed period to 
the actual sleep onset, computed from the actigraphy data, in minutes.
9.3
Pharmacoeconomic Assessments
Pharmacoeconomic assessments include ePROs (HIT-6, mMIDAS, MSQ v2.1, EQ-5D-5L, 
HCRU, WPAI:M, and TSQM-9). 
Patients will complete these ePROs along with the efficacy assessment ePROs (section 9.2.1). 
The ePROs should preferably be completed in the following order: HIT-6, mMIDAS, PGIC, 
MBS, MSQ v2.1, HADS, EQ-5D-5L, WPAI:M, TSQM-9, and HCRU.  It is preferable that 
the same order of assessments is used per patient and if the scheduled time of the day for the 
assessments is as consistent as possible across all the study visits.
ePROs will be completed in alignment with on-site visits and decentralized contacts:
ePROs which are scheduled in alignment with an on-site visit (see Panel 2): can be 
completed in the clinical site or in the remote setting within 3 days prior to the scheduled 
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on-site visit date. On the Baseline Visit day and Week 12 Visit day, patients must 
complete the ePROs on the visit date and prior to infusion. 
ePROs which are scheduled in alignment with a decentralized contact (see Panel 2): must 
be completed in the remote setting and can be completed on the day or within 3 days prior 
to the scheduled decentralized contact date.
9.3.1
Clinical Outcome Assessments 
9.3.1.1
Use of eCOA Tools
Refer to section 9.2.1.1 for further information on use of eCOA tools.
The following eCOA tools will be used for pharmacoeconomic assessments:
HIT-6 - to assess the impact of an occurring headache and its effect on the ability to 
function normally in daily life 
mMIDAS - to assess the disability related to migraine
MSQ v2.1 - to assess quality of life related to migraine 
EQ-5D-5L - to assess the overall state of health 
WPAI:M - to assess overall effect of health on productivity at work and daily activities
TSQM-9 - to assess the patient’s satisfaction with the medication (IMP)
HCRU - to assess migraine-specific health care resource utilization 
9.3.1.2
Headache Impact Test
The HIT-6 (v1.0)39 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. 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 is the sum of each response score and ranges from 36 to 78.  The life 
impact derived from the total score is described as followed: Severe (≥60), Substantial 
(56-59), Some (50-55), Little to None (≤49). It takes less than 5 minutes to complete the 
HIT-6 questionnaire.
9.3.1.3
Migraine Disability Assessment, Modified Version
The mMIDAS40  is a self-reporting questionnaire designed to assess absenteeism (complete 
disability) and presenteeism (reduced participation) in several domains, including work, 
school, family, social, and leisure activities. The total number of days with disability is rated 
on a 4-point scale, from the lower total score that indicates a Little or No Disability; Mild 
Disability; Moderate Disability to the higher total score that indicates a Severe Disability. It 
takes approximately 5 to 10 minutes to complete the mMIDAS.
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9.3.1.4
Migraine-Specific Quality of Life Questionnaire, Version 2.1
The MSQ v2.141  is a patient-reported outcome designed to assess the quality of life in 
patients with migraine. It consists of 14 items covering three domains: role function 
restrictive (7 items); role function preventive (4 items); and emotional function (3 items). 
Each item is scored on a 6-point scale ranging from 1 (none of the time) to 6 (all of the time). 
Raw domain scores are summed and transformed to a 0-to-100-point scale. Higher scores 
indicate better quality of life. It takes approximately 5 to 10 minutes to complete the MSQ 
v2.1.
9.3.1.5
Euroqol 5 Dimension – 5 Levels
The EQ-5D-5L42 is a patient-reported assessment designed to measure the patient’s well-
being.  It consists of 5 descriptive items (mobility, self-care, usual activities, pain/discomfort, 
and depression/anxiety) and a 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) and a single 
summary index (from 0 to 1) can be calculated.  The VAS ranges from 0 (worst imaginable 
health state) to 100 (best imaginable health state).  It takes approximately 5 minutes to 
complete the EQ-5D-5L.
9.3.1.6
Health Care Resource Utilization
Migraine-specific health care resource utilization information will be collected in terms of 
outpatient health care professional visits, emergency room visits, hospital admissions, as well 
as duration of hospital stays.  Clinical site personnel and patients will be instructed to capture 
utilization that takes place outside of visits associated with their participation in the clinical 
study. It takes approximately 5 minutes to complete the HCRU.
9.3.1.7
Work Productivity and Activity Impairment: Migraine
The WPAI43 is a patient self-rated scale designed to provide a quantitative measure of the 
work productivity and activity impairment due to a specific health problem (WPAI:M). The 
WPAI assesses activities over the preceding 7 days and consists of 6 items: 1 item assess 
employment status, 3 items assess the number of hours worked, the number of hours missed 
from work due to the patient’s condition, or due to other reasons, and 2 visual numerical 
scales to assess how much the patient’s condition affects their productivity at work and their 
ability to complete normal daily activities. It takes approximately 5 minutes to complete the 
WPAI.
9.3.1.8
Treatment Satisfaction Questionnaire for Medicine – 9 Items
The TSQM-9 is a generic questionnaire assessing the patient’s satisfaction with the 
medication (IMP). The tool consists of 9 items addressing effectiveness, side effects, 
convenience, and overall satisfaction of the IMP. It takes approximately 5 minutes to 
complete the TSQM-9.
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9.3.1.9
External eCOA Monitoring Oversight
Refer to section 9.2.1.7 for further information.
9.3.1.10
eCOA Tool Training
Refer to section 9.2.1.8 for further information.
9.4
Safety Assessments
9.4.1
Adverse Events
The patients will be asked a non-leading question (for example, “how do you feel?”, “how 
have you felt since your last visit?”) at each visit, starting at the Screening Visit.  Adverse 
events (including worsening of concurrent disorders, new disorders, and pregnancies) either 
observed by the investigator or reported spontaneously by the patient will be recorded, and the 
investigator will assess the seriousness and the intensity of each adverse event and its 
relationship to the IMP.  Results from relevant tests and examinations, such as vital signs, or 
their corresponding conditions will also be recorded as adverse events if considered by the 
investigator to be clinically significant.
See chapter 10 for further information on adverse events.
9.4.2
Clinical Safety Laboratory Tests
The clinical safety laboratory tests are listed in Panel 6.
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Panel 6
Clinical Safety Laboratory Tests
Haematology
Liverb
Serology
B-haemoglobin [HGB]
B-erythrocyte count [RBC]
B-total leucocyte count [WBC]
B-neutrophilsa [NEUTLE]
B-eosinophilsa [EOSLE]
B-basophilsa [BASOLE]
B-lymphocytesa [LYMLE]
B-monocytesa [MONOLE]
B-thrombocyte count [PLAT]
B-haematocrit [HCT]
P-prothrombin time [PT]
S-total bilirubin [BILI]
S-conjugated bilirubin [BILDIR]
S-alkaline phosphatase [ALP]
S-alanine aminotransferase [ALT]
S-aspartate aminotransferase [AST]
S-gamma-glutamyl transferase 
[GGT]
S-HIV [HIVAB] consent is 
required
S-HBsAg [HBSAG]
S-anti-HBs [HBSAB]
S-anti-HBc [HBCAB]
S-anti-HCV [HCAB]
Infection
S-C-reactive protein [CRP]
Electrolytesb
Kidneyb
Urinef
S-sodium [SODIUM]
S-potassium [K]
S-calcium (total) [CA]
S-creatinine [CREAT]
S-urea nitrogen [UREAN]
U-protein (dipstick) [PROT]
U-glucose (dipstick) [GLUC]
U-blood (dipstick) [OCCBLD]
Urine drug screen 
Urine alcohol
Endocrine and Metabolicb
Lipidsb,c
Pregnancyd
S-albumin [ALB]
S-glucosed [GLUC]
B-HbA1c [HBA1C]
S-creatine phosphokinase [CK]
S-thyroid-stimulating hormonec [TSH]g
S-follicle-stimulating hormone [FSH]e
S-low density lipoprotein [LDL]
S-high density lipoprotein [HDL]
S-triglycerides [TRIG]
S-cholesterol (total) [CHOL]
S-human chorionic 
gonadotropin [β-HCG]
Urine dipstick
B = blood; P = plasma; S = serum; U = urine; [ ] = CDISC term
a
Count and % of total leucocytes
b
Clinical chemistry
c
Fasting, when possible
d
Only for women of childbearing potential.  Pregnancy test at the Screening Visit is to be conducted using 
serum β-HCG. At all other visits, where this is applicable the urine pregnancy testing will be performed and 
in case of a positive finding, further confirmatory testing will be performed via serum β-HCG.
e
Only for women
f
If urine dipstick is positive, a urine microscopic panel will be conducted.
g
In case of abnormal TSH, reflex testing of T3 and T4 will be conducted.
Blood samples for the clinical safety laboratory tests will be collected as outlined in Panel 2.  
The blood sampling and handling procedures are described in the study-specific Laboratory 
Specification Manual.
The blood samples will be analysed at the central laboratory. In case of exceptional 
circumstances or emergency, the investigator may need to request additional laboratory 
testing at a local laboratory. The investigator will record only out-of-range clinical safety 
laboratory test values considered clinically significant, which must be recorded as an adverse 
event on an Adverse Event Form.
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Urine pregnancy testing will be performed and analysed at site. All other urine samples will 
be collected and analysed at the central laboratory.
The investigator must review (initial and date) the results of the clinical safety laboratory tests 
as soon as possible after receipt of those results.  Out-of-range values must be interpreted by 
the investigator as “not clinically significant” or “clinically significant” with a comment 
concerning the planned follow-up.  Tests for clinically significant out-of-range values must be 
repeated, or an appropriate clinical follow-up must be arranged by the investigator and 
documented on the laboratory report, until the value has stabilized or until the value has 
returned to a clinically acceptable value (regardless of relationship to the IMP).  Any 
out-of-range values followed after the last protocol-specified contact with the patient will be 
documented in the patient’s medical records.
Any out-of-range clinical safety laboratory test value considered clinically significant by the 
investigator must be recorded as an adverse event on an Adverse Event Form.
The central laboratory will be notified by the sponsor when the biological samples may be 
destroyed.
9.4.3
Vital Signs Including Body Temperature
The investigator may appoint a designee (nurse or paramedic) 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 using a standard digital meter.  Pulse rate and 
blood pressure will be measured in the following order:  supine, sitting, and standing after the 
patient has rested in each position for at least 3 minutes.  
Vital signs including blood pressure, pulse, respiratory rate and body temperature must be 
assessed prior to blood sampling.
Respiratory rate will be measured by counting the number of breaths over a full minute.
Body temperature will be measured by a thermometer that is used at the site.
Any out-of-range vital signs considered clinically significant by the investigator must be 
recorded as an adverse event on an Adverse Event Form.
9.4.4
Height and Weight
The patient’s height without shoes will be measured.  The patients will be weighed wearing 
light clothing and no shoes.  A similar amount of clothing must be worn on each occasion.
Any weight change considered clinically significant by the investigator must be recorded as 
an adverse event on an Adverse Event Form.
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9.4.5
Electrocardiograms
All ECG apparatus must be calibrated, meaning that an electrical impulse of a given strength 
always results in a wave of a given height. Standard calibration is 10 mm/mV. This means 
that an electrical impulse of 1 mV results in a wave height of 10 mm on the ECG. A 
calibration test must be present on the ECG hardcopy. 
The ECG recording should be a 12-lead recording. All leads should be clearly identified.  
There should be 3 evaluable beats per lead.
Paper speed (preferably 25 mm/sec) should be stated on the ECG. The relevant following 
information should also be stated on the ECG recording: Study number, patient’s name and 
date of birth, and date and time of recording. The person (investigator or its designee) who 
interprets the ECG should preferably sign and date the ECG after it has been reviewed.
Upon request from the investigator, a standard 12-lead ECG will be provided to the 
investigator or its designee.
The results of ECG will include the RR, PR, QRS, QT, and QTc intervals.
If the ECG is out of the reference range, it is the investigator’s responsibility to assess the 
value as “Normal,” “Abnormal Not Clinically Significant,” or “Abnormal Clinical 
Significant” and handle it in the appropriate manner.  The investigator has the final decision 
on the interpretation of the ECG results.  
Any abnormal ECG result or out-of-range ECG parameter value considered clinically 
significant by the investigator must be recorded as an adverse event on an Adverse Event 
Form and must be described in words with a diagnosis or value (for example, Second-degree 
AV-Block type Wenckebach) in the eCRF.
9.4.6
Physical and Neurological Examinations
The investigator may appoint a designee to be primarily responsible for performing the 
physical examinations, provided this is permitted according to local regulations.  The 
investigator must take responsibility for reviewing the findings.  Whenever possible, the same 
individual should perform all the physical and neurological examinations.
The physical examination must, at a minimum, include an examination of appearance, 
extremities, skin, head, neck, eyes, ears, nose, throat, lungs, chest, heart, abdomen, genito-
urinary system, and musculoskeletal system and must be performed by a physician or a 
designee.
If genito-urinary system evaluation is not clinically indicated based on patient medical history 
or symptoms, it is accepted by Lundbeck not to conduct such evaluation. Examination of 
renal regions are to be included as part of abdominal examination.
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The neurological examination must be performed by a physician.  The neurological 
examination must cover the following areas: mental status, examination of all cranial nerves, 
the motor system, reflexes, the sensory system, and the cerebellar functions.  
Any abnormal finding or out-of-range value considered clinically significant by the 
investigator must be recorded as an adverse event on an Adverse Event Form.
9.4.7
Columbia-Suicide Severity Rating Scale
The C-SSRS is a semi-structured interview developed to systematically assess suicidal 
ideation and behaviour of patients participating in a clinical study.44 The C-SSRS has 5 
questions addressing suicidal ideation, 5 sub-questions assessing the intensity of ideation, and 
4 questions addressing suicidal behaviour. For this study, the following versions of the scale 
are used: the “Baseline/Screening” version (lifetime and 1 year assessment). It takes 
approximately 5 to 15 minutes to administer and rate the C-SSRS. 
The C-SSRS must be administered in the local language.
The C-SSRS should only be administered by a rater who has adequate experience with 
clinical studies in CNS indications. The rater should be a medical doctor, research nurse, 
psychologist, site/study coordinators, or health care with 2 years of clinical experience and 
administration of semi-structured interview. Any exceptions must be discussed and approved 
by H. Lundbeck A/S and/or its designee. In case of unforeseen circumstances, certified back-
up raters should be available throughout the study. 
Rater training and certification will be conducted by the CRO as agreed with the sponsor. 
Raters will complete their designated training curriculum based on their initial qualification 
status and assigned role. Only raters who qualify on study specific Rater Certification 
Programme will be authorized to administer the C-SSRS in the study. Documentation of 
training and certification will be provided to raters for archiving in the investigator TMF. No 
patient must be rated before the documentation has been archived. New raters joining the 
study must be trained and certified by using the same certification process. Detailed 
instructions on how to administer the C-SSRS will be provided to the site in a C-SSRS 
Guideline. 
9.5
Order of Assessments
No study-related activities must be conducted until after the applicable Informed Consent 
Form is signed. 
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At the Screening Visit:
Blood and urine sampling for clinical safety laboratory tests and ECG recording must be 
scheduled and results reviewed prior to the Baseline Visit.
At the Screening Visit the “Baseline/Screening” version of the C-SSRS must be used. 
ePROs:
ePROs scheduled in alignment with an on-site visit without IMP infusion (see Panel 2) can 
be completed at the clinical site or in the remote setting within 3 days prior to the 
scheduled on-site visit date. On the Baseline Visit day and Week 12 Visit day, patients 
must complete the ePROs on the visit date and prior to infusion. 
ePROs which scheduled in alignment with a decentralized contact (see Panel 2) must be 
completed in the remote setting and can be completed on the day or within 3 days prior to 
the scheduled phone contact date
HIT-6 should preferably be the first ePRO completed, followed by mMIDAS, PGIC, MBS, 
MSQ v2.1, HADS, EQ-5D-5L, WPAI:M, TSQM-9, and HCRU.
It is preferable that the same order of assessments is used per patient and if the scheduled 
time of the day for the assessments is as consistent as possible across all the study visits. 
At the Baseline and Week 12 Visits prior to infusion: 
Patients must complete recording of headaches that ended prior to infusion (that is, events 
not yet recorded in the headache eDiary or events ongoing). 
Patients must complete the ePROs. ePROs can be completed at the patient’s convenience
before the pre-infusion sampling. 
The following assessments must be conducted: vital signs including body temperature, 
concomitant medications, adverse events, urine sampling (for pregnancy tests), optional 
digital device (actigraphy) assessment (for patients on a consenting subset), and BI 
including SDS:H.  Vital signs must be assessed prior to blood sampling at Baseline Visit. 
See sections 8.3 and 8.5 for procedures preceding IMP administration.
At the Baseline and Week 12 Visits during infusion: 
Adverse events, including IRRs, must be checked during the infusion. 
At the Baseline and Week 12 Visits after end-of-IMP-infusion and before the patient is 
discharged from the site: 
The following assessments must be conducted: vital signs including body temperature and 
adverse events, including IRRs.
See sections 8.3 and 8.5 for procedures following IMP administration.
9.6
Total Volume of Blood Drawn and Destruction of Biological Material
The total volume of blood drawn from each patient will be approximately 19.2 mL during the 
study.
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Additional blood samples may be required if the original blood samples are not viable or if 
re-testing is required.
9.7
Treatment Compliance
Responsible study personnel will administer the infusions of IMP.  Treatment compliance 
verification should be documented in the patient’s source documents and study specific IMP 
documents and verified by a CRA during monitoring. 
Anyone administering the IMP to the patient must be listed in the delegation log. 
The information from the IMP Administration Form must be entered in the eCRF.
10 Adverse Events
10.1
Definitions
10.1.1
Adverse Event Definitions45
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 unfavourable 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 H. Lundbeck A/S 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.
SAE – 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)
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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.
SUSAR – is any adverse event that is assessed as serious, unexpected (its nature or intensity 
is not consistent with the current version of the Investigator’s Brochure23) and related to a 
medicinal product by either the investigator or H. Lundbeck A/S.
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:
Mild – the adverse event causes minimal discomfort and does not interfere in a significant 
manner with the patient’s normal activities.
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.
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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):
Probable – the adverse event has a strong temporal relationship to the IMP or recurs on 
rechallenge, and another aetiology is unlikely or significantly less likely.
Possible – the adverse event has a suggestive temporal relationship to the IMP, and an 
alternative aetiology 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 and the Serious Adverse Event Form (if applicable):
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
10.2
Management of Reactions to Study Drug
There are no specific antidotes to an infusion of eptinezumab.
A medical emergency should be treated appropriately by the investigator using proper 
standard of care, according to their typical clinical practice and local guidelines for that 
emergency condition.
Should a medical condition arise that the investigator believes is related to the study drug, 
clinical judgement should be used to provide appropriate response including the consideration 
of discontinuation of study drug. If a patient experiences an anaphylactic reaction or another 
severe and/or serious hypersensitivity reaction during the IMP infusion, as assessed by the 
investigator, the infusion must be discontinued immediately (see section 5.4) and appropriate 
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therapy instituted. Any events believed to be allergic reactions should be discussed with the 
medical monitor. 
Per investigator judgement, it can be considered to collect additional immune response 
samples in accordance with local clinical practice, such as histamine, tryptase, 
immunoglobulin E, and complement components C3 and C4.
10.3
Pregnancy
Although not necessarily considered an adverse event, a pregnancy in a patient in the study 
must be recorded on an Adverse Event Form, as well as on a Pregnancy Form (paper), even if 
no adverse event associated with the pregnancy has occurred.  Pregnancies must be reported 
to H. Lundbeck A/S using the same expedited reporting timelines as those for SAEs.
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 Serious Adverse Event Form.  
Examples of pregnancies to be reported as SAEs (medically important) are spontaneous 
abortions, stillbirths, and malformations.
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.
10.4
Recording Adverse Events
Adverse events (including pre-treatment adverse events) must be recorded on an Adverse 
Event Form.  The investigator must provide information on the adverse event, preferably with 
a diagnosis, or at least with signs and symptoms; start and stop dates (and start and stop time 
if the adverse event lasts less than 24 hours); intensity; causal relationship to the IMP; action 
taken; and outcome.  If the adverse event is not related to the IMP, an alternative aetiology 
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 Intensity Log.
If the adverse event is serious, this must be indicated on the Adverse Event Form.  
Furthermore, the investigator must fill out a Serious Adverse Event Form and report the SAE 
to H. Lundbeck A/S immediately (within 24 hours) after becoming aware of it (see 
section 10.5).
If individual adverse events are later linked to a specific diagnosis, the diagnosis should be 
reported and linked to the previously reported adverse events.
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10.5
Reporting Serious Adverse Events 
The investigator must report SAEs to H. Lundbeck A/S immediately (within 24 hours) after 
becoming aware of them by completing a Serious Adverse Event Form.
The initial Serious Adverse Event Form must contain as much information as possible and, if 
more information about the patient’s condition becomes available, the Serious Adverse Event 
Form must be updated with the additional information.
If the investigator cannot report the SAE in Rave®, then he or she must complete and sign the 
Serious Adverse Event Fallback Form and send it to:  
Fax:
+45 36 30 99 67
email:
ICSRquery@lundbeck.com
H. Lundbeck A/S 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 EC or IRB and to act accordingly.
H. Lundbeck A/S will assume responsibility for reporting SUSARs to the authorities in 
accordance with local requirements.  In those Member States of the European Union that have 
implemented the European Union Clinical Trials Directive46 and in Norway, Liechtenstein, 
and Iceland, that is, in the countries where unblinded expedited safety reporting is required, 
H. Lundbeck A/S will also assume responsibility for reporting SUSARs to the ECs.
H. Lundbeck A/S will assess the expectedness of SAEs and inform the investigators about 
SUSARs in the blinded SUSAR listings.
10.6
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.
Non-serious adverse events must be followed up until resolution or the Withdrawal 
visit/Safety Follow-up Contact, whichever comes first.  At the Withdrawal visit/Safety 
Follow-up Contact, information on new adverse events, 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 H. Lundbeck A/S 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 after the Safety 
Follow-up Contact must be handled in the same manner as SAEs that occur during the study.  
These SAEs will be recorded in the safety database at H. Lundbeck A/S.
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11 Data Handling and Record Keeping
11.1
Data Collection
11.1.1
Electronic Case Report Forms 
eCRFs will be used to collect all the data related to the study, except the external data 
described in section 11.1.3.
The eCRFs use third party software (Rave®) to capture data via an online system on a 
computer.  When the investigator enters data in the eCRF (ideally during the visit or as soon 
as possible <3 days thereafter), the data will be recorded electronically in a central database 
over encrypted lines, and all entries and modifications to the data will be logged in an audit 
trail.  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 will be 
reviewed and evaluated for accuracy by the sponsor and/or representatives from CRO.  All 
entries, corrections, and changes must be made by the investigator or a delegate.
11.1.2
Patient Binders
11.1.2.1
Use of Patient Binders
A Patient Binder will be provided for each patient.  The Patient Binder contains different 
types of source documents, organized by visit and type.  A ballpoint pen with waterproof ink 
must be used to enter information in the Patient Binder.
11.1.2.2
Serious Adverse Event Fallback Forms
Serious Adverse Event Fallback Forms must be used when the eCRF cannot be accessed.
11.1.3
External Data
All electronic data will be transferred using a secure method accepted by H. Lundbeck A/S.
The following electronic data will be transferred by the vendor and kept in a secure 
designated storage area outside the eCRF:
Safety laboratory test data
eDiary data
Actigraphy
ePRO data
HIT-6
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mMIDAS
PGIC
MBS
MSQ v2.1
EQ-5D-5L
HCRU
WPAI:M
HADS
TSQM-9
SDS:H
11.2
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.  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.
11.2.2
Other Study Documents
The investigator must keep the investigator’s set of documents in the investigator TMF for at 
least 25 years after the Clinical Study Report has been approved or in accordance with 
national requirements, whichever is longer.  H. Lundbeck A/S 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.
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12 Monitoring Procedures
Prior to allowing patients to participate in the study, the investigator must sign a source data 
agreement that identifies the source documents (original documents, data, and records) at the 
site.  The document will also list which data may be recorded directly on the eCRFs.
If the investigator does not have a patient’s medical records, the investigator must attempt to 
obtain copies or a written summary of relevant medical records from the doctor who had 
treated the patient earlier and include the pertinent documentation in the patient’s medical 
records at the site.  The investigator should demonstrate due diligence in trying to obtain 
migraine and MOH history, general medical history, recent medication, previous migraine 
preventive medication use including treatment failures (within 5 years prior to the Screening 
Visit). 
Acceptable adequately documented records of previous migraine preventive medication use 
(including treatment failures) are as follows.
Medical record that includes migraine history and the name of the medications used to treat 
migraine and if available treatment stop and start dates including dose levels, including 
treatment failures on preventive treatment for migraine. If the investigator is also the 
treating physician, the investigator can provide a dated and signed written note with the 
above information, OR, 
If the investigator is not the treating physician, the investigator can interview the treating 
physician to confirm the above information and document the interview with date and 
name of treating physician, OR
If the investigator is not the treating physician and medical records cannot be obtained via 
the treating physician, the investigator should document the lack of availability and 
confirm medical history
via electronic records (for example prescriptions or pharmacy purchase listing when 
available for shorter term periods) and/or 
via patient interview
During the study, the CRA will visit the site to ensure that the protocol is being adhered to 
and that all issues are being recorded, to perform source data verification, and to monitor IMP 
accountability.  The visit intervals will depend on the outcome of the remote monitoring of 
the eCRFs, the site’s recruitment rate, and the compliance of the site to the protocol and Good 
Clinical Practice.  In addition, the CRA will be available for discussions by telephone.
Source data verification requires that the CRA be given direct access to all the source 
documents.  Direct access includes permission to examine and verify any records that are 
important for the evaluation of the study.
It must be possible to verify all other data in the eCRFs against source documents in the 
patient’s medical records, or in the location stated in the source data agreement.
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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 
H. Lundbeck A/S, 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 or randomization 
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
H. Lundbeck A/S has a “no-waiver” policy, which means that permission will not be given to 
deviate from the protocol.
If a deviation occurs, the investigator must inform the CRA and they must review, discuss, 
and document the implications of the deviation.
15 Study Termination
H. Lundbeck A/S 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
proven lack of efficacy of the IMP in other studies
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 EC or 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 EC or IRB if it will have an impact on the planned follow-up of the patients 
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who participated in the study.  If so, the actions needed to protect the patients must be 
described.
16 Statistical Methodology
16.1
Responsibilities
Biostatistics at the CRO with the agreement with Biostatistics, H. Lundbeck A/S, will perform 
the statistical analyses described below.
16.2
Analysis Sets
The following analysis sets will be used to analyse and present the data:
APRS - all randomized patients
APTS - all patients in the APRS who received an infusion of the IMP in the 
placebo-controlled period
FAS - all patients in the APTS who had a valid baseline assessment and at least one valid 
post-baseline 4-week assessment of MMDs in Weeks 1-12
APTS-OL - all patients in the APRS who received an infusion of the IMP in the open-label 
period
The FAS will be used for all efficacy analyses in the placebo-controlled period, and the APTS 
will be used for all safety analyses in the placebo-controlled period, while the APTS-OL will 
be used for the safety and efficacy analysis of the open-label period.
After all patients have completed the study, all data will be cleaned and the database will be 
locked when there are no more patients in the study. The patients and data will be classified 
into the analysis sets (APRS, APTS, FAS, and APTS-OL) according to these definitions at a 
Classification Meeting held after the database has been released but before unblinding of the 
study. Next, data will be unblinded for the reporting team, and all analyses specified in the 
Statistical Analysis Plan (SAP) will be performed and included in the Clinical Study Report. 
16.3
Descriptive Statistics
In general, summary statistics (n, arithmetic mean, standard deviation, median, lower and 
upper quartiles, minimum and maximum values) will be presented for continuous variables 
and counts and, if relevant, percentages will be presented for categorical variables.
16.4
Patient Disposition
Patient disposition will be summarized by treatment group and include the number of patients 
in the APTS who completed or withdrew from the study for each period, as well as the 
number of patients in each analysis set.  Note that withdrawal from treatment is not possible 
for the APTS patients, as they only receive the treatment on one occasion during the 
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placebo-controlled period. Withdrawal from study after IMP has been infused leads to 
missing data and the handling of these will be described in the SAP (see also section 16.8.1).
The number of patients who withdrew from the study will be summarized by treatment group 
and primary reason for withdrawal as well as by treatment group and all reasons for 
withdrawal.
The summary of patient disposition will be presented for each country and overall.
16.5
Demographics and Baseline Characteristics
Demographics (age, sex, and race), baseline characteristics (height, weight, and BMI), and 
other disease characteristics will be summarized by treatment group for the APTS.  Baseline 
efficacy variables will be summarised by treatment group for the FAS. 
The summary of demographics, baseline characteristics, and other disease characteristics will 
be presented for each country and overall.
16.6
Recent and Concomitant Medication
Recent and concomitant medication will be summarized by Anatomical Therapeutic Chemical
code and generic drug name by treatment group.
Prior and concomitant use of preventive migraine medication will be summarized by 
treatment group. If relevant, medication overuse status at the screening visit will be provided.
16.7
Exposure 
All patients in the APTS are expected to receive one single infusion of the IMP in the 
placebo-controlled period and one infusion of the IMP in the open-label period.  The duration 
of infusion will be summarized by treatment group and period.  Randomized patients whose 
infusion took more than 45 minutes and patients who had their infusion interrupted will be 
listed by treatment group, infusion start date/time and end date/time, infusion related 
reactions, and reasons if any.
16.8
Efficacy Analyses
16.8.1
General Efficacy Analysis Methodology
All the statistical tests of the efficacy endpoints will be two-sided tests performed at the 5%
significance level and all CIs will be 95% CIs, unless otherwise specified.
Efficacy analyses will be based on FAS.
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A detailed plan for the selection of values for each patient, as well as the handling of missing 
data and intercurrent events, in alignment with the estimands specified under chapter 2, will 
be described in the SAP.
16.8.2
Primary Analysis of the Primary Endpoint
The main estimator for the primary estimand is defined as the estimated effect from the 
MMRM.
The number of MMDs will be summarized by daily eDiary data across Weeks 1 to 4, 
Weeks 5 to 8, and Weeks 9 to 12. Details on derivation and imputations of days with missing 
or incomplete eDiary data will be described in the SAP.
The primary endpoint, change from baseline in the number of MMDs, will be analysed using 
MMRM with the number of MMDs at baseline as a continuous covariate and including 
treatment group (eptinezumab versus placebo), month (Month 1: Weeks 1 to 4; Month 2: 
Weeks 5 to 8; Month 3: Weeks 9 to 12), country, and previous treatment failures (≤2; >2), as 
categorical variables.  An interaction term between month and treatment as well as between 
month and number of MMDs at baseline will be included.  The model will assume an 
unstructured covariance matrix to model the within patient variance.  The statistical test will 
be based on the treatment contrast for change from baseline in MMDs (Weeks 1-4).
16.8.3
Sensitivity Analyses of the Primary Endpoint
Sensitivity analyses of the primary endpoint will be described in the SAP.
The primary analysis model will be applied, including an adjustment for whether or not a 
patient had a COVID-19 vaccination during the 4 weeks following IMP administration.
16.8.4
Analysis of the Key Secondary Endpoints
Estimands for the key secondary endpoints will be described in the SAP. The main estimator 
for each of the key secondary estimands is defined as the estimated effect from the analysis
models described below.
Change from Baseline in MMDs (Weeks 1-12)
The endpoint will be analysed using the same methodology as that described for the primary 
analysis, except that the test will be based on the estimated mean MMDs, which is averaged 
over Weeks 1 to 4 (Month 1), Weeks 5 to 8 (Month 2), and Weeks 9 to 12 (Month 3).
Not Fulfilling the ICHD-3 Diagnostic Criteria for CM nor MOH (Week 4) 
The ICHD-3 diagnostic criteria for CM and/or MOH will be checked during Weeks 1 to 4 (as 
described in the ICHD-3 diagnostic criteria defined respectively in Panel 4 and Panel 5; 
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further details will be described in the SAP). A response of Yes, if not fulfilling CM and 
MOH, and No otherwise. The treatment effect will be tested by a 2×2 table using Cochran-
Mantel-Haenszel including previous treatment failures as a stratification variable.
Not Fulfilling the ICHD-3 Diagnostic Criteria for CM nor MOH (Week 12) 
The endpoint will use the same method as that described for Weeks 1 to 4, except that the 
ICHD-3 diagnostic criteria for CM and/or MOH will be checked during Weeks 1 to 12.
Change from Baseline in MHDs (Weeks 1-4)
The endpoint will be analysed using the same methodology as that described for the primary 
analysis, except that the test will be based on the number of MHDs.
Change from Baseline MHDs (Weeks 1-12)
The endpoint will be analysed using the same methodology as that described for the primary 
analysis, except that the test will be based on the estimated mean MHDs, which is averaged 
over Weeks 1 to 4 (month 1), Weeks 5 to 8 (month 2), and Weeks 9 to 12 (month 3).
Change from Baseline in Average Daily Pain Assessment Score (Weeks 1-2)
The average daily pain will be calculated using the daily pain assessment collected during 
Weeks 1-2. Change from baseline in average Daily Pain will be analysed using ANCOVA
with the average Daily Pain at baseline as a covariate and including treatment group, country,
and previous treatment failures, as categorical variables.
Change from Baseline in Monthly Days with Acute Medication Use (Weeks 1-4)
The endpoint will be analysed using the same methodology as that described for the primary 
analysis, except that the test will be based on the number of monthly days with acute 
medication use during Weeks 1-4.
Change from Baseline in Average Monthly Days with Acute Medication Use 
(Weeks 1-12)
The endpoint will be analysed using the same methodology as that described for the primary 
analysis, except that the test will be based on the estimated mean monthly days with acute 
medication use, which is averaged over Weeks 1 to 4 (Month 1), Weeks 5 to 8 (Month 2), and 
Weeks 9 to 12 (Month 3). All the medication collected in eDiary as acute medication taken to 
stop headache/migraine attack will be accounted for in the analysis.
16.8.5
Sensitivity Analyses of the Key Secondary Endpoints
Sensitivity analyses of the key secondary endpoints will be described in the SAP.
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16.8.6
Testing Strategy
For the primary endpoint (change from baseline in MMDs [Weeks 1-4]), test the hypothesis 
of no difference between the eptinezumab and placebo using a two-sided test on 5% 
significance level.  If rejected and if the test shows a numerical advantage to eptinezumab, 
then continue to the first key secondary endpoint (change from baseline in MMDs 
[Weeks 1-12]). 
On the first key secondary endpoint, test the hypothesis of no difference between the 
eptinezumab and placebo groups. If rejected and if the test shows a numerical advantage to 
eptinezumab, then continue to the second key secondary endpoint (change from baseline in 
MHDs [Weeks 1-4]). This continues through the list of key secondary endpoints (change 
from baseline in MHD [Weeks 1-12], not fulfilling the ICHD-3 diagnostic criteria for CM nor 
MOH [Week 4], not fulfilling the ICHD-3 diagnostic criteria for CM nor MOH [Week 12], 
change from baseline in average Daily Pain assessment score [Weeks 1-2], change from 
baseline in monthly days with acute medication use [Weeks 1-4], change from baseline in 
monthly days with acute medication use [Weeks 1-12]), until an endpoint fails to reach 
significance.
16.8.7
Analysis of the Secondary Endpoints
The binary secondary endpoints will be analysed using Cochran-Mantel-Haenszel test 
including previous treatment failures as stratification variables.
All continuous secondary endpoints addressing changes from baseline to Weeks 1 to 4.
Weeks 1 to 12, or Weeks 12 to 24 will be analysed using the same methodology as that 
described for the primary analysis.
50% Response in MMDs (Weeks 1-4): Defined as a 50% reduction in the average MMDs 
across the available data from Weeks 1 to 4, will compare eptinezumab versus placebo. A 
logistic regression model will be used, with treatment group as a factor, baseline MMDs as a 
continuous covariate, and previous treatment failures as a binary covariate. Similar analysis 
will be done for Weeks 1 to 12. The analyses on 75% response in MMDs during 
Weeks 1 to 4 and Weeks 1 to 12 will be performed as well.  Similar response analyses will be 
performed for MHDs.
For other secondary efficacy endpoints based on response rates, treatment effects of 
eptinezumab compared to placebo will be analysed using a logistic regression model, similar 
to the model defined above.
Health-related quality of life scores test between eptinezumab and placebo at Week 4, 
Week 12, or Week 24 will use the similar ANCOVA model defined in the analysis of key 
secondary endpoints.
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16.8.8
Analysis of the Exploratory Endpoints
The analysis of the exploratory endpoints will be described in the SAP.
16.8.9
Analysis of Subgroups
The analysis specified for the primary and the key secondary endpoints will be repeated for 
each region (North America and Europe), excluding the region factor, if there are sufficient 
data collected from the region. 
No hypothesis testing will be conducted in the subgroup analysis. Only the treatment 
differences relative to placebo and their associated 95% CIs will be estimated and displayed 
using a forest plot. 
Other subgroup analyses will be specified in the SAP.
16.9
Safety Analyses
16.9.1
Analysis of Adverse Events
Adverse events will be classified according to the time of onset of the adverse event:
pre-treatment adverse event – an adverse event that starts on or after the date the patient 
signed the Informed Consent Form and prior to the date of first dose of IMP
treatment-emergent adverse event – an adverse event that starts or increases in intensity on 
or after the date of first dose of IMP
Adverse events, sorted by system organ class and preferred term, will be summarized by 
treatment group.
Allocation of Treatment-Emergent Adverse Events to Study Periods
Treatment-emergent adverse events may be allocated to study periods (these will be defined 
in the SAP).
16.9.2
Analysis of Other Safety Endpoints
The vital signs will be summarized by treatment group and period. Potentially clinically 
significant values will be flagged and summarized.
16.10 Handling of Missing Data
eDiary
Patients who do not complete the eDiary daily will have missing data. It is expected that most 
missing eDiary data will be sporadic.
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For each 28-day period, missing data from the eDiary will be imputed in the following way:
If the number of days with observations, n, is ≥14 days, the MMDs for the 28-day interval 
will be calculated as the number of migraine days observed/n×28 (prorated) and rounded 
off to 2 decimals.
If n <14, the MMDs for the period will be set to missing.
Further details on derivation and imputations of days with missing or incomplete eDiary data 
will be described in the SAP.
Quality of Life Questionnaires
For those questionnaires, missing items will not be imputed. However, strategies will be 
provided separately in the SAP for calculating sub-score or total score with missing individual 
scores. 
Digital Device Data
No imputation will be taken for missing data in the wearable digital device during the study 
period.
16.11 Interim Analyses
No interim analysis is planned.
16.12 Sample Size and Power
It is assumed that the treatment effect of eptinezumab 100 mg compared to placebo in change 
from baseline in MMDs (Weeks 1 to 4) will be -1.5 MMDs. The difference between 
eptinezumab 100 mg and placebo was -2.0 in Study 011, a study that did not include 
education on MOH, after 4 weeks and –3.1 in the subgroup of patients with CM and MOH.
The difference between withdrawal from treatment with and without preventive treatment was 
–1.7 and –1.4 days after 2 and 4 months.47
The SD is assumed to be 6.2, based on the averaged SD across treatment groups in the MOH
subgroup of Study 011 on the change from baseline in MMDs (Weeks 1 to 4).
Based on the assumed effect size and SD, using a two-sided test on the 5% significance level, 
270 patients per treatment group will provide 80% power for showing an effect on the 
primary endpoint. Assuming that 5% of patients will not contribute data to the analysis, 285
patients randomized per treatment group or 570 patients randomized in total will be needed.
Sample size re-assessment will be conducted on blinded data when approximately 70% of the 
patients have been randomized. The SD is estimated in the same model as for the primary
endpoint, except that all terms including treatment (main effect of treatment group and 
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interaction between treatment group and month) are excluded. Based on this estimate, the 
sample size may be increased, but not decreased.
16.13 Statistical Analysis Plan
An SAP describing the handling of data issues and the planned statistical analyses in more 
detail will be prepared by Biostatistics at the CRO before the study is unblinded.
17 Clinical Study Report and Publications
17.1
Data Ownership
The data collected in this study are the property of H. Lundbeck A/S.
17.2
Clinical Study Report
Upon completion of the study, a Clinical Study Report will be prepared by the CRO agreed 
with H. Lundbeck A/S.
17.3
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.
17.4
Publications
The results of this study will be submitted for publication.
H. Lundbeck A/S will submit results information:
to ClinicalTrials.gov
to EudraCT
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.48
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.
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19 Finance
19.1
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.
19.2
Financial Disclosure
All the investigators, including sub-investigators, and raters participating in the study must 
complete a Financial Disclosure Form.
19.3
Equipment
Equipment owned or rented by H. Lundbeck A/S that has been provided to the sites for use 
during the study must be returned at the end of the study.
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Appendix I
Clinical Study Protocol
Authentication and Authorization
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Clinical Study Protocol
Authentication and Authorization
Study title:
Interventional, randomized, double-blind, parallel-group, placebo-controlled study 
of add-on eptinezumab treatment to brief educational intervention for the 
preventive treatment of migraine in patients with dual diagnosis of migraine and 
medication overuse headache
Study No.:
20007A (RESOLUTION)
Edition No.:
1.0
Date of edition:
22 December 2021
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.
International study manager:
Study Lead/Clinical research scientist:
Head of Biostatistics:
Head of Medical Safety:
Authorization
I hereby confirm that I am of the opinion that the ethical and scientific basis of this study is sound.
Therapeutic Area Lead:
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Appendix II
Recent and Concomitant Medication
Disallowed or Allowed with Restrictions
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Recent and Concomitant Medication:  
Disallowed or Allowed with Restrictions 
In the table below, recent and concomitant medications that are disallowed or allowed with 
restrictions with respect to their use prior to or during the study are listed.
Drug Class
Details
Any investigational drug
Do not use within 30 days or 5 plasma half-lives (whichever is longer) 
prior to the Screening Visit.
Anticonvulsants
See restrictions in use under antimigraine agents. Other medication in 
the same class is allowed if prescribed for non-migraine indications.
Antihypertensives
See restrictions in use under antimigraine agents.  Other medication in 
the same class is allowed if prescribed for non-migraine indications.
Anti-impotence agents
Allowed if the dose has been stable for at least 12 weeks prior to the 
Screening Visit and expected to be maintained until the EoS Visit (Week 
24).
Antimigraine agents
Allowed with restrictions:
preventive treatment of migraine (prescription or OTC medication 
recommended by a health care professional) is allowed provided the 
dose and regimen has been stable for at least 12 weeks prior to the 
Screening Visit and expected to be maintained until the EoS Visit 
(Week 24)
Disallowed:
do not use oral anti-CGRPs for acute treatment <4 weeks prior to the 
Screening Visit and until EoS Visit (Week 24)
do not use eptinezumab or other mAb targeting the CGRP pathway 
<24 weeks prior to the Screening Visit and until EoS Visit (Week 24).
do not use botulinum toxin for migraine or any other medical/cosmetic 
reason in the head and/or neck region <16 weeks prior to the 
Screening Visit and until EoS Visit (Week 24)
do not use monoamine oxidase inhibitors, ketamine, methysergide, 
methylergonovine, or nimesulide <12 weeks prior to the Screening 
Visit and until EoS Visit (Week 24) 
do not use injectable therapy (trigger point injections, extracranial
nerve blocks, or facet joint injections) <8 weeks prior to the Screening 
Visit and until EoS Visit (Week 24)
Hormones
Hormonal therapy (for example, contraceptives, hormone replacement 
therapy) is allowed provided the dose and regimen has been stable for at 
least 12 weeks prior to the Screening Visit and expected to be 
maintained until the EoS Visit (Week 24).
Opioid analgesics
Prescription opiates (including single-ingredient or combination 
medications containing opiates, opioids, tramadol, or tapentadol) are 
allowed provided a stable dose and regimen has been maintained for at 
least 12 weeks prior to the Screening Visit for acute and/or symptomatic 
treatment of headache. These agents may be prescribed when 
considered medically indicated by the investigator during the study 
(including the screening period). 
LU Study Number: 
Pluto ID: 
Status:  
Version: 1.0
20007A
Final
CLI_01719596

H. Lundbeck A/S
Confidential
Study 20007A – Clinical Study Protocol
Page 97 of 99
Drug Class
Details
Other interventions and devices
Allowed with restrictions:
non-pharmacological interventions and therapies for the treatment of 
migraine (for example, behavioural therapy, massage, and 
acupuncture) are allowed provided their use has been stable for at 
least 12 weeks prior to the Screening Visit and expected to be
maintained until the EoS Visit (Week 24).
Disallowed:
do not use CNS- and migraine-related devices (neuromodulation, 
neurostimulation) <8 weeks prior to the Screening Visit and until the 
EoS Visit (Week 24)
Sedatives/hypnotics
Barbiturates (including Fiorinal®, Fioricet®, or any other combination 
containing butalbital) are allowed provided a stable dose and regimen 
has been maintained for at least 12 weeks prior to the Screening visit 
and expect to be maintained until the EoS Visit (Week 24). These 
agents may be prescribed when considered medically indicated by the 
investigator during the study (including the screening period) and a 
stable dose and regimen is expected to be maintained.
Traditional herbal medicines for the 
treatment of migraine
Allowed for the treatment of migraine providing a stable regimen has 
been maintained for at least 12 weeks prior to the Screening Visit and 
maintained until the EoS Visit (Week 24).
COVID-19 vaccines
Allowed during the study with the following guidance if possible:
a time window of at least 14 days should be allowed between 
COVID-19 vaccination and prior to the Screening Visit. 
if the patient has recently received a COVID-19 vaccine, the 
investigator should judge if the patient can be administered with the 
IMP infusion at the scheduled visit based upon the patient’s individual 
response to the COVID-19 vaccine. 
COVID-19 vaccine should not be given within ±3 days of the IMP 
infusion.
LU Study Number: 
Pluto ID: 
Status:  
Version: 1.0
20007A
Final
CLI_01719596

H. Lundbeck A/S
Confidential
Study 20007A – Clinical Study Protocol
Page 98 of 99
Appendix III
Interpretation of Hepatitis B Serologic Test Results
LU Study Number: 
Pluto ID: 
Status:  
Version: 1.0
20007A
Final
CLI_01719596

H. Lundbeck A/S
Confidential
Study 20007A – Clinical Study Protocol
Page 99 of 99
Interpretation of Hepatitis B Serologic Test Results
HBsAg
negative
Susceptible
anti-HBc
negative
anti-HBs
negative
HBsAg
negative
Immune due to natural infection
anti-HBc
positive
anti-HBs
positive
HBsAg
negative
Immune due to hepatitis B vaccination
anti-HBc
negative
anti-HBs
positive
HBsAg
positive
Acutely/Chronically infected
anti-HBc
positive
anti-HBs
negative
HBsAg
negative
Interpretation unclear; four possibilities:
1. Resolved infection (most common)
2. False-positive anti-HBc, thus susceptible
3. “Low level” chronic infection
4. Resolving acute infection
anti-HBc
positive
anti-HBs
negative
LU Study Number: 
Pluto ID: 
Status:  
Version: 1.0
20007A
Final
CLI_01719596