Conditions: Migraine
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 892
Healthy volunteers: no

Brief summary:
Evaluation of eptinezumab in the prevention of migraine in participants with unsuccessful prior preventive treatments.

Detailed description:
The total study duration from the screening visit to the completion visit is approximately 76 weeks and includes a screening period (28-30 days), a placebo-controlled treatment period (24 weeks) and a treatment extension period (48 weeks).

The participant will start treatment at the baseline visit and follow a 12-week dosing schedule with either eptinezumab (100 or 300 milligrams \[mg\]) or placebo by intraveneous (IV) infusion. Participants who were assigned to placebo in the placebo-controlled treatment period, will be randomly allocated to one of two treatment groups: eptinezumab 300 mg or eptinezumab 100 mg.

Arms:
arm 1: Participants will receive placebo matching to eptinezumab by IV infusion, every 12 weeks starting from Baseline (Day 0) through Week 24. arm 2: Participants will receive eptinezumab 100 mg by IV infusion, every 12 weeks starting from Baseline (Day 0) through Week 24. arm 3: Participants will receive eptinezumab 300 mg by IV infusion, every 12 weeks starting from Baseline (Day 0) through Week 24.

Interventions: intervention 1: Eptinezumab intervention 2: Placebo
Intervention descriptions: intervention 1: Eptinezumab, concentrate for solution for infusion 100 mg/milliliter (mL) intervention 2: concentrate for solution for infusion, intravenously

Protocol document:
Prot_000.pdf: 
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Study 18898A – Clinical Study Protocol
Page 1 of 98
Clinical Study Protocol
Interventional, randomized, double-blind, parallel-group, 
placebo-controlled study with an extension period to evaluate the 
efficacy and safety of eptinezumab for the prevention of migraine 
in patients with unsuccessful prior preventive treatments
Eptinezumab
Study No.:
18898A
EudraCT/IND No.:
2019-004497-25 / 114,647
Sponsor:
H. Lundbeck A/S (Lundbeck)
2500 Valby (Copenhagen), Denmark
Edition No.:
3.0
(the version No. in the footer is the system version No.)
Date of edition:
30 November 2021
Edition history:
Edition 1.0 (original protocol), 12 December 2019
Edition 2.0, 22 January 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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Synopsis – Study 18898A
Sponsor
H. Lundbeck A/S
Investigational Medicinal Product
Eptinezumab
Study Title
Interventional, randomized, double-blind, parallel-group, placebo-controlled study with an extension period to 
evaluate the efficacy and safety of eptinezumab for the prevention of migraine in patients with unsuccessful 
prior preventive treatments
Objectives and Endpoints
Objectives
Endpoints 
Primary Objective
To evaluate the efficacy of eptinezumab for 
the prevention of migraine in patients with 
unsuccessful prior preventive treatments
Primary endpoint:
Change from baseline in the number of monthly migraine 
days (Weeks 1-12)
Key secondary endpoints:
Response: patients with 50% reduction from baseline in 
monthly migraine days (Weeks 1-12)
Response: patients with 75% reduction from baseline in 
monthly migraine days (Weeks 1-12) 
Change from baseline in the number of monthly migraine 
days (Weeks 13-24)
Secondary endpoints:
Response: patients with 50% reduction from baseline in 
monthly migraine days (Weeks 13-24)
Response: patients with 75% reduction from baseline in 
monthly migraine days (Weeks 13-24)
Response: patients with 100% reduction from baseline in 
monthly migraine days (Weeks 1-12) 
Response: patients with 50% reduction from baseline in 
monthly headache days (Weeks 1-12)
Response: patients with 75% reduction from baseline in 
monthly headache days (Weeks 1-12)
Response: patients with 100% reduction from baseline in 
monthly headache days (Weeks 1-12)
Change from baseline in the number of monthly headache 
days (Weeks 1-12)
Migraine/headaches with severe pain intensity (Weeks 
1-12)
Change from baseline in the number of monthly migraine 
days with use of acute medication (Weeks 1- 12)
Change from baseline in number of monthly migraine days 
with use of acute medication (Weeks 13-24)
Patient Global Impression of Change (PGIC) score at 
Week 12
PGIC score at Week 24


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Objectives and Endpoints (continued)
Objectives
Endpoints
Change from baseline in the number of monthly migraine 
days in patients with Medication Overuse Headache
(MOH) (Weeks 1-12)
Patients with a migraine on the day after first dosing
Change from baseline to Week 12 in Most Bothersome 
Symptom (MBS) score
Exploratory endpoints:
Change from baseline in monthly number of Migraine 
attacks for each 12-week period
Change from baseline in monthly number of Headache 
episodes for each 12-week period
Secondary Objectives
To evaluate the health-related quality of life 
and work productivity impact of eptinezumab
To evaluate the effect of long-term treatment 
with eptinezumab
Key secondary endpoints:
Change from baseline to Week 12 in the Headache Impact 
Test (HIT-6) score
Secondary endpoints:
Change from baseline to Week 24 in the HIT-6 score
Change from baseline to Week 12 in the Migraine-Specific 
Quality of Life (MSQ v2.1) sub-scores (Role Function-
Restrictive, Role Function-Preventive, Emotional 
Function)
Change from baseline to Week 12 in the Health-Related 
Quality of Life (EQ-5D-5L) Visual Analogue Scale (VAS)
score
Change from baseline to Week 12 in Health Care 
Resources Utilization (HCRU)
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
Change from baseline to Week 24 in HCRU
Change from baseline to Week 12 in the Work 
Productivity and Activity Impairment Questionnaire 
(WPAI) sub-scores (Absenteeism, Presenteeism, Work 
productivity loss, Activity impairment)
Change from baseline to Week 24 in WPAI sub-scores
Secondary endpoints:
Change from baseline in the number of monthly migraine 
days (Weeks 25-36, 37-48, 49-60, 61-72)
Response: patients with 50% reduction from baseline in 
monthly migraine days (Weeks 25-36, 37-48, 49-60, 
61-72)
Response: patients with 75% reduction from baseline in 
monthly migraine days (Weeks 25-36, 37-48, 49-60, 
61-72)


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Objectives and Endpoints (continued)
Objectives
Endpoints
Change from baseline in the HIT-6 score (at Weeks 36, 48, 
60, and 72)
Exploratory endpoints:
Response: patients with 100% reduction from baseline in 
monthly migraine days
Response: patients with 50% reduction from baseline in 
monthly headache days
Response: patients with 75% reduction from baseline in 
monthly headache days
Response: patients with 100% reduction from baseline in 
monthly headache days
Migraine/headaches with severe pain intensity
Change from baseline in the number of monthly migraine 
days with use of acute medication
PGIC score
Change from baseline in the number of monthly migraine 
days in patients with MOH
Patients with a migraine on the day after first dosing 
Change from baseline in MBS score
Change from baseline in monthly number of Migraine 
attacks for each 12-week period
Change from baseline in monthly number of Headache 
episodes for each 12-week period
Change from baseline in the MSQ v2.1 sub-scores
Change from baseline in the EQ-5D-5L VAS score
Change from baseline in HCRU
Change from baseline in WPAI sub-scores
Safety Objective
To evaluate the safety and tolerability of 
eptinezumab
To evaluate the long-term safety and 
tolerability of eptinezumab
Safety Endpoints
Adverse events
Absolute values and changes from baseline in clinical 
safety laboratory test values, vital signs, weight, and ECG 
parameter values
Potentially clinically significant clinical safety laboratory 
test values, vital signs, weight changes, and ECG 
parameter values
Development of specific anti-eptinezumab antibodies 
(ADA) including neutralizing antibodies (NAbs)
Columbia-Suicide Severity Rating Scale (C-SSRS) score


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Study Methodology
This is an interventional, multi-national, multi-site, randomized, double-blind, placebo-controlled Phase IIIb 
study designed to demonstrate efficacy and safety of eptinezumab for migraine prevention in patients with 
unsuccessful prior preventive treatments. The placebo-controlled period will be followed by an extension 
period where all patients will receive active treatment to assess the long-term safety, tolerability and effect of 
eptinezumab.
The total study duration from the Screening Visit to the Completion Visit is approximately 76 weeks and 
includes a Screening Period (28-30 days), Placebo-controlled Period (24 weeks) and Extension Period 
(48 weeks). 
The target population for this study is defined as patients with chronic migraine (CM) or episodic migraine 
(EM), as outlined in the IHS ICHD-3 guidelines,1 and with documented evidence of failure to 2-4 different 
preventive migraine medications in the past 10 years. The aim is that approximately 40% of the randomized 
patients are patients with EM.
840 patients will be randomly allocated via a randomization system to one of three treatment groups: 
eptinezumab 300 mg, eptinezumab 100 mg, or placebo, in a ratio of 1:1:1.
Randomization will be stratified by monthly headache days (MHDs) at baseline (14 MHDs/ 14 MHDs) and 
by country. 
The patient will receive IMP starting from the Baseline Visit to follow a Q12W dosing schedule (every 
12 weeks) with either eptinezumab or placebo by IV infusion over 30 minutes (+15 minutes). 
At Visit 8 patients will enter the Extension Period. Patients who were assigned to placebo in the Placebo-
controlled Period will be randomly allocated to one of two treatment groups: eptinezumab 300 mg or
eptinezumab 100 mg with a ratio of 1:1. Patients assigned to eptinezumab 300 mg or eptinezumab 100 mg in 
the Placebo-controlled Period will continue on their original assignments.
Patients will complete a daily headache eDiary from the time of screening until the Completion/Withdrawal 
Visit.
During infusion visits, assessments of safety will be performed before and after each infusion. At these visits, 
AEs will be collected as well as safety laboratory tests, ECG, weight, and vital signs. Patient-reported 
outcomes (PROs) must be administered prior to infusion.
Patients who complete the study will attend a Completion Visit which will include a Safety Follow-up 
evaluation at 12 weeks after their last dose of IMP. 
Patients who withdraw, except for those who withdraw their consent, will be asked to attend a Withdrawal 
Visit 12 weeks after their last dose of IMP and undergo Safety Follow-Up evaluations. Patients who withdraw 
prior to the Week 24 Visit will additionally undergo Efficacy Follow-Up evaluations.
An independent Safety Data Monitoring Committee (DMC) will regularly monitor the patients' safety data 
according to the DMC Charter.
In general, no information about individual treatment codes will be available to investigators, patients or site-
facing CRO personnel until after all patients have completed the study.
The results of the Placebo-controlled Period will be reported when ended for all patients. All data from the 
Placebo-controlled Period will be cleaned and the database for the Placebo-controlled Period will be locked. 
Data will be unblinded for the reporting team (Sponsor), and all analyses specified in the SAP for data 
collected in the Placebo-controlled Period will be performed and included in the Clinical Study Report (CSR). 
After all patients have completed the study, an addendum to the CSR, including the results from the Extension 
Period, will be produced. Investigators and patients will be informed about which treatment (active or 
placebo) their patients received in the Placebo-controlled Period and the actual dose of eptinezumab received 
in the Extension period only after the last patient has completed the study.
Assessments performed in a subset of patients:
Exit interviews will be performed shortly (no later than 2 weeks) after the last assessment of the Week 24
Visit or Withdrawal Visit (for patients who withdraw prior to Week 24) on a subset of patients (hereafter 
referred to as the ‘Exit Interview subset’) after all visit assessments are completed. The aim is to complete 
exit interviews for 100 patients out of the first 345 randomized patients.
The study design is presented in Panel 1 and the scheduled study procedures and assessments are summarized 
in Panel 2.


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Number of Patients Planned
840 patients, recruited from specialist settings are planned for randomization: 280 patients in the eptinezumab 
300 mg group, 280 patients in the eptinezumab 100 mg group and 280 patients in the placebo group.
Target Patient Population
Main Inclusion Criteria
The patient has a diagnosis of migraine as defined by IHS ICHD-3 guidelines with a history of chronic or 
episodic migraines of at least 12 months prior to the Screening Visit.
The patient has a migraine onset of <50 years of age.
The patient has ≥4 migraine days per month for each month within the past 3 months prior to the Screening 
Visit.
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 fulfils the following criteria for CM or EM in prospectively collected information in the eDiary 
during the screening period:
For patients with CM: Migraine occurring on ≥8 days and headache occurring on >14 days
For patients with EM: Migraine occurring on ≥4 days and headache occurring on ≤14 days
(a) The patient has documented evidence of treatment failure(must be supported by medical record or by 
physician's confirmation specific to each treatment) in the past 10 years of 2-4 different migraine preventive 
medications out of the following:
propranolol/metoprolol 
topiramate 
amitriptyline 
flunarizine 
candesartan 
valproate/divalproex 
botulinum toxin A/B (if documented that botulinum toxin was taken for chronic migraine) 
AND
   (b) The patient has failed two of the below of which at least one must be due to inadequate efficacy:
propranolol/metoprolol
topiramate 
amitriptyline
flunarizine
candesartan
The patient has a history of either previous or active use of triptans for migraine.
The patient is aged ≥18 and ≤75 years at the Screening Visit.
Main Exclusion Criteria
The patient has experienced failure on a previous treatment targeting the calcitonin gene-related peptide
(CGRP) pathway. 
The patient has a treatment failure on valproate/divalproex or botulinum toxin A/B and the treatment is not 
the latest preventive medication prior to study inclusion. The medication is regarded as the latest if the 
medication start date is after the start date of the other preventive medications and the medication stop date is 
after the stop date of the other preventive medications.

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 events) and/or contraindications (that is, ineligibility due to medical 
reasons). Treatment failure corresponds to the first documented failure for each medication.


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Target Patient Population (continued)
The patient has confounding and clinically significant pain syndromes, (for example, fibromyalgia, chronic 
low back pain, complex regional pain syndrome).
The patient has a diagnosis of acute or active temporomandibular disorder.
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), ophthalmoplegic migraine, and migraine with neurological accompaniments 
that are not typical of migraine aura (diplopia, altered consciousness, or long duration).
The patient has a psychiatric condition that is uncontrolled and/or untreated for a minimum of 6 months prior 
to the Screening Visit. Patients with a lifetime history of psychosis and/or mania in the last 5 years prior to the 
Screening Visit are excluded.
The patient has a history of clinically significant cardiovascular disease or vascular ischaemia or 
thromboembolic events (for example, cerebrovascular accident, deep vein thrombosis, or pulmonary 
embolism).
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 comprehensive):
Disallowed: any investigational products within 30 days or 5 plasma half-lives (whichever is longer) before 
the Screening Visit; eptinezumab or other monoclonal antibody treatment targeting the CGRP pathway; 
preventive migraine treatments; oral anti-CGRPs for acute 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 restriction: prescription or over-the-counter medication for acute treatment of migraine 
prescribed or recommended by a healthcare 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 
(including CBT).
Investigational Medicinal Product, Doses and Mode of Administration
Eptinezumab – 100 or 300 mg, Concentrate for Solution for Infusion 100 mg/ml added to 100 mL of 0.9% 
normal saline, intravenously
Placebo – 100 mL of 0.9% normal saline, intravenously
The IMP will be administered by intravenous infusion over 30 minutes (+15 minutes), once every 12 weeks. 
Assessment Details
The assessments are summarized in Panel 2. Details for selected assessments which are non-standard/require 
more explanation/description are provided below. All scales used to assess efficacy and pharmacoeconomic 
information in this study, are patient-reported instruments.
eDiary
Patients will complete a daily headache eDiary from the time of screening until the Completion/Withdrawal 
Visit consisting of applications and reports which will be used to derive the migraine and headache endpoints. 
The eDiary will be distributed to each subject at the Screening Visit after subject training on eDiary use by site 
staff. The eDiary data from the 28 days following the Screening Visit will be used to determine eligibility 
criteria, baseline migraine and headache values and eDiary compliance. At the relevant study visits, compliance 
data from the eDiary will be reviewed at the study site.
Headache Impact Test (HIT-6)
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 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.


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Assessment Details (continued)
Most Bothersome Symptom
The Investigator will verbally obtain the most bothersome symptom associated with the patient’s migraines 
during the Baseline Visit. Patients will be asked to rate the improvement in this symptom from baseline 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, other. It takes less than 
5 minutes to complete the MBS.
Migraine-Specific Quality-of-Life Questionnaire (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; role function preventive; and emotional 
function. Each item is scored on a 6-point scale ranging from 1 (none of the time) to 6 (all of the time). Scores 
are obtained for each domain and ranges from 0-100. Higher scores indicate better quality of life. It takes 
approximately 5-10 minutes to complete the MSQ v2.1.
Health Care Resource Utilization (HCRU)
Migraine-specific healthcare 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 trial.
Exit interview (applies to Exit Interview subset)
Exit interviews will be conducted on patients, tailored to the target population and this trial to help better 
understand experiences with disease, gain additional insight into trial data, support interpretation of quantitative 
assessments and endpoints to discuss meaningfulness of change.
Statistical Methodology 
The following analysis sets will be used to analyse and present the data:
all-patients-randomized set (APRS) - all randomized patients
all-patients-treated (APTS) - all patients in the APRS who received at least one infusion of double-blind IMP 
full-analysis set (FAS) - all patients in the APTS who had a valid baseline assessment and at least one post-
baseline 4-week assessment of MMDs in Weeks 1-12
all-patients-treated long-term set (APTS_LT) - all patients in the APRS who received at least one infusion of 
IMP and had a visit in the Extension Period
full-analysis long-term set (FAS_LT) - all patients in the APTS_LT who had a valid baseline assessment and 
a valid assessment of monthly migraine days in the Extension Period
The patients and data will be classified into the analysis sets according to these definitions at separate
Classification Meetings. For the reporting of the Placebo-controlled Period, the Classification meeting will be 
held after the data base release for the reporting of the Placebo-controlled Period but before the blind has been 
broken and will concern the classification into APTS and FAS. For the addendum to CSR, the Classification 
meeting will be held after the data base release for the reporting of the Extension Period and will concern the 
classification into APTS_LT and FAS_LT.
If not otherwise stated, tables, figures and listings (TFLs) in the Placebo-controlled Period will be summarized
by randomized treatment group and TFLs in the Extension Period will be summarized by treatment group in the 
extension (eptinezumab 300 mg or 100 mg). 
Efficacy analyses of the Placebo-controlled Period will be based on FAS, and efficacy analyses in the Extension 
Period will be based on FAS_LT. 
Demographics and Baseline characteristics will be based on FAS, and safety tables (including exposure and 
medications) will be based on APTS in the Placebo-controlled Period, and on FAS_LT and APTS_LT 
respectively in the Extension Period.
Unless otherwise specified, all testing will be done two-sided, based on a 5% significance level.


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Statistical Methodology (continued)
Primary analysis of the primary endpoint:
The number of monthly migraine days (MMDs) Week 1-12 summarises diary data across Weeks 1 to 12.
Details on derivation and imputations of days with missing or incomplete eDiary data will be described in 
the SAP. Changes from baseline in MMDs at the 6 first 4-week intervals will be analysed using a restricted 
maximum likelihood (REML)-based mixed model for repeated measures (MMRM) approach. The analysis 
will be performed using all available monthly change scores for the first 6 months in the study. The model 
will include the following fixed effects: month (Weeks 1-4, Weeks 5-8, Weeks 9-12, Weeks 13-16, Weeks
17-20, and Weeks 21-24), country, stratification factor (MHDs at baseline: ≤14/>14) and treatment as 
factors, baseline MMDs as a continuous covariate, treatment-by-month interaction, baseline score-by-month 
interaction, and stratum-by-month interaction. An unstructured variance structure will be used to model the 
within-patient errors. The mean differences between each dose of eptinezumab and placebo will be 
estimated based on the least squares means for the treatment-by-visit interaction in the MMRM model. The 
primary comparisons will be the contrasts between each dose of eptinezumab and placebo averaged across 
Weeks 1-12.
Analysis of the key secondary endpoints:
For the key secondary endpoints based on response rates, treatment effects compared to placebo will be
analyzed using logistic regression. The model will include baseline MMDs as a continuous covariate, and 
treatment and stratification (MHDs at baseline: ≤14 />14) as factors.  
The change from baseline in HIT-6 score for the Placebo-controlled Period will be analysed using a mixed 
model repeated measures (MMRM) including baseline HIT score as covariate, treatment, country, 
stratification factor (MHDs at baseline: ≤14 />14), and week as fixed factors. In addition, the model will 
include treatment-by-week interaction, baseline HIT-6 score-by-week interaction, and stratum-by-week
interaction. An unstructured covariance structure will be used to model the within-patient errors. The 
Kenward-Roger approximation will be used to estimate denominator degrees of freedom. Treatment effects 
will be calculated based on least squares means for the treatment-by-week interaction estimated at Week 12.
Change from baseline in the number of MMDs (Weeks 13-24), will be analysed using the same MMRM 
methodology as for the primary endpoint. The comparisons will be the contrasts between each dose of 
eptinezumab and placebo averaged across Weeks 13-24.
Sensitivity analyses of the primary endpoint:
The impact of missing data in the derivation of the primary endpoint (days with missing or incomplete 
information in the eDiary) will be evaluated by applying different methods of imputation. 
Sensitivity analyses of the key secondary endpoints:
endpoints where data imputation is used, the impact of the imputations will be assessed in sensitivity 
analyses, applying different methods of imputation. 
Secondary endpoints:
Analyses of continuous data based on diary data will use a similar model to the primary analysis, and 
continuous scale endpoints will be analysed by the same MMRM methodology as for HIT-6. Response 
variables will use similar analyses as the key secondary response endpoints. The endpoints; patients with a 
migraine on the day after first dosing and 100% responders for MMDs and MHDs (Weeks 1-12) will be 
analysed using an extended Cochran-Mantel-Haenszel (CMH) test, adjusting for the stratification factor 
(MHDs at baseline: ≤14 />14).
Testing Strategy
The testing strategy will be a sequence of tests, either testing one endpoint at a time or using Bonferroni-Holm 
to test a group of endpoints. Only if one step has shown a statistically significant effect will the formal testing 
continue with the next step, thus ensuring protection of the type 1 error. 
A significance level of 0.05 will be used. The significance level is denoted by α below.
Step1
Test the primary endpoint change from baseline in MMDs (Weeks 1-12) for the 300 mg dose compared to 
placebo on a significance level of α. Only if the p-value <α in favour of the 300 mg dose is the effect considered 
statistically significant and the testing continues with the next step.


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Testing Strategy (continued)
Step 2
Test the key secondary endpoint 50% responders for MMD (Weeks 1-12) for the 300 mg dose compared to 
placebo, using a significance level of α. Only if the p-value <α in favour of the 300 mg dose is the effect 
considered statistically significant and the testing continues with the next step.
Step 3
Test the primary endpoint change from baseline in MMDs (Weeks 1-12) for the 100 mg dose compared to 
placebo on a significance level of α. Only if the p-value <α in favour of the 100 mg dose is the effect considered 
statistically significant and the testing continues with the next step.
Step 4
Test the key secondary endpoint 50% responders for MMD (Weeks 1-12) for the 100 mg dose compared to 
placebo, using a significance level of α. Only if the p-value <α in favour of the 100 mg dose is the effect 
considered statistically significant and the testing continues with the next step. 
Step 5
Uses Bonferroni-Holm to test the 3 key secondary endpoints: Change from baseline in MMDs (Weeks 13-24), 
75% responders for MMD (Weeks 1-12), Change from baseline to Week 12 in HIT-6. All comparisons are of 
the 300 mg dose compared to placebo. If the smallest of the 3 p-values is <α /3 in favour of the 300 mg dose 
then the effect seen on this endpoint is considered statistically significant, and the testing continues. Next, if the 
second smallest p-value is <α/2 in favour of the 300 mg dose, then the effect seen on this endpoint is considered 
statistically significant, and the testing continues. If the largest p-value is <α in favour of the 300 mg dose then 
the effect seen on this endpoint is considered statistically significant, and the testing continues.
Step 6
Uses Bonferroni-Holm to test the 3 key secondary endpoints: Change from baseline in MMDs (Weeks 13-24), 
75% responders for MMD (Weeks 1-12), Change from baseline to Week 12 in HIT-6. All comparisons are of
the 100 mg dose compared to placebo. If the smallest of the 3 p-values is <α /3 in favour of the 100 mg dose,
then the effect seen on this endpoint is considered statistically significant, and the testing continues. Next, if the 
second smallest p-value is <α/2 in favour of the 100 mg dose, then the effect seen on this endpoint is considered 
statistically significant, and the testing continues. If the largest p-value is <α in favour of the 100 mg dose then,
the effect seen on this endpoint is considered statistically significant.
Sample Size Considerations
The two prior eptinezumab Phase III studies, PROMISE-1 performed in an EM population and PROMISE-2
performed in a CM population, had the following effect sizes for the primary endpoint when compared to placebo 
(standard deviations):
•
EM: 100 mg 0.69 (3.1), 300 mg: 1.11 (3.1)
•
CM: 100 mg 2.03 (5.8), 300 mg 2.60 (5.8)
The power was determined by simulating the testing strategy (10000 simulations) assuming normal 
distributions with similar mean and SD for continuous endpoints and similar success rates as the response 
variables in the Phase III studies for the corresponding population (EM or CM) without assuming the variables 
to be correlated. With 280 patients per treatment group, assuming that 40% of the patients will be from the EM 
population and 60% from the CM population, and that 2% of the patients do not have a post-baseline 
assessment of the primary endpoint, simulations show that the power for the test of the primary endpoint is 
approximately 94% for the comparison of 100 mg to placebo and 99% power for the comparison of 300 mg to 
placebo. The individual key secondary endpoints had a power of at least 68% for showing an effect, with a 
combined power of 58% for seeing an effect for all primary and key secondary endpoints and both doses in the 
testing strategy.  


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Study 18898A – Clinical Study Protocol
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Panel 1
Study Design
The study consists of a Screening Period and a Placebo-controlled Period. IMP (eptinezumab 100 mg, 
eptinezumab 300 mg, or Placebo) is administered by intravenous infusion every 12 weeks, starting at the 
Baseline Visit. Patients completing the 24-week Placebo-controlled Period will enter an Extension Period 
where all patients will receive eptinezumab once every 12 weeks. 


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Study 18898A – Clinical Study Protocol
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Panel 2
Study Procedures and Assessments
Visit Name
Screening
Baselinee + IMP
Phone Contactk
Phone Contactk
Primary Outcome + IMP 
Phone Contactk
Phone Contactk
IMP 
Phone Contactk
Phone Contactk
IMP
Phone Contactk
Phone Contactk
IMP
Phone Contactk
Phone Contactk
IMP
Phone Contactk
Phone Contactk
Completion
Withdrawalv
Placebo-controlled Period
Extension Period
Visit Number
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19 20
End of Weeka
-4
0
4
8
12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72
Visit Windowb (days 
relative to nominal 
visit)
-2
-2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 +2 +2
Screening and Baseline Procedures and Assessments
Signed informed 
consents

Demographics (age, 
sex, race)

Diagnosis

Documented evidence 
of previous failure of
2-4 migraine 
preventive 
medicationsc

Disease-specific 
history

Relevant history 
(social, medical, 
psychiatric, 
neurological)

Recent medication


Substance use

Height

Blood sampling for 
serology (HIV, 
HBsAg, anti-HCV)

Blood sampling for 
other screening (for 
example, β-hCG, 
FSH)

Inclusion/exclusion 
criteria

f




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Study 18898A – Clinical Study Protocol
Page 14 of 98
Visit Name
Screening
Baselinee + IMP
Phone Contactk
Phone Contactk
Primary Outcome + IMP 
Phone Contactk
Phone Contactk
IMP 
Phone Contactk
Phone Contactk
IMP
Phone Contactk
Phone Contactk
IMP
Phone Contactk
Phone Contactk
IMP
Phone Contactk
Phone Contactk
Completion
Withdrawalv
Placebo-controlled Period
Extension Period
Visit Number
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19 20
End of Weeka
-4
0
4
8
12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72
Visit Windowb (days 
relative to nominal 
visit)
-2
-2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 +2 +2
Vital signs body 
temperature including, 
weight, ECGs

n
n
n
n
n
n


Physical Examination

n
n
n
n
n
n


C-SSRSo









Biobanking
Blood sampling for 
gene expression 
profiling (RNA)w
n
n
n
n


Blood sampling for 
metabolomics/
proteomics (plasma)w
n
n
n
n


Blood sampling for 
pharmacogenetics 
(DNA) – optionalx
n
Blood sampling for
possible future ADA 
assessmenty
n


Other Study Procedures and Assessments
IMP administeredr
q
q
q
q
q
q
IMP accountabilitys






Concomitant 
medication 
(prescription and non-
prescription)




















eDiary trainingi

PRO trainingi

eDiary closeoutj


Pregnancy test
t










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Study 18898A – Clinical Study Protocol
Page 15 of 98
Visit Name
Screening
Baselinee + IMP
Phone Contactk
Phone Contactk
Primary Outcome + IMP 
Phone Contactk
Phone Contactk
IMP 
Phone Contactk
Phone Contactk
IMP
Phone Contactk
Phone Contactk
IMP
Phone Contactk
Phone Contactk
IMP
Phone Contactk
Phone Contactk
Completion
Withdrawalv
Placebo-controlled Period
Extension Period
Visit Number
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19 20
End of Weeka
-4
0
4
8
12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72
Visit Windowb (days 
relative to nominal 
visit)
-2
-2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 +2 +2
Exit Interview 
u
u
ADA = anti-drug antibody; C-SSRS = Columbia-Suicide Severity Rating Scale; ECG = electrocardiogram; 
EQ-5D-5L = Euroqol 5 Dimensions; HBsAg = hepatitis B surface antigen; FSH = follicle-stimulating 
hormone; HCRU = Health Care Resource Utilization; βhCG = beta-human chorionic gonadotropin;
HCV = hepatitis C virus; HIT-6 = Headache Impact Test; HIV = human immunodeficiency virus; 
IMP = investigational medicinal product; MBS = Most Bothersome Symptom; MSQ v2.1 = Migraine-
Specific Quality of Life Questionnaire Version 2.1; PGIC = Patient Global Impression of Change; PRO = 
patient-reported outcome; WPAI = Work Productivity and Activity Impairment questionnaire
a
All assessments  may be completed over a maximum of 2 consecutive days with the exception of PROs (see 
footnote g below); if so, the first day is considered the “visit” day according to the schedule.
b
If the date of a clinic visit or phone contact does not conform to the schedule, subsequent visits should be 
planned to maintain the visit schedule relative to the Baseline Visit.
c
The patients must have documented evidence of failure in the past 10 years of 2-4 different pharmacological 
migraine preventive medications. Acceptable documentation of previous treatment failures includes medical 
or pharmacy record or physician’s confirmation specific to each treatment. 
d
Randomization will occur at the Baseline Visit 28-30 days after the Screening Visit and after eligibility 
criteria are confirmed by the investigator.
e
Dosing must occur at the Baseline Visit. 
f
Inclusion and exclusion criteria review must be done prior to dosing at the Baseline Visit.
g
Assessments involving interviews and scales must be done before the infusions. All efficacy and 
pharmacoeconomic assessments are PROs. PROs which are scheduled in alignment with a clinic visit can be 
completed in the clinic or in the remote setting within 3 days prior to the scheduled clinic visit date. 
Additionally, PGIC (at Week 4 only), HIT-6, EQ-5D-5L, HCRU, WPAI which are scheduled in alignment 
with a phone contact 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. 
h
The eDiary assessments will be completed in the remote setting on a daily basis. 
i
At the Screening Visit, the patient must be assisted with the provisioning and training of the eDiary and 
training of efficacy and pharmacoeconomic assessments (PROs). Details will be provided in a separate user 
manual.
j
The eDiary closeout will take place at the Completion/Withdrawal Visit, while the patient is at site. Details 
will be provided in a separate user manual.


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Study 18898A – Clinical Study Protocol
Page 16 of 98
k
The patients will be contacted via phone every 4 weeks between infusion visits for eDiary compliance check, 
to ensure that selected assessments have been completed and for collection of relevant information such as 
AEs and concomitant medication.
l
PGIC at Week 4 must be completed in the remote setting. 
m At infusion visits, infusion related reactions (IRRs) must be checked as part of the overall AE collection, 
after infusion and before the patient is discharged from the site.
n
At infusion visits, physical examination, ECG, blood sampling (for clinical safety laboratory tests, ADA and 
biobank) and urine samples (for clinical safety laboratory tests and pregnancy) must be conducted before 
infusion. AEs, vital signs including body temperature should be checked before and after infusion.
o
The C-SSRS will be administered by the authorized rater at the clinic and prior to infusion.
p
Patients who test positive for ADA at the Completion Visit will be asked to provide up to two additional 
blood samples for immunogenicity testing at 12-week intervals for up to 24 weeks.
q
At infusion visits, patients must be monitored for a period of 1 hour from the end-of-infusion. Patients will be 
requested to stay longer should the investigator determine this is clinically warranted.
r
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.
s
A designated unblinded CRA is responsible for the IMP accountability.
t
Pregnancy test at Screening to be performed using serum β-HCG. At all other visits, urine pregnancy testing 
will be performed and in case of a positive finding, confirmatory testing will be performed via serum β-HCG.
u
Exit Interview subset: Patients undergoing the exit interviews must provide signed subset-specific Informed 
Consent. The exit interview will be conducted shortly (no later than 2 weeks) after the last assessment of the 
Week 24 Visit or Withdrawal Visit for patients who withdraw prior to Week 24. The exit interview must be 
conducted after all visit assessments are completed. Details will be provided in a separate exit interview 
guide.
v
Patients who withdraw, except for those who withdraw their consent, will be asked to attend a Withdrawal 
Visit 12 weeks after the last dose of IMP and undergo Safety Follow-Up evaluations. Patients who withdraw 
prior to Week 24 will undergo additional Efficacy Follow-Up evaluations.
w Exploratory gene expression profiling (RNA) and metabolomics/proteomics are an integrated part of the
study and are covered by the main Informed Consent.
x
Sampling for pharmacogenetics is optional and a separate signed Informed Consent must be in place to cover 
this analysis.
y
Whole blood samples for serum separation and potential future ADA analyses will be drawn at Week 24 and 
at the Completion or Withdrawal Visit.


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Page 17 of 98
Table of Contents
List of Panels........................................................................................................................... 22
List of Abbreviations and Definitions of Terms..................................................................... 23
Major Changes Since Last Edition......................................................................................... 26
1
Introduction.................................................................................................................... 30
Background........................................................................................................... 30
Overview ............................................................................................... 30
Nonclinical Data .................................................................................... 31
Clinical Data.......................................................................................... 32
Rationale for the Study.......................................................................................... 33
2
Objectives and Endpoints............................................................................................... 33
3
Study Design................................................................................................................... 36
Overview of the Study Design............................................................................... 36
Rationale for the Study Design.............................................................................. 38
4
Ethics .............................................................................................................................. 39
Ethical Rationale................................................................................................... 39
Informed Consent.................................................................................................. 40
Personal Data Protection ....................................................................................... 42
Ethics Committees (ECs) and Institutional Review Boards (IRBs)......................... 42
5
Study Population ............................................................................................................ 43
Number of Patients and Planned Countries and Regions........................................ 43
Patient Recruitment............................................................................................... 43
Selection Criteria .................................................................................................. 43
Withdrawal Criteria............................................................................................... 47
6
Investigational Medicinal Product(s) (IMP(s)).............................................................. 47
Treatment Regimen............................................................................................... 47
IMP(s), Formulation(s), and Strength(s) ................................................................ 48
Manufacturing, Packaging, Labelling, and Storage of IMPs................................... 48
Method of Assigning Patients to Treatment ........................................................... 49
IMP Accountability............................................................................................... 49
Unblinding Procedures.......................................................................................... 49
Post-study Access to IMP(s).................................................................................. 50
7
Concomitant Medication................................................................................................ 50
General ................................................................................................................. 50
Use of Coronavirus Disease 2019 Vaccine ............................................................ 50
8
Study Visit Plan.............................................................................................................. 51
Overview .............................................................................................................. 51
Screening Visit (Visit 1)........................................................................................ 51
Pre-screening ......................................................................................... 52
Patient Identification Card...................................................................... 52
Re-screening .......................................................................................... 52
Baseline Visit + IMP (Visit 2)............................................................................... 53
Primary Outcome + IMP (Visit 5) ......................................................................... 53


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IMP Visits (Visits 2, 5, 8, 11, 14, 17)..................................................................... 53
Phone Contacts (Visits 3, 4, 6, 7, 9, 10, 12, 13, 15, 16, 18, 19)............................... 54
Completion Visit (Visit 20)................................................................................... 54
Unscheduled Visit................................................................................................. 55
Withdrawal Visit................................................................................................... 55
Safety Follow-up at Completion or Withdrawal Visit ............................................ 56
End-of-study Definition ........................................................................................ 56
9
Assessments .................................................................................................................... 56
Screening and Baseline Procedures and Assessments............................................. 56
Demographics and Baseline Characteristics............................................ 56
Diagnostic Assessments ......................................................................... 58
Classifications for Eligibility.................................................................. 58
Definitions for Baseline Disease Activity and Analysis........................... 59
Efficacy Assessments............................................................................................ 60
Use of COA Tools.................................................................................. 61
eDiary .................................................................................................... 61
Patient Global Impression of Change (PGIC).......................................... 62
Most Bothersome Symptom (MBS)........................................................ 62
External COA Monitoring Oversight...................................................... 62
COA Tool Training................................................................................ 62
Pharmacoeconomic Assessments........................................................................... 63
Clinical Outcome Assessments (COAs).................................................. 63
9.3.1.1
Use of COA Tools.................................................................. 63
9.3.1.2
Headache Impact Test (HIT-6)................................................ 63
9.3.1.3
Migraine-Specific Quality of Life Questionnaire, version 2.1 
(MSQ v2.1) ............................................................................ 64
9.3.1.4
Euroqol 5 Dimension – 5 Levels (EQ-5D-5L)......................... 64
9.3.1.5
Health Care Resource Utilization (HCRU).............................. 64
9.3.1.6
Work Productivity and Activity Impairment: Migraine 
(WPAI:M).............................................................................. 64
9.3.1.7
External COA Monitoring Oversight ...................................... 65
9.3.1.8
COA Training......................................................................... 65
Safety Assessments............................................................................................... 65
Adverse Events ...................................................................................... 65
Clinical Safety Laboratory Tests............................................................. 65
Vital Signs ............................................................................................. 67
Height and Weight ................................................................................. 67
Electrocardiograms (ECGs).................................................................... 67
Physical Examination............................................................................. 68
Columbia-Suicide Severity Rating Scale................................................. 68
Anti-Drug Antibody (ADA) including Neutralizing Antibody (NAb) 
Assessments........................................................................................... 69
Other Assessments................................................................................................ 69
Exit Interview (subset) ........................................................................... 69
Biobanking ........................................................................................................... 70
General Considerations........................................................................... 70
Blood Sampling for Gene Expression Profiling....................................... 70
Blood Sampling for Metabolomics and/or Proteomics ............................ 71
Blood Sampling for Pharmacogenetics ................................................... 71
Blood sampling for possible future anti-drug antibody assessments......... 71


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Order of Assessments............................................................................................ 71
Total Volume of Blood Drawn and Destruction of Biological Material.................. 72
Treatment Compliance .......................................................................................... 73
10
Adverse Events ............................................................................................................... 73
Definitions............................................................................................................ 73
Adverse Event Definitions...................................................................... 73
Adverse Event Assessment Definitions................................................... 74
Pregnancy ............................................................................................................. 75
Recording Adverse Events .................................................................................... 76
Reporting Serious Adverse Events (SAEs) ............................................................ 76
Treatment and Follow-up of Adverse Events......................................................... 77
Management of Reactions to Study Drug............................................................... 77
Data Monitoring Committee (DMC)...................................................................... 78
11
Data Handling and Record Keeping.............................................................................. 78
Data Collection ..................................................................................................... 78
Electronic Case Report Forms (eCRFs) .................................................. 78
Patient Binders....................................................................................... 79
11.1.2.1
Use of Patient Binders ............................................................ 79
11.1.2.2
Serious Adverse Event Fallback Forms................................... 79
External Data ......................................................................................... 79
Retention of Study Documents at the Site.............................................................. 79
eCRF Data ............................................................................................. 79
Other Study Documents.......................................................................... 80
12
Monitoring Procedures................................................................................................... 80
13
Audits and Inspections ................................................................................................... 81
14
Protocol Compliance ...................................................................................................... 81
15
Study Termination.......................................................................................................... 82
16
Statistical Methodology.................................................................................................. 82
Responsibilities..................................................................................................... 82
Analysis Sets......................................................................................................... 82
Descriptive Statistics............................................................................................. 83
Patient Disposition................................................................................................ 83
Demographics and Baseline Characteristics........................................................... 83
Recent and Concomitant Medication..................................................................... 84
Exposure............................................................................................................... 84
Efficacy Analyses ................................................................................................. 84
General Efficacy Analysis Methodology................................................. 84
Primary Analysis of the Primary Endpoint.............................................. 84
Sensitivity Analyses of the Primary Endpoints........................................ 84
Analysis of the Key Secondary Endpoints............................................... 85
Sensitivity Analyses of the Key Secondary Endpoints............................. 85
Testing Strategy ..................................................................................... 85
Analysis of the Secondary Endpoints...................................................... 86
Analysis of the Exploratory Endpoints.................................................... 87
Analysis of Subgroups............................................................................ 87
Safety Analyses..................................................................................................... 87
Analysis of Adverse Events.................................................................... 87


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Analysis of Other Safety Endpoints........................................................ 87
Sample Size and Power......................................................................................... 88
Statistical Analysis Plan........................................................................................ 88
17
Clinical Study Report and Publications......................................................................... 88
Data Ownership .................................................................................................... 88
Clinical Study Report............................................................................................ 88
Summary of Clinical Study Results ....................................................................... 88
Publications .......................................................................................................... 89
18
Indemnity and Insurance ............................................................................................... 89
19
Finance............................................................................................................................ 89
Site Agreements.................................................................................................... 89
Financial Disclosure.............................................................................................. 89
Equipment............................................................................................................. 89
References ............................................................................................................................... 90


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Appendices
Appendix I
Clinical Study Protocol Authentication and Authorization.............................. 94
Appendix II
Recent and Concomitant Medication Disallowed or Allowed with Restrictions
...................................................................................................................... 96


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List of Panels
Panel 1
Study Design.........................................................................................................11
Panel 2
Study Procedures and Assessments........................................................................12
Panel 3
Objectives and Endpoints......................................................................................33
Panel 4 
IHS ICHD-3 guidelines for Migraine.....................................................................58
Panel 5
Clinical Safety Laboratory Tests............................................................................66


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List of Abbreviations and Definitions of Terms
β-hCG
beta-human chorionic gonadotropin
ADA
anti-drug antibody
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
APRS
all-patients-randomized set
APTS
all-patients-treated set
APTS_LT
all-patients-treated long-term set
AST
aspartate aminotransferase
ATC
anatomical therapeutic chemical
BMI
body mass index
Bpm
beats per minute
BSC
best supportive care
CGRP
calcitonin gene-related peptide
CI
confidence interval
CM
chronic migraine
CMH
Cochran-Mantel-Haenszel
CNS
central nervous system
CNV
copy number variation
CRA
clinical research associate
CRF
case report form
CRO
clinical research organisation
CRP
C-reactive protein
CSR
clinical study report
C-SSRS
Columbia-Suicide Severity Rating Scale 
DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid
DSM-5®
Diagnostic and Statistical Manual of Mental Disorders, 5th edition
EC
ethics committee
ECG
Electrocardiogram
eCRF
electronic case report form
EM
episodic migraine
EMA
European Medicines Agency
EQ-5D-5L
Euroqol 5 Dimensions
EudraCT
European Union Drug Regulating Authorities Clinical Trials
FAS
full-analysis set
FAS_LT
full-analysis long-term set


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FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
HBsAg
hepatitis B surface antigen
hCG
human chorionic gonadotropin
HCRU
health care resource utilization
HCV
hepatitis C virus
HDL
high density lipoprotein
HIT-6
headache impact test
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
ICD-10
International Statistical Classification of Diseases and Related Health Problems, 
10th Revision
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
ICMJE
International Committee of Medical Journal Editors
IMP
investigational medicinal product
IND
Investigational New Drug Application
IRB
institutional review board
IRR
infusion related reactions
IRT
interactive response technology
IV
intravenous 
LDL
low density lipoprotein
Lu
Lundbeck
MBS
most bothersome symptom
MHDs
monthly headache days
MMDs
monthly migraine days 
MMRM
mixed model for repeated measurements
MOH
medication overuse headache
MSQ v2.1
Migraine-Specific Quality of Life Questionnaire Version 2.1
NA
not applicable
NAb
neutralizing antibody
OC
observed case(s)
PCR
polymerase chain reaction
PCS
potentially clinically significant
PGIC
patient global impression of change
PR
specific ECG interval describing atrioventricular conduction 
PRO
patient-reported outcome
Q12W
every 12 weeks
QP
qualified person
qPCR
quantitative polymerase chain reaction
QRS
specific ECG interval describing ventricular depolarization


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QT
specific ECG interval describing ventricular depolarization/repolarization
QTc
heart-rate corrected QT interval
QTcF
heart-rate corrected QT interval using Fridericia’s correction formula
RNA
ribonucleic acid
RR
specific ECG interval describing the ventricular depolarization/repolarization cycle
SAE
serious adverse event
SAP
Statistical Analysis Plan
SAS
statistical software package from the SAS® Institute
SD
standard deviation
SNP
single-nucleotide polymorphism
SOC
system organ class
SUSAR
suspected unexpected serious adverse reaction
TEAE
treatment-emergent adverse event
TFL
tables, figures and listings
TMF
trial master file
TNC
trigeminal nucleus caudalis
TSH
thyroid stimulating hormone
WPAI
Work Productivity and Activity Impairment


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Major Changes Since Last Edition
The following summarizes the major changes since the last edition of this Clinical Study 
Protocol. The changes are made to align with study-specific documents developed after the 
finalisation of the protocol, for consistency and alignment across sections, or to reflect the 
changes to implement for the remainder of the study. Minor wording clarifications/edits are 
also made but not included in the list below.
General:
Text and panels related to the interim analysis are deleted throughout the protocol as Sponsor 
decision was taken to cancel the interim analysis and inform sites as per memo 18898A 
Interim Analysis (dated 03-Mar-2021). 
Text is added throughout the protocol to clarify that only those patients who withdraw prior to 
Week 24 will undergo Exit Interview. This is done for consistency and alignment across 
sections. 
Text about requirement for eDiary data review is deleted throughout the protocol, as site staff
are not required to conduct a review of eDiary data at each study visit.
In addition, the following changes have been implemented:
Chapter/Section 
Number
Section Title
Change
Synopsis
Study Methodology
Updated: Bullet 5 – to align with the update under 3.1 Overview of the 
Study Design (bullet 1) – see below.
Synopsis
Target Patient 
Population
Updated: Inclusion Criteria bullet 4 – to align with the update under 
5.3 Selection Criteria (Inclusion Criterion 9) – see below.
Synopsis
Assessment Details 
Updated: To align with the update under 9.2.4 Most Bothersome 
Symptom (MBS) – see below.
Panel 2
Screening and 
Baseline Procedures 
and Assessments
Updated: To align with the update under 9.1.1 Demographics and 
Baseline Characteristics – see below.
Panel 2
Footnotes
Updated:

Footnote a: text related to ‘requirement of screening assessments 
prior to the Baseline Visit’ is deleted for clarification purposes.

Footnote t: clarifying text related to ‘serum testing for pregnancy’ 
is added to align with the Laboratory Services Agreement
(version 1.0, dated 31-Mar-2020) effective at study start.

Footnote u: to align with the information in section 9.5.1 Exit 
Interview (subset).

Footnote y: to align with the assessments ticked in Panel 2.


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Study 18898A – Clinical Study Protocol
Page 27 of 98
Chapter/Section 
Number
Section Title
Change
Chapter 3 
3.1 Overview of the 
Study Design
Updated:

Country is added as a stratification factor to align with the
Randomization Specification (signed 12-Dec-2019) and Endpoint 
IRT Specification (version 1.0, dated 11-Feb-2020). Both 
documents were effective at study start.

Sponsor is deleted from list of personnel who are without access 
to information on individual treatment codes during the study. 
Following the data-base lock for the Placebo-controlled Period, 
Sponsor personnel involved in the review of the CSR were 
unblinded to individual treatment codes.
Chapter 3
3.2 Rationale for the 
Study Design
Added: Clarifying text to explain:

the definitions of EM or CM (number of migraine and headache 
days) according to the eligibility criteria.

that patients with concurrent Medication Overuse Headache were 
allowed to be included in the study as aligned with the eCRF 
(effective at study start).

the capture of aura occurrence and migraine medication for 
qualifying a migraine day in the eDiary.
Chapter 5
5.3 Selection 
Criteria
Updated:

Inclusion Criterion 9: clarification is made that the 28-day 
screening period was calculated relative to the Screening Visit
date (and not the randomization date) as aligned with the Project 
Design Specification (version 1.0, effective at study start).

Inclusion Criteria 9 and 10: reference is added to the definitions 
explained in new section 9.1.3 Classifications for Eligibility – see 
below.

Inclusion Criterion 14: updated to align with the Clinical Trials 
Facilitation and Coordination Group (CTFG) guidance to loosen 
the requirements for contraception during study conduct. Update 
applies after enrolment was completed and after completion of the 
Placebo-controlled Period.

Exclusion Criterion 4: clarifying text is added (has taken any 
investigational drug within) to align with Appendix II.
Deleted:

Inclusion Criterion 15: to align with the CTFG guidance to 
remove the requirements for contraception during study conduct.
Update applies after enrolment was completed and after 
completion of the Placebo-controlled Period.
Chapter 7
7.2 Use of 
Coronavirus Disease 
2019 Vaccine
Added: New section regarding use of the COVID-19 vaccine as per 
memo 18898A COVID-19 Vaccine Guidance (dated 26-Mar-2021) 
which was provided to sites.
Chapter 8
8.1 Overview
Updated: Text related to ‘requirement of screening assessments prior 
to the Baseline Visit’ is deleted for clarification purposes.
Added: New text to explain that headache data from the eDiary will be 
made available during the study to site staff for the remainder of the 
study.
Chapter 8
8.2 Screening Visit 
(Visit 1)
Added: Clarifying text to align with the main master Informed 
Consent Form (version 3.0, dated 27-May-2020) to explain that some 
patients were invited to attend up to two Screening Visits to complete 
all assessments at screening.


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Chapter/Section 
Number
Section Title
Change
Chapter 8
8.2.3 Re-screening
Added: Text to explain that rescreening was allowed for patients being 
in quarantine due to a positive COVID-19 test as per memo 18898A 
COVID-19 Extension of the Screening Visit or Rescreening (dated 05-
Nov-2020) which was provided to sites.
Chapter 8
8.8 Unscheduled 
Visit
Added: Clarifying section to explain when an unscheduled visit can 
occur and which assessments can be performed, as aligned with the 
eCRF (effective at study start).
Chapter 9
9.1.1 Demographics 
and Baseline 
Characteristics
Updated: Smoking and alcohol consumption is corrected to substance 
use and moved from Screening to Baseline Visit in Panel 2. This is to 
reflect the collection of other substance use during the Screening 
Period as aligned with the eCRF (effective at study start).
Chapter 9
9.1.2 Diagnostic 
Assessments
Deleted: Definition of a migraine day as a corrected definition is 
added to new section 9.1.3 – see below.
Chapter 9
9.1.3 Classifications 
for Eligibility
Added: New section to explain the definitions of a migraine day, 
headache day and eDiary compliant day (linked to inclusion criteria 9 
and 10) applied when the patients were enrolled in the study. 
Definitions are aligned with the eligibility algorithm in the Project 
Design Specification (version 1.0, effective at study start). 
Chapter 9 
9.1.4 Definitions for 
Baseline Disease 
Activity and 
Analysis
Added: New section to explain the definitions applied for calculation 
of number of EM/CM patients (and low/high frequency EM patients) 
for subgroup analyses. Definitions are based on IHS guidelines42 and 
are aligned with the Statistical Analysis Plan (version 2, dated 13-Oct-
2021).
Chapter 9
9.2 Efficacy 
Assessments
Added: Sentence added about PRO completion for consistency and 
alignment with other sections (8.5 IMP Visits, 9.3 Pharmacoeconomic 
Assessments, 9.7 Order of Assessments). Aligned with the Project 
Design Specification (version 1.0, effective at study start).
Chapter 9
9.2.2 eDiary
Deleted: Text for missed completion of eDiary is deleted as it is not in 
alignment with the Project Design Specification (version 1.0, effective 
at study start).
Chapter 9
9.2.3 Patient Global 
Impression of 
Change (PGIC)
Updated: Numerical representation of PGIC scoring is corrected to 
align with the coding of the responses done for similar clinical 
outcome assessments in other studies and to align with the Statistical 
Analysis Plan (version 2, dated 13-Oct-2021).
Chapter 9
9.2.4 Most 
Bothersome 
Symptom (MBS)
Updated: Text is corrected to indicate that patient will rate 
improvement in the symptom from baseline (and not screening) to 
align with Panel 2 and the Project Design Specification (version 1.0, 
effective at study start).
Updated: Text is corrected to include additional symptoms (mental 
cloudiness, fatigue, pain with activity, mood changes, other) to align 
with the eCOA specifications in the Project Design Specification
(effective at study start). 
Chapter 9
Panel 5
Updated: Clarifying text is added to footnotes to align with the 
Laboratory Services Agreement (version 1.0, dated 31-Mar-2020) 
effective at study start. This applies to the requirement for reflex 
testing for TSH, confirmatory testing for serology, microscopic 
evaluation for urine and serum testing for pregnancy.


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Chapter/Section 
Number
Section Title
Change
Chapter 9
9.6.3 Blood 
Sampling for 
Metabolomic and/or 
Proteomics
Updated: Gene expression profiling is corrected to metabolomic 
and/or proteomics.
Chapter 10
10.2 Pregnancy
Updated: Text regarding partner pregnancy is removed as there is no 
longer requirement to collect data on pregnancies for female partners 
of male study subjects in eptinezumab studies.
Chapter 12 
Monitoring 
Procedure
Deleted: Text regarding collection of medical history for the prior 3 
months is removed to align with eCRF (effective at study start).
Updated: Clarifying text is added for acceptable documented evidence 
of previous treatment failures to reflect the requirements when the 
patients were enrolled in the study. 
Added: Text to explain that remote source data verification may be 
conducted by CRA in accordance with local and national regulations
if on-site visits are not possible.
Chapter 16
16.9.1 Analysis of 
Adverse Events
Updated: Clarifying text is added that the TEAE applies during or 
after administration of IMP.
Appendix II
Vaccinations
Added: COVID-19 vaccine guidance is added as per memo 18898A 
COVID-19 Vaccine Guidance (dated 26-Mar-2021) which was 
provided to sites.


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1
Introduction
Background
Overview
Migraine is a disabling disorder characterised by headache and often accompanied by nausea, 
vomiting, photophobia, and phonophobia.1 Attacks of migraine typically last between 4 and 
72 hours, produce significant disability, and recur often without warning, over decades of 
time.  Migraine is more common in women and most prevalent through the 3rd and 4th 
decades of life, amplifying its impact on family and career development.2 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 
2nd leading cause of disability worldwide.3,4 Generally, migraine begins as an episodic 
disease.  Between attacks of migraine, the nervous system returns to a normal (premorbid) 
state of function.  However, approximately 2.5% of people with episodic migraine will 
annually transform from episodic to chronic migraine, meaning they are experiencing 
migraine on greater than 15 days per month for at least 3 consecutive months.5,6,7
Currently pharmacological treatments of migraine include acute treatments and preventive 
medications. Preventive treatments are used on a sustained basis for periods of months to 
years to prevent migraine from occurring. Preventive drug treatment may be appropriate in a 
number of instances, including where frequency of attacks per month is two or higher, or 
where a patient’s quality of life is severely impaired.8 Conventional preventive medications
belong to different pharmacological categories (for example, beta blockers, anticonvulsants) 
and were all initially developed for other conditions. These treatments show little efficacy 
and often poor tolerability in patients with migraine, resulting in frequent early 
discontinuation of treatment.2,9,10,11,12,13,14 Thus, there is a substantial proportion of patients
who do not respond to, or cannot tolerate, existing treatments and there is a need for 
preventive medications which are more effective and better tolerated than the current standard 
of care.15
Calcitonin gene-related peptide (CGRP) is thought 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 central nervous system (CNS).16,17 Studies in 
animals and humans indicate that the trigeminal ganglion and the trigeminal nucleus caudalis 
(TNC) are likely to be sites of action of CGRP in migraine. In addition, CGRP is expressed in 
many locations within the CNS, including regions that may be relevant to migraine pain.18,19
During migraine attacks, there is an increase in the plasma levels of CGRP in the external 
jugular vein.20 In addition, IV 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.21 CGRP dilates intracranial and extracranial blood vessels, and 
regulates mast cell degranulation, that during migraine, leads to the secretion of vasoactive, 
proinflammatory, and neurosensitizing mediators, thereby contributing to migraine 
pathogenesis.22,23


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A large body of evidence has established the CGRP pathway as a potential target for the 
treatment of migraine. Studies with monoclonal antibodies targeting CGRP or the CGRP 
receptor have shown that inhibition of CGRP is efficacious in the treatment of CM and EM.24
Further recent trials with these agents have shown good efficacy and tolerability in patients 
who experienced previous failure of 2 to 4 different pharmacological migraine preventive 
medications.25,26
Eptinezumab (Lu AG09221) is a humanised monoclonal antibody that inhibits the action of
CGRP. It is in development by H. Lundbeck A/S for the preventive treatment of migraine. 
Results from two pivotal, placebo-controlled, Phase III trials showed that eptinezumab led to 
significant reductions in monthly migraine days in patients with episodic or chronic migraine 
(ALD403-CLIN-006 and ALD403-CLIN-011).27,28 Unique to eptinezumab’s profile is that it 
is administered as an intravenous infusion and throughout its Phase II and Phase III
development programs, it has consistently demonstrated preventive efficacy as soon as the 
first day following infusion and has potential for a sustained benefit over the 12-week dosing 
cycle.  Eptinezumab is currently being reviewed by the Food and Drug Administration (FDA) 
for an indication in migraine prevention.
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 Brochure29 for 
more detailed information.
Nonclinical Data
Several primary pharmacodynamic animal studies (rats, rabbits and cynomolgus monkeys) 
have demonstrated the ability of eptinezumab to block CGRP-driven neurogenic dermal 
vasodilation30 in a generally dose dependent manner with doses of eptinezumab as low as 
0.1 mg/kg. 
Furthermore, 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. In these studies, eptinezumab 
induced no functional effects upon the CNS or renal system in rats or monkeys, or upon the 
cardiovascular or respiratory (excluding the 6-month study) systems in monkeys.
Eptinezumab is not expected to interact directly with deoxyribonucleic acid (DNA) or other 
chromosomal materials, and genotoxicity assessments have not been performed. The 
carcinogenic potential for eptinezumab has not been thoroughly investigated based upon an 
extensive evaluation of the literature related to inhibition of CGRP, angiogenesis, and tumor 
growth, as well as the absence of eptinezumab-related proliferative findings in long term 
studies in cynomolgus monkeys or clinical trials.
Eptinezumab is being developed for the prophylaxis of migraine, and a significant proportion 
of migraineurs are women of childbearing potential.31 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 


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eptinezumab by intravenous injection to pregnant female rats or rabbits at 75 or 
150 mg/kg/dose was well tolerated and there were no maternal effects or evidence of 
embryofetal mortality (embryolethality), alterations in growth (fetotoxicity) or structural 
abnormalities (teratogenicity) for either species.
The local tolerance of eptinezumab was assessed following multiple dose studies in rats and 
cynomolgus monkeys utilizing eptinezumab administered IV. No gross observations 
including erythema and edema, 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.
Clinical Data
The clinical program of eptinezumab is composed of 5 completed studies to date; 4 studies are 
placebo-controlled (Phase Ib study in frequent EM (ALD403-CLIN-002),32 Phase II study in 
CM (ALD403-CLIN-005),33 PIII study in frequent EM (ALD403-CLIN-006),27 PIII study in 
CM (ALD403-CLIN-011)28 and 1 study is open-label (PIII study in CM (ALD403-CLIN-
013)).34,35 Another study (ALD403-CLIN-015)36 is ongoing to assess treatment of 
eptinezumab in patients experiencing an acute attack of migraine. 
Results from the two pivotal, placebo-controlled, Phase III trials showed that eptinezumab at 
doses of 100 mg or 300 mg administered by IV infusion every 12 weeks (2 infusions) led to 
significant reductions in monthly migraine days in patients with episodic or chronic migraine 
(ALD403-CLIN-006 and ALD403-CLIN-011).27 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. 
Eptinezumab is currently being reviewed by the FDA for an indication in migraine 
prevention.
In the completed eptinezumab clinical studies, the most common adverse reaction in ≥2% of 
treated patients and ≥2% of placebo patients were nasopharyngitis. The majority of these 
adverse events were categorized as mild to moderate. The safety of eptinezumab has been 
evaluated in 2,076 patients with migraine who received at least one dose of eptinezumab, 
representing 1615 patient-years of exposure. Long term data with eptinezumab is limited; 
however, 128 subjects 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 
favorable risk-benefit profile based on review of nonclinical, clinical, and scientific literature 
data.


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Rationale for the Study
There is a substantial proportion of patients who do not respond to, or cannot tolerate, existing 
treatments and there is a need for preventive medications which are more effective and better 
tolerated than the current standard of care.15
The demonstrated efficacy and tolerability profile of eptinezumab supports its use as a 
potential therapeutic candidate for patients who failed prior preventive treatment for CM and 
EM. Unique to eptinezumab’s profile is that it is administered as an intravenous infusion and, 
throughout its Phase II and Phase III development programs, it has consistently demonstrated 
preventive efficacy as soon as the first day following infusion and has potential for a sustained 
benefit over the 12-week dosing cycle. 
Thus the current study will evaluate the efficacy and tolerability of eptinezumab in this target 
population and provide evidence-based treatment guidance for these patients with difficult-to-
treat migraine. The onset of the preventive effect will be explored specifically with early 
timepoints. Additionally, endpoints evaluating health-related quality of life, including most 
bothersome symptoms, as well as work productivity, are included in the study to demonstrate 
the impact of preventive treatment beyond the reduction in pain and migraine days. The 
preventive effect will be studied over a treatment duration of 24 weeks and the extension 
period will allow further investigation of the long-term safety and efficacy profile of 
eptinezumab.
2
Objectives and Endpoints
The study objectives and endpoints are summarized in Panel 3.
Panel 3
Objectives and Endpoints
Objectives
Endpoints
Primary Objective
To evaluate the efficacy of 
eptinezumab for the prevention of 
migraine in patients with 
unsuccessful prior preventive 
treatments
Primary endpoint:
Change from baseline in the number of monthly migraine days 
(Weeks 1-12)
Key secondary endpoints:
Response: patients with 50% reduction from baseline in monthly 
migraine days (Weeks 1-12)
Response: patients with 75% reduction from baseline in monthly 
migraine days (Weeks 1-12) 
Change from baseline in the number of monthly migraine days 
(Weeks 13-24)
Secondary endpoints:
Response: patients with 50% reduction from baseline in monthly 
migraine days (Weeks 13-24)


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Objectives
Endpoints
Response: patients with 75% reduction from baseline in monthly 
migraine days (Weeks 13-24)
Response: patients with 100% reduction from baseline in monthly 
migraine days (Weeks 1-12) 
Response: patients with 50% reduction from baseline in monthly 
headache days (Weeks 1-12)
Response: patients with 75% reduction from baseline in monthly 
headache days (Weeks 1-12)
Response: patients with 100% reduction from baseline in monthly 
headache days (Weeks 1-12)
Change from baseline in the number of monthly headache days 
(Weeks 1-12)
Migraine/headaches with severe pain intensity (Weeks 1- 12)
Change from baseline in the number of monthly migraine days with 
use of acute medication (Weeks 1- 12)
Change from baseline in number of monthly migraine days with use 
of acute medication (Weeks 13-24)
Patient Global Impression of Change (PGIC) score at Week 12
PGIC score at Week 24
Change from baseline in the number of monthly migraine days in 
patients with Medication Overuse Headache (MOH) (Weeks 1-12)
Patients with a migraine on the day after first dosing
Change from baseline to Week 12 in Most Bothersome Symptom 
(MBS) score 
Exploratory endpoints:
Change from baseline in the number of monthly headache attacks for 
each 12-week period
Change from baseline in the number of monthly migraine attacks for 
each 12-week period


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Objectives
Endpoints
Secondary Objectives
To evaluate the health-related 
quality of life and work 
productivity impact of eptinezumab
To evaluate the effect of long-term 
treatment with eptinezumab
Key secondary endpoints:
Change from baseline to Week 12 in the Headache Impact Test 
(HIT-6) score
Secondary endpoints:
Change from baseline to Week 24 in the HIT-6 score
Change from baseline to Week 12 in the Migraine-Specific Quality 
of Life (MSQ v2.1) sub-scores (Role Function-Restrictive, Role 
Function-Preventive, Emotional Function)
Change from baseline to Week 12 in the Health-Related Quality of 
Life (EQ-5D-5L) Visual Analogue Scale (VAS) score
Change from baseline to Week 12 in Health Care Resources 
Utilization (HCRU) 
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
Change from Baseline to Week 24 in HCRU
Change from baseline to Week 12 in the Work Productivity and 
Activity Impairment questionnaire (WPAI) sub-scores (Absenteeism, 
Presenteeism, Work productivity loss, Activity impairment)
Change from baseline to Week 24 in the WPAI sub-scores
Secondary endpoints:
Change from baseline in the number of monthly migraine days 
(Weeks 25-36, 37-48, 49-60, 61-72)
Response: patients with 50% reduction from baseline in monthly 
migraine days (Weeks 25-36, 37-48, 49-60, 61-72)
Response: patients with 75% reduction from baseline in monthly 
migraine days (Weeks 25-36, 37-48, 49-60, 61-72)
Change from baseline in the HIT-6 score (at Weeks 36, 48, 60, and 
72)
Exploratory endpoints:
Response: patients with 100% reduction from baseline in monthly 
migraine days
Response: patients with 50% reduction from baseline in monthly 
headache days
Response: patients with 75% reduction from baseline in monthly 
headache days
Response: patients with 100% reduction from baseline in monthly 
headache days
Migraine/headaches with severe pain intensity
Change from baseline in the number of monthly days with use of 
acute migraine medication 
PGIC score 
Change from baseline in the number of monthly migraine days in 
patients with MOH


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Objectives
Endpoints
Patients with a migraine on the day after first dosing 
Change from baseline in MBS score 
Change from baseline in monthly number of Migraine attacks for 
each 12-week period 
Change from baseline in monthly number of Headache episodes for 
each 12-week period 
Change from baseline in the MSQ v2.1 sub-scores
Change from baseline in the EQ-5D-5L VAS score 
Change from baseline in HCRU
Change from baseline in the WPAI sub-scores
Safety Objective
To evaluate the safety and 
tolerability of eptinezumab
To evaluate the long-term safety 
and tolerability of eptinezumab
Safety Endpoints
Adverse events
Absolute values and changes from baseline in clinical safety 
laboratory test values, vital signs, weight, and ECG parameter values
Potentially clinically significant clinical safety laboratory test values, 
vital signs, weight changes, and ECG parameter values
Development of specific anti-eptinezumab antibodies (ADA) 
including neutralizing antibodies (NAbs)
Columbia-Suicide Severity Rating Scale (C-SSRS) score
3
Study Design
Overview of the Study Design
This study has been designed in accordance with the Declaration of Helsinki.37
This is an interventional, multi-national, multi-site, randomized, double-blind, placebo-
controlled Phase IIIb study designed to demonstrate efficacy and safety of eptinezumab for 
migraine prevention in patients with unsuccessful prior preventive treatments. The Placebo-
controlled Period will be followed by an Extension Period where all patients will receive 
active treatment to assess the long-term safety, tolerability and effect of eptinezumab.
This study will be conducted in compliance with the protocol, Good Clinical Practice,38 and 
applicable regulatory requirements.
An overview of the study is presented in Panel 1.
840 patients, recruited from specialist settings are planned for randomization:  280 patients in 
the eptinezumab 300 mg group, 280 patients in the eptinezumab 100 mg group and 
280 patients in the placebo group.
The target population for this study is defined as patients diagnosed with chronic migraine 
(CM) or episodic migraine (EM), as outlined in the IHS ICHD-3 guidelines,1 and with 
documented evidence of failure to 2-4 different preventive migraine medications in the past 


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10 years (see section 9.1.1). The aim is that approximately 40% of the randomized patients 
are patients with EM.
Patients will be randomly allocated via a randomization system to one of three treatment 
groups: eptinezumab 300 mg, eptinezumab 100 mg, or placebo, in a ratio of 1:1:1. 
Randomization will be stratified by monthly headache days (MHDs) at baseline
(14 MHDs/ 14 MHDs) and by country. 
The total study duration from the Screening Visit to the Completion Visit is approximately 
76 weeks and includes a Screening Period (28-30 days), Placebo-controlled Period (24 weeks) 
and Extension Period (48 weeks). The patient will receive IMP starting from the Baseline 
Visit to follow a Q12W dosing schedule (every 12 weeks) with either eptinezumab or placebo 
by IV infusion over 30 minutes (+15 minutes).
At Visit 8 patients will enter the Extension Period. Patients who were assigned to placebo in 
the Placebo-controlled Period will be randomly allocated to one of two treatment groups: 
eptinezumab 300 mg or eptinezumab 100 mg with a ratio of 1:1. Patients assigned to 
eptinezumab 300 mg or eptinezumab 100 mg in the Placebo-controlled Period will continue 
on their original assignments.
Patients will be assigned a headache eDiary at the Screening Visit and will be required to 
complete this daily from the time of screening until the Completion/Withdrawal Visit. During 
infusion visits, assessments of safety will be performed before and after each infusion. At 
these visits, AEs will be collected as well as safety laboratory tests, ECG, weight, and vital 
signs. Patient-reported outcomes (PROs) must be completed prior to infusion.
Patients who complete the study will attend a Completion Visit which will include a Safety 
Follow-up evaluation at 12 weeks after their last dose of IMP. 
Patients who withdraw, except for those who withdraw their consent, will be asked to attend a 
Withdrawal Visit 12 weeks after their last dose of IMP which will include Safety Follow-Up 
evaluations. Patients who withdraw prior to the Week 24 Visit will additionally undergo 
Efficacy Follow-Up evaluations.
Patients in the study will have access to appropriate medical care in accordance with normal 
clinical practice after they complete or withdraw from the study.
An independent Safety Data Monitoring Committee (DMC) will regularly monitor the 
patients' safety data according to the DMC Charter.
In general, no information about individual treatment codes will be available to investigators 
patients or site-facing CRO personnel (blinded team) until after the last patient has completed 
the study. 
The results of the Placebo-controlled Period will be reported on when ended for all patients. 
All data from the Placebo-controlled Period will be cleaned and the database for the Placebo-
controlled Period will be locked. Data will be unblinded for the reporting team (Sponsor) and 


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all analyses specified in the SAP for data collected in the Placebo-controlled Period will be 
performed and included in the Clinical Study Report (CSR). After all patients have completed 
the study, an addendum to the CSR, including the results from the Extension Period, will be 
produced.  Investigators and patients will be informed about which treatment (active or 
placebo) their patients received in the Placebo-controlled Period and the actual dose of 
eptinezumab received in the Extension period only after the last patient has completed the 
study.
Assessments performed in a subset of patients:
Exit interviews will be performed shortly (no later than 2 weeks) after the last assessment of 
the Week 24 Visit or Withdrawal Visit (for patients who withdraw prior to Week 24) on a 
subset of patients (hereafter referred to as the ‘Exit Interview subset’) after all visit 
assessments are completed. The aim is to complete exit interviews for 100 patients out of the 
first 345 randomized patients.
Rationale for the Study Design
The current study includes a 24-week double-blind, randomized placebo-controlled period to
investigate whether eptinezumab can lead to clinically significant improvement in patients 
with unsuccessful prior preventive treatments. The primary endpoint is the change in the 
number of monthly migraine days and will be evaluated at Week 12 as this is expected (on the 
basis of Phase III data) to be an adequate duration to investigate the efficacy of eptinezumab.
Additionally, endpoints will be evaluated at Week 24 to investigate if the relative efficacy is 
sustained in this difficult-to-treat population. The extended period beyond Week 12 will also
allow adequate time to investigate a beneficial effect on quality of life and on potential 
reduction in new migraine attacks, after a reduction in the number of monthly migraine days
is observed. A 48-week dose-blinded Extension Period with eptinezumab treatment is 
included to enable further investigation on the long-term safety and efficacy and for further 
insights into the effectiveness profile of eptinezumab. Endpoints evaluating health-related 
quality of life, including most bothersome symptoms, as well as work productivity, are 
included in the study to demonstrate the impact of preventive treatment beyond the reduction 
in pain and migraine days.
The study population is selected on the basis that there is a substantial proportion of patients
who do not respond to, or cannot tolerate, existing treatments and there is a need for 
preventive medications which are more effective and better tolerated than the current standard 
of care.15 Thus the study will include patients with EM or CM in whom 2 to 4 migraine 
preventive medications of different pharmacological class were previously unsuccessful.
The proposed study population are patients with EM (migraine occurring on ≥4 days and 
headache occurring on <14 days) or CM (migraine occurring on ≥8 days and headache 
occurring on >14 days), which reflect the commonly used definitions of EM and CM patients. 
This target population corresponds to the patient populations in the completed phase III 
studies in EM (ALD403-CLIN-006) and CM (ALD403-CLIN-011)27,28 and in which 
eptinezumab demonstrated efficacy and consequently justifies the patient population for this 


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study. Fulfilment of criteria for EM or CM, according to the eligibility criteria in this 
protocol, will be confirmed via prospectively collected information in the eDiary during the 
Screening Period. Amongst patients with CM, there is a proportion of patients with 
concurrent Medication Overuse Headache (MoH).39,40 These patients are allowed to be 
included in the study.
During the study, the patients will be asked about occurrence of aura in the eDiary. To 
minimize patient burden during the study for migraine with aura, the patient's usual aura will 
only be described and diagnosed at the Screening Visit. Subsequently, the patient will be 
asked about occurrence of aura in the eDiary based on a question in the eDiary; “Have you 
experienced aura with this headache?” Patients will be asked in the eDiary to fill in if they 
took any medications to treat a headache and if so, if they took this medication because they
believed this was a migraine. As several medications are used both to treat non-migraine-
headache and migraine, the classification of a migraine-specific medication is not feasible by 
registering the product used alone. Furthermore, the intention is to avoid that, for example, a 
mild tension-type headache that was treated with paracetamol is counted as a migraine day.
The placebo group is representative of the best supportive care (BSC) as the study allows
acute treatment of migraine when prior preventive treatments have not worked. Thus, the 
study will compare the efficacy of eptinezumab and BSC versus BSC alone. 
Doses of 100 and 300 mg eptinezumab administered by IV infusion every 12 weeks have 
shown to be efficacious and to generally be well tolerated in the treatment of EM and CM in 
the Phase III studies. Thus, these doses and dosing interval are recommended for the target 
population in this study.
The sample size of 840 patients for the primary endpoint is based on the Phase III data, on the 
expected change from baseline to Week 12 in the number of monthly migraine days and 
should provide adequate power for detection of a clinically meaningful treatment effect.
Blood sampling will be required at several time points during the study to evaluate standard 
safety laboratory parameters, ADA including NAbs.
4
Ethics
Ethical Rationale
This study will evaluate eptinezumab as a potential therapeutic candidate for a target patient
population who failed prior preventive treatment for CM and EM.
Inclusion of a placebo group is justified since the group is representative of the BSC allowing 
acute treatment of migraine when prior preventive treatments have not worked. Thus, 
no patient will be denied access to standard treatments.
The randomization ratio of 1:1:1 increases the possibility that the patient will receive an 
active treatment and ensures that the majority of patients will receive eptinezumab in the 


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Placebo-controlled Period. Furthermore, all patients will receive eptinezumab in the 
Extension Period. Thus, no patient will be denied access to active treatment with 
eptinezumab.
Two dose groups (100 mg or 300 mg) are considered for the current study as these have 
shown to be efficacious and to generally be well tolerated in the treatment of episodic and 
chronic migraine in the Phase III studies and will help guide the dose selection for this target 
difficult-to-treat population.
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. Throughout the study, signs of 
suicidal risk will be assessed and the patients at risk will be withdrawn from the study.
In general, safety data with eptinezumab have not raised any clinical safety concerns at doses 
of 100 and 300 mg from the Phase III studies, supporting that eptinezumab can be safely used 
in the current study in patients with difficult-to-treat migraine. However, it cannot be ruled 
out that the IMP could have adverse effects that have not yet been reported. 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.
In accordance with Good Clinical Practice,38 qualified medical personnel at Lundbeck 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 Lundbeck Safety Committee to ensure that prompt action is taken, if needed.
In accordance with Good Clinical Practice,38 the investigator will be responsible for all study-
related medical decisions.
Informed Consent
No study-related procedures, including any screening procedures, may be performed before 
the investigator has obtained written informed consent from the 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 is 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.


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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.
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 8.9)
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 last patient has completed the 
study and the full study has been reported, about which treatment they received. In the case 
where enrolment stops early, some patients will be informed about which treatment they 
received prior to the study being reported
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 Lundbeck and authorized personnel 
from certain authorities (domestic, foreign, data protection agencies, or ethics committees 
(ECs) or institutional review boards (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 ethics committees.
As the blood sampling for the exploratory genomic, proteomic, and metabolomic analyses is 
an integral part of this study, the main Informed Consent Form covers these analyses.  


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Conversely, the blood sampling for potential future genetic biomarker analysis is optional and 
a separate Informed Consent Form covers this analysis. The Exit Interview is optional, and a 
separate Informed Consent Form covers this interview.
The blood samples for potential future exploratory biomarker analysis, or the data derived 
from these blood samples, may be shared with academic and public institutions and other 
companies.  However, Lundbeck will retain full control of the samples and their use in 
accordance with the information in the Informed Consent Form and a Material Transfer 
Agreement.
A patient may, at any time and without stating a reason, specifically request the destruction of 
the patient’s biobank sample, irrespective of the patient’s continued participation in the study.  
The investigator must send a written request on behalf of the patient to the international study 
manager.  The investigator will receive written confirmation from Lundbeck when the 
biobank sample has been destroyed.
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 legislation41 to ensure that 
requirements regarding personal data protection are met. If an external organization will 
process data on behalf of Lundbeck, a contractual procedure will be signed between 
Lundbeck or delegate and the external organization to ensure compliance with the above-
mentioned legislation.
Ethics Committees (ECs) and Institutional Review Boards (IRBs)
This study will be conducted only after Lundbeck has received confirmation that the 
regulatory authorities have approved or confirmed notification of the study and that written 
approval of the protocol has been granted by the appropriate EC or IRB.
The investigator must not allow any patients to participate in the study before receiving 
confirmation from Lundbeck 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.


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5
Study Population
Number of Patients and Planned Countries and Regions
Planned countries and regions:
Europe and North America
Planned number of screened patients (approximately):
Planned number of randomized patients:
1680
840
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.
The investigators will be notified immediately when the recruitment period comes to an end.
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, if part of the Exit Interview subset has provided a signed subset-specific 
Informed Consent Form.
4.
The patient is an outpatient.
5.
The patient has adequate venous access for administration of study drug.
6.
The patient has a diagnosis of migraine as defined by IHS ICHD-3 guidelines1 (see 
section 9.1.2) with a history of chronic or episodic migraines of at least 12 months prior 
to the Screening Visit.
7.
The patient has a migraine onset of <50 years of age.
8.
The patient has ≥4 migraine days per month for each month within the past 3 months 
prior to the Screening Visit. (A migraine day is defined in section 9.1.2).
9.
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 (see section 9.1.3 for Definition of 
a Compliant Day).
10. The patient fulfils the following criteria for CM or EM in prospectively collected 
information in the eDiary during the Screening Period (see section 9.1.3 for Definition of 
a Migraine Day and Headache Day):


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For patients with CM: Migraine occurring on ≥8 days and headache occurring on >14 
days
For patients with EM: Migraine occurring on ≥4 days and headache occurring on <14 
days
11. (a) The patient has documented evidence of treatment failure(must be supported by 
medical record or by physician’s confirmation specific to each treatment – see 
chapter 12) in the past 10 years of 2-4 different migraine preventive medications out of 
the following:
propranolol/metoprolol 
topiramate 
amitriptyline 
flunarizine 
candesartan 
valproate/divalproex 
botulinum toxin A/B (if documented that botulinum toxin was taken for chronic 
migraine) 
AND
(b) The patient has failed two of the below of which at least one must be due to 
inadequate efficacy:
propranolol/metoprolol
topiramate 
amitriptyline
flunarizine
candesartan
12. The patient has a history of either previous or active use of triptans for migraine.
13. The patient is aged ≥18 and ≤75 years at the Screening Visit.  
14. The patient, if a woman, must:
have had her last natural menstruation ≥12 months prior to the Screening Visit, OR
have been surgically sterilized 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 following contraceptive methods: 
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 events) and/or contraindications (that is, 
ineligibility due to medical reasons). Treatment failure corresponds to the first documented failure 
for each medication.


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o
combined oral, intravaginal or transdermal hormonal contraception
o
progestogen-only oral, injectable or implantable hormonal contraception
o
intrauterine devices (IUD) 
o
intrauterine hormone-releasing system (IUS) 
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 the Screening Visit)
15. The patient agrees to have regular contact with another adult throughout the study (if 
applicable for sites in the Czech Republic).
Exclusion Criteria
1.
The patient has previously been enrolled in this study.
2.
The patient has experienced failure on a previous treatment targeting the CGRP pathway. 
3.
The patient has a treatment failure on valproate/divalproex or botulinum toxin A/B and 
the treatment is not the latest preventive medication prior to study inclusion. The 
medication is regarded as the latest if the medication start date is after the start date of the 
other preventive medications and the medication stop date is after the stop date of the 
other preventive medications.
4.
The patient has participated in a clinical study <30 days or has taken any investigational 
drug within 5 plasma half-lives (whichever is longer) prior to the Screening Visit.
5.
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.
6.
The patient is pregnant or planning to become pregnant or breastfeeding.
7.
The patient has a history of severe drug allergy or hypersensitivity or known 
hypersensitivity or intolerance to the IMP or its excipients.
8.
The patient has confounding and clinically significant pain syndromes, (for example, 
fibromyalgia, chronic low back pain, complex regional pain syndrome).
9.
The patient has a diagnosis of acute or active temporomandibular disorder.
10. The patient has a history or diagnosis of chronic tension-type headache, hypnic headache, 
cluster headache, hemicrania continua, new daily persistent headache, unusual migraine 
subtypes such as hemiplegic migraine (sporadic and familial), ophthalmoplegic migraine, 
or migraine with neurological accompaniments that are not typical of migraine aura 
(diplopia, altered consciousness, or long duration).
11. The patient has any current psychiatric condition that is uncontrolled and/or untreated for 
a minimum of 6 months prior to the Screening Visit. Patients with a lifetime history of 
psychosis and/or mania in the last 5 years prior to the Screening Visit are excluded.
12. The patient has a current diagnosis or history of substance abuse or alcohol abuse 
(DSM-5® criteria) <24 months prior to the Screening Visit.


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13. 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.
14. 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 
central nervous system functioning.
15. 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.
16. The patient has a history of clinically significant cardiovascular disease or vascular 
ischaemia or thromboembolic events (for example, cerebrovascular accident, deep vein 
thrombosis, or pulmonary embolism).
17. 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.
18. 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.
19. The patient has one or more clinically significant out-of-range vital signs at the Screening 
Visit.
20. The patient has a Body Mass Index (BMI) >39 kg/m2 at the Screening Visit.
21. The patient has tested positive for human immunodeficiency virus (HIV), hepatitis B 
surface antigen (HBsAg), or hepatitis C virus antibody (anti-HCV) at the Screening Visit.
22. 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
a serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) value 
>2 times the upper limit of the reference range
23. The patient has, at the Screening Visit:
an abnormal ECG that is, in the investigator’s opinion, clinically significant
a PR interval >200 ms
a QRS interval >130 ms
a QTcF interval >450 ms (for men) or >470 ms (for women) (based on the Fridericia 
correction where QTcF = QT/RR0.33) OR a QTcF interval >440 ms (for men) or 
>460 ms (for women) if the patient has a heart rate <60 bpm. 
24. The patient is, at the Screening Visit or Baseline 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).


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25. The patient has a disease or takes medication that could, in the investigator’s opinion, 
interfere with the assessments of safety, or 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.
Withdrawal Criteria
A patient must be withdrawn from the study if:
the patient withdraws consent (defined as a patient who explicitly takes back their
consent); section 8.9 states how the patient’s data will be handled
the patient has been randomized in error and has not received IMP
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])
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
any site personnel break the randomization code for that patient
the patient becomes pregnant
the patient experiences an anaphylactic reaction or another severe and/or serious 
hypersensitivity reaction to the IMP infusion, as assessed by the investigator. If the event 
occurs during the IMP infusion, the infusion must be discontinued immediately
the patient has a serum ALT or AST value >3 times the upper limit of the reference range 
and a serum total bilirubin value >2 times the upper limit of the reference range
the patient has a serum ALT or AST value >5 times the upper limit of the reference range 
that is confirmed by testing <2 weeks later
the patient has a QTcF interval >500 ms; the decision to withdraw the patient may be 
postponed until a repeat ECG is taken, if it is taken within 24 hours
the patient is at significant risk of suicide (defined as answering "yes" to suicidal ideation 
questions 4 or 5 or answering "yes" to suicidal behaviour on the C-SSRS at any time 
during the study)
Patients who withdraw will not be replaced.
6
Investigational Medicinal Product(s) (IMP(s))
Treatment Regimen
Patients will be randomly allocated via a centralized randomization system to one of three 
treatment groups: eptinezumab 300 mg, eptinezumab 100 mg, or placebo, in a ratio of 1:1:1.


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The patient will receive IMP starting from the Baseline Visit to follow a Q12W dosing 
schedule with either eptinezumab or placebo by IV infusion.
At Visit 8 patients will enter the Extension Period. Patients who were assigned to placebo in 
the Placebo-controlled Period will be randomly allocated to one of two treatment groups: 
eptinezumab 300 mg or eptinezumab 100 mg with a ratio of 1:1. Patients assigned to 
eptinezumab 300 mg or eptinezumab 100 mg in the Placebo-controlled Period will continue
their original assignments.
IMP(s), Formulation(s), and Strength(s)
The IMP(s) supplied by Lundbeck in this study are:

Eptinezumab 100 mg/ml (1ml/ vial) as Concentrate for Solution for Infusion.
Patients allocated to the 300 mg eptinezumab treatment group will be dispensed 3 x 100 mg, 
Solution for Infusion 100 mg/ml added to 100 mL of 0.9% normal saline, intravenously.
Patients allocated to the 100 mg eptinezumab treatment group will be dispensed 1 x 100 mg, 
Solution for Infusion 100 mg/ml added to 100 mL of 0.9% normal saline, intravenously.
Patients allocated to the placebo treatment group will be dispensed 100 mL of 0.9% normal 
saline, intravenously.
The pharmacist or designee responsible for receiving, storing, preparing, and dispensing 
eptinezumab and placebo IV 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 (+15) minutes by the blinded 
investigator or designee.
Further instructions on preparation and procedures associated with administering the IV can 
be found in the Pharmacy Manual and Infusion Guidelines.
Manufacturing, Packaging, Labelling, and Storage of IMPs
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 Lundbeck.
The IMP will be provided in single-use vials (as a concentration 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.


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No manipulation, repackaging, or relabelling of IMP is permitted after QP release by 
Lundbeck, 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 IMP number.
The IMPs must be stored in a safe and secure location, and in accordance with the storage 
conditions specified on the labels. Please refer to the Pharmacy Manual for additional storage 
and handling procedures.
Method of Assigning Patients to Treatment
Interactive response technology (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.  
When a patient is to be randomized, the unblinded pharmacist or designee will use the IRT.  
The IRT will allocate the patient to a treatment group during the call and assigns the patient a 
randomization number in accordance with the specifications from Biostatistics, 
H. Lundbeck A/S.
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 pharmacist must maintain an adequate record of the receipt and distribution of 
the IMP(s). This record must be available for inspection at any time.
Unblinding Procedures
Pharmacovigilance, H. Lundbeck A/S, and the investigator or the pharmacist (if applicable), 
and the DMC 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 must 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.  When the code is broken for a patient, the patient must 
be immediately withdrawn from the study.  If this occurs during a visit, the investigator must 


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complete the visit as a Withdrawal Visit; otherwise, the patient will be asked to attend a 
Withdrawal Visit 12 weeks after his/her last dose of IMP.
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.
7
Concomitant Medication
General
Concomitant medication is any medication other than the IMP that is taken during the study
up until the Completion/Withdrawal Visit, including during the Screening Period.
The concomitant medications that are disallowed or allowed with restrictions during the study 
are summarized in Appendix II.
Details of all concomitant medication (prescription and over-the-counter) taken <3 months 
prior to the Screening Visit must be recorded in the eCRF at the first visit.  Any changes 
(including reason for changes) in concomitant medication must be recorded at each 
subsequent visit.
Details of all migraine preventive treatment failures (prescription and over-the-counter) taken 
<10 years prior to the Screening Visit must be recorded in the eCRF at the Screening Visit.  
For any concomitant medication 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 concomitant medication initiated due to a new disorder after enrolment in the study, 
the disorder must be recorded as an adverse event.
Use of Coronavirus Disease 2019 Vaccine
There are currently no data indicating that eptinezumab interacts with or impairs 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 
described in Appendix II. All adverse events, including those judged by the investigator to be 
related to the COVID-19 vaccine, must be recorded in the eCRF (see section 10.1.1). A 
causality assessment, including an alternative causality as relevant, must be provided. 


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8
Study Visit Plan
Overview
An overview of the procedures and assessments to be conducted during the study and their 
timing is presented in Panel 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 are divided into Phone Contacts and IMP Visits. The Primary 
Outcome Visit (Visit 5) is performed 12 weeks after the Baseline Visit. Patients will continue 
until the Completion Visit (Visit 20) or until the Withdrawal Visit. 
At Visit 8 patients will enter the Extension Period and receive either one of two treatments: 
eptinezumab 300 mg or eptinezumab 100 mg until the Completion Visit (Visit 20).
Patients will complete a daily headache eDiary from the time of screening until the 
Completion/Withdrawal Visit. Patients will be given a headache eDiary at the Screening Visit 
and must be trained in its use and compliance requirements. Patients will complete electronic 
headache diary entries daily. At each clinic visit and phone contact (that is every 4 weeks), a 
compliance check of the eDiary will be conducted. Patients must continue to complete the 
daily eDiary during the transfer to the Extension Period. Headache data from the eDiary will 
be made available during the study to site staff for review via the eDiary system portal. See 
section 9.2.2 for further details on eDiary.
All assessments  may be completed over a maximum of 2 consecutive days (with the 
exception of PROs - see below); if so, the first day is considered the “visit” day according to 
the schedule. If the date of a clinic visit or phone contact does not conform to the schedule, 
subsequent visits should be planned to maintain the visit schedule relative to the Baseline
Visit.
PROs which are scheduled in alignment with a clinic visit can be completed in the clinic or in 
the remote setting within 3 days prior to the scheduled clinic visit date. PROs which are 
scheduled in alignment with a phone contact (PGIC (at Week 4 only), HIT-6, EQ-5D-5L, 
HCRU, WPAI) 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.
After completing or withdrawing from the study, the patient must be treated in accordance 
with usual clinical practice.
Screening Visit (Visit 1)
Signed informed consent must be in place before any study-related assessments are performed 
and may be obtained prior to the Screening Visit.


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In some cases patients may be asked to attend up to 2 Screening Visits to complete all 
assessments at screening. In exceptional cases, the screening period (visit interval between 
Screening and Baseline Visits) may be extended with approval from the sponsor provided the 
Lundbeck medical expert accepts the rationale provided for the extension.
At the Screening Visit, the patient must be assisted with the provisioning and training of the 
eDiary and with training of efficacy and pharmacoeconomic assessments (PROs). Details will 
be provided in a separate user manual. See section 9.2.2 for further details on eDiary.
Exit Interview subset: at the Screening Visit, the patients undergoing the Visit 8 exit 
interviews must provide a signed subset-specific Informed Consent. Details will be provided 
in a separate exit interview guide. See section 9.5.1 for further details on exit interview.
Pre-screening
Each site must record in a pre-screening log which patients attended the Screening Visit.
Prior to the Baseline Visit, a study-specific Eligibility Form must be completed by the site and 
transmitted to the CRO for their review. A confirmation that the patient can continue further 
with the study procedures is required before randomization.
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.
Re-screening
Rescreening is only allowed for patients with a complete Screening Visit and who do not 
fulfil:
the required duration of a washout period for a medication that is disallowed prior to 
screening, or,
a stable usage period for a medication that is allowed with restrictions prior to screening. 
Rescreening may also be allowed for patients with a complete Screening Visit but are required 
to be in quarantine due to a positive COVID-19 test.
The patient must already have either started the washout prior to screening or be on the 
allowed dosage as part of their standard clinical care. Washout or change in dosage may not 
be done specifically for inclusion into this study. 


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Authorization for re-screening may only be granted by the sponsor’s medical expert (or the 
CRO’s medical monitor) after a thorough review of all data from the original Screening Visit.
At the new Screening Visit, the patient must sign a new Informed Consent Form.  At the new 
Screening Visit, the patient will be assigned a new screening number.  A re-screened patient 
must have a complete new Screening Visit, and all the eligibility criteria must be re-assessed 
at the new Screening Visit.
The following information will also be recorded in the eCRF at the new Screening Visit:
that the patient has previously been screened for the study
that re-screening has been authorized by the sponsor’s medical expert (or the CRO’s 
medical monitor)
the screening number that was assigned to the patient at the original Screening Visit
If a patient is re-screened, no data from the original Screening Visit will be used.
A patient may only be re-screened once.
Baseline Visit + IMP (Visit 2)
In exceptional cases, the screening period (visit interval between Screening and Baseline
Visits) may be extended with approval from the sponsor provided the Lundbeck medical 
expert accepts the rationale provided for the extension.
The Baseline Visit also includes IMP administration and will occur 28-30 days after the 
Screening Visit. Inclusion and exclusion criteria review must be done prior to dosing at the 
Baseline Visit.
For procedures preceding and following IMP administration, see section 8.5.
Primary Outcome + IMP (Visit 5)
The Primary Outcome Visit comprises assessments of the primary, secondary and exploratory 
endpoints. The Primary Outcome Visit also includes IMP administration. For procedures 
preceding and following IMP administration, see section 8.5.
IMP Visits (Visits 2, 5, 8, 11, 14, 17)
At the IMP Visits, the infusion is preceded by assessments of vital signs including body 
temperature, concomitant medications, AEs, physical examination, ECG, blood and urine 
sampling and C-SSRS administration.
Assessments involving interviews and scales must be administered before the infusion. PROs 
will be completed in the clinic the following order; HIT-6, PGIC, MBS, MSQ v2.1, EQ-5D-
5L, HCRU, WPAI. Alternatively, PROs which are scheduled in alignment with an IMP visit 
can be completed in the remote setting within 3 days prior to the scheduled clinic visit date.


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Patients must complete the daily eDiary entries prior to infusion. A compliance check of the 
eDiary will be conducted and the patient must be assisted with re-training if necessary. See 
section 9.2.2 for further details on eDiary.
Patients will be monitored for at least 1 hour following end-of-infusion and before being 
discharged from the clinic. Patients will be requested to stay longer should the investigator 
determine this is clinically warranted. After the infusion, the patients will be under 
observation, but not confined to bed, unless the investigator decides, based on the patient’s 
condition, that it is in the best interest of the patient to be confined to bed. Vital signs 
including body temperature, infusion related reactions (IRRs) and AEs will be checked after 
infusion and before the patient is discharged from the site. AEs should be collected prior to 
assessment of IRRs. 
Exit Interview subset: The exit interview will be conducted at Visit 8 (Week 24 Visit or at the 
Withdrawal Visit for patients who withdraw prior to Week 24). The exit interview must be 
conducted after all visit assessments are completed. A visit window of 2 weeks is allowed for 
the exit interview from the last assessment conducted for Visit 8/Withdrawal Visit (for
patients who withdraw prior to Week 24). See section 9.5.1 for further details on the exit 
interview.
Phone Contacts (Visits 3, 4, 6, 7, 9, 10, 12, 13, 15, 16, 18, 19)
The patient will be contacted via phone every 4 weeks between infusion visits for eDiary 
compliance check, to ensure that selected assessments have been completed and for collection 
of relevant information such as AEs and concomitant medication.
A compliance check of the eDiary will be conducted and the patient must be assisted with re-
training if necessary. See section 9.2.2 for further details on eDiary.
Additionally, the following PROs must be completed in the remote setting in alignment with 
the scheduled phone contacts (see Panel 2): PGIC (at Week 4 only), HIT-6, EQ-5D-5L, 
HCRU, WPAI. These can be completed on the day or within 3 days prior to the scheduled 
phone contact date.
Only site staff trained and listed in the delegation log will conduct phone contacts and hence 
be allowed to call the patient. Each phone contact must be documented in medical notes and 
used for source data verification when completing the eCRF and for subsequent monitoring.
Phone contacts should be planned to maintain the visit schedule relative to the Baseline Visit.
Completion Visit (Visit 20)
Patients who complete the study will attend a Completion Visit. As the visit will be scheduled 
12 weeks after the last dose of IMP, the Completion Visit will also serve as a Safety 
Follow-up Visit for all patients (section 8.10).


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At the Completion Visit, the patient must be assisted with the closeout of the eDiary.
Patients who test positive for ADA at the Completion Visit will be asked to provide up to two 
additional blood samples for immunogenicity testing at 12-week intervals for up to 24 weeks.
Unscheduled Visit
An unscheduled visit may occur throughout this study if needed. Unscheduled visits can be 
completed if required as either site or telephone visits. At these visits clinical safety laboratory 
tests, ECG, vital signs can be performed. In case of any additional tests performed not 
covered by the existing tests specified in the protocol and the eCRF, the results can be 
reported in connection with an AE reporting (see chapter 10) or documented in the medical 
notes as applicable.
Withdrawal Visit
Patients who withdraw from the study will be asked to attend a Withdrawal Visit, if at all 
possible.  The visit must be scheduled 12 for weeks after the last dose of IMP after 
withdrawal.  
As the Withdrawal Visit will be scheduled 12 weeks after the last dose of IMP, this visit will 
also serve as a Safety Follow-up Visit for all withdrawn patients (section 8.10). Patients who 
withdraw prior to Week 24 will undergo additional efficacy evaluations, thus for these 
patients the Withdrawal Visit will also serve as an Efficacy Follow-up Visit.
At the Withdrawal Visit, the patient must be assisted with the closeout of the eDiary.
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 10.5).
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 telephone conversation, the investigator will ask 
the patient if they will attend a Withdrawal Visit 12 weeks after their last dose.  If the 
patient:
agrees to attend a Withdrawal Visit, all the data collected up to and including that visit 
will be used
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


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Safety Follow-up at Completion or Withdrawal Visit
As the Completion or Withdrawal Visit will be scheduled 12 weeks after the last dose of IMP, 
these visits will also serve as Safety Follow-up Visits.
A safety follow-up is conducted to capture adverse events that occur after the last IMP or 
Phone Contact Visit (whichever is later) as well as to follow up on the outcome of adverse 
events ongoing at that visit at the Completion/Withdrawal Visit.
For adverse events that were ongoing at the last IMP or Phone Contact Visit and that resolved 
by the Completion/Withdrawal Visit, the stop date must be recorded. For non-serious adverse 
events still ongoing at the Completion/Withdrawal Visits, the Ongoing Adverse Event 
checkbox on the Adverse Event Form must be ticked.  SAEs must be followed until resolution 
or the outcome is known.
For patients with a clinically significant out-of-range clinical safety laboratory test value at 
the Completion or Withdrawal Visit or who withdrew due to an elevated AST or ALT value 
(see section 5.4), safety follow-up should be scheduled and recorded in the patients’ medical 
records and not in the eCRF; see section 10.5 for details.
The safety follow-up for patients who withdraw consent must be performed, if at all possible; 
any information collected will be recorded in the patients’ medical records.
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.
9
Assessments
Screening and Baseline Procedures and Assessments
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, race)
Prior migraine treatment history for review and documentation of previous treatment 
failure of different migraine preventive medications (see below for definition of previous 
treatment failure and chapter 12 for required documentation)
Other recent medication 


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Disease-specific history
Relevant history (medical, psychiatric, neurological)
Physical examination
Substance use
Height and weight without shoes
Signs and symptoms present at screening and/or baseline (before IMP intake)
Vital signs, ECGs   
C-SSRS
Blood and urine samples for screening (for example., β-HCG, FSH, HIV, HBsAg, anti-
HCV) and other clinical safety laboratory tests (as listed in Panel 5)
Definition of previous treatment failure of different migraine preventive medications.
(a) The patient has documented evidence of treatment failurein the past 10 years of 2-4
different migraine preventive medications out of the following:
propranolol/metoprolol 
topiramate 
amitriptyline 
flunarizine 
candesartan 
valproate/divalproex 
botulinum toxin A/B (if documented that botulinum toxin was taken for chronic 
migraine) 
AND

(b) The patient has failed two of the below of which at least one must be due to inadequate 
efficacy:
propranolol/metoprolol
topiramate 
amitriptyline
flunarizine
candesartan
See chapter 12 for acceptable documented evidence of previous treatment failures.

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 events) and/or contraindications (that is, 
ineligibility due to medical reasons). Treatment failure corresponds to the first documented failure 
for each medication.


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Diagnostic Assessments
IHS ICHD-3 guidelines1 sections 1.1, 1.2 and 1.3 for Migraine or Chronic Migraine are the 
diagnostic criteria to be used when assessing patient eligibility. 
Panel 4
IHS ICHD-3 guidelines1 for Migraine
1.1 Migraine without aura
A. At least five attacks fulfilling criteria B–D
B. Headache attacks lasting 4–72 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–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.
Classifications for Eligibility
Fulfilment of criteria for EM or CM according to the inclusion criteria in this protocol will be 
confirmed via prospectively collected information in the eDiary during the screening period.


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Definition of a Migraine Day: A migraine day is defined as a day with a headache that:

lasts ≥4 hours and meets ICHD-3 criteria C and D for migraine without aura (1.1),
OR

lasts ≥30 minutes and < 4 hours AND the patient took medication because he/she
believed that he/she had a migraine AND meets ICHD-3 criteria C and D for migraine 
without aura (1.1)
The characteristics of each headache, will be collected in the eDiary at the end of the 
headache, and for each headache it will be determined whether it qualifies as a migraine. If a 
headache qualifies as migraine, every day the headache lasted will count as a migraine day.
Headaches that were ongoing on the last day of the Screening Period will be classified as 
migraines for the eligibility calculation.
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 an eDiary Compliant Day: A compliant day is defined as any day where an 
evening diary is completed OR a headache diary is completed
Definitions for Baseline Disease Activity and Analysis
The following definitions will be applied for calculation of number of EM/CM patients (and 
low/high frequency EM patients) for subgroup analyses:
Definition of a Migraine Day: The definition is based on the IHS guidelines42 for controlled 
studies of preventive treatment of CM in adults.  A migraine day is defined as a day with a 
headache that:

lasts ≥4 hours and meets ICHD-3 criteria C and D for migraine without aura (1.1),

or lasts ≥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, C and D for migraine 
without aura (1.1) (probable migraine**),

or is a day where the patient took migraine medication because he/she believed that 
he/she had a migraine***
The characteristics of each headache, will be collected in the eDiary at the end of the 
headache, and for each headache it will be determined whether it qualifies as a migraine. If a 
headache qualifies as migraine, every day the headache lasted will count as a migraine day.
If a headache lasts ≥72 hours, the days will be counted as headache days or migraine days as 
aligned with the IHS guidelines.42


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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: “Have you experienced 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) . For criterion B in 1.1 Migraine without aura if a 
headache lasts more than 72 hours, the days will still be counted as headache/migraine days
as aligned with the IHS guidelines.42 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?” and “Did you take this 
medication because you believed that you were having a migraine?” Only if both are 
affirmed, 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 meets the definition of a migraine is also 
referred to as a migraine attack.
Definition of a Headache Episode: A headache that either lasts ≥30 minutes or meets the 
definition of a migraine, is also referred to as a headache episode.
Efficacy Assessments
The eDiary assessments will be completed by the patient in the remote setting on a daily 
basis. At each clinic visit and phone contact (that is every 4 weeks), a  compliance check of 
the eDiary will be conducted. On clinic visit days, patients must complete the daily eDiary 
entries prior to infusion. 
On clinic visit days, efficacy assessments include PROs (PGIC and MBS) and will be 
completed in the clinic along with the pharmacoeconomic PROs (see section 9.3). The PROs 
must be completed before the infusion and in the following order; HIT-6, PGIC, MBS, MSQ 
v2.1, EQ-5D-5L, HCRU, WPAI. Alternatively, PROs that are scheduled in alignment with a 
clinic visit can be completed in the remote setting within 3 days prior to the scheduled clinic 
visit date.
PGIC which is scheduled in alignment with a phone contact (at Week 4) 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.


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Use of COA Tools
The COA tools are PROs, and guidance will be given to the patients on how to complete 
them.
The COA tools will be administered in the local language. Only those provided by Lundbeck 
that have been validated in the language to which they have been translated will be used in 
this study.
The following COA tools will be used:
eDiary – to assess daily headache and migraine variables, that is the number of hours with 
headache, presence of associated symptoms, and use of acute migraine medications start and 
stop dates, 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
Detailed instructions on how to complete/administer the COA tools will be provided to the 
site in a PRO Guideline.
eDiary
The patient will be instructed to complete an electronic diary (eDiary) daily from the 
Screening Visit until the Completion/Withdrawal Visit. The eDiary consists of applications 
and reports which will be used to derive the migraine and headache endpoints. At the 
Screening Visit, the patient must be assisted with the provisioning and training of the eDiary. 
During the Completion/Withdrawal Visit, eDiary close out must be performed while the 
patient is on site. Details will be provided in a separate user manual.
At the Screening Visit, each patient will receive comprehensive training from site staff on the 
use of the eDiary. Site staff will also instruct patients on the requirement for timely and daily 
completion of the eDiary. The content of the headache diary is developed on key symptoms 
and characteristics as mentioned in the definition of migraine (see section 9.1.2). The day of 
eDiary distribution will start the 28-day eDiary Screening Period during which the patient will 
record daily information regarding headache characteristics, severity, length, and intake of 
headache/migraine medication. Headache and migraine items will be assessed with a yes/no 
response; and severity will be rated as mild, moderate or severe. An eDiary Eligibility Report
will be used to summarize baseline headache and migraine days and eDiary compliance
during the Screening Period. Any patient found to be ineligible for the study during the 
screening period or prior to randomization or dosing will not be randomized or dosed.
On each day during the study until the Completion/Withdrawal Visit, the patient will be asked 
to record diary data for the previous 24-hour period. For each day, the patient should record if 
they experienced any headache. For each experienced headache, the start and stop date and 
time will be collected. Information included in the definition of a migraine (for instance, 
headache severity, additional symptoms, and use of acute medication) will also be collected. 
Additional details regarding the questions that patients will answer can be found in the eDiary 


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User Manual. Headache and Compliance data from the eDiary will be made available during 
the study to site staff for review via the eDiary system portal. At least 85% compliance is 
needed during the screening period and throughout the study until the 
Completion/Withdrawal Visit. Site staff will counsel patients as needed on the importance of 
completing the eDiary daily. All follow-up with patients regarding eDiary compliance should 
be documented in the source records.
At the Completion/Withdrawal Visit, the patient must be assisted with the closeout of the 
eDiary.
Patient Global Impression of Change (PGIC)
The PGIC is a single patient-reported item reflecting the patient’s impression of change in 
their disease status since the start of the study (that is, in relation to activity limitations, 
symptoms, emotions, and overall quality of life). The item is rated on a 7-point scale (very 
much improved; much improved; minimally improved; no change; minimally worse; much 
worse; very much worse), where a high score indicates worsening. It takes approximate 1 
minute to complete the scale.
Most Bothersome Symptom (MBS)
The Investigator will verbally obtain the most bothersome symptom associated with the 
patient’s migraines during the Baseline Visit. Patients will be asked to rate the improvement 
in this symptom from baseline 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, other. It takes less than 5 minutes to 
complete the MBS.
External COA Monitoring Oversight
Lundbeck reserves the right to use external quality oversight methods to ensure eDiary 
compliance and PRO data quality, as well as ensure accurate administration of the COAs. For 
this study, the CRO will conduct the external data monitoring (to be agreed with the sponsor) 
which will include the following quality oversight methods:
Compliance check
Independent review of source documents 
Clinical data analytics review 
COA Tool Training 
COA training will be conducted by the CRO (as agreed with the sponsor). Site staff will
complete their designated training curriculum based on their initial qualification status and 
assigned role. The training program will also include general COA quality assurance and 
management guidance.


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The patients will be trained on how to use the PROs by site staff who have adequate 
experience with migraine and have received adequate training on good standards in providing 
guidance to patients on how to use the PROs. Any exceptions must be discussed and approved 
by Lundbeck and/or its designee.
Only site staff who have received adequate training on good standards in administering the 
HIT-6, PGIC, MBS, MSQ v2.1, EQ-5D-5L, HCRU, WPAI will be authorized to train the 
patients on completion of PROs in the study.  Documentation of training will be provided to 
site staff for archiving in the investigator trial master file (TMF). New PRO trainers joining 
the study must be trained similarly.
COA training will be conducted by the CRO.
Pharmacoeconomic Assessments
On clinic visit days, pharmacoeconomic assessments include PROs (HIT-6, MSQ v2.1, EQ-
5D-5L, HCRU, WPAI) and will be completed in the clinic along with the efficacy PROs (see 
section 9.2). The PROs must be completed before the infusion and in the following order; 
HIT-6, PGIC, MBS, MSQ v2.1, EQ-5D-5L, HCRU, WPAI. Alternatively, PROs that are 
scheduled in alignment with a clinic visit can be completed in the remote setting within 3 days 
prior to the scheduled clinic visit date. 
Additionally, HIT-6, EQ-5D-5L, HCRU, WPAI which are scheduled in alignment with phone 
contacts 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 (see Panel 2).
Clinical Outcome Assessments (COAs)
9.3.1.1
Use of COA Tools
Refer to section 9.2.1 for further information on use of COA tools. 
The following COA tools will be used:
HIT-6 - to assess the impact of an occurring headache and its effect on the ability to 
function normally in daily life 
MSQ v2.1 - to assess quality of life related to migraine 
EQ-5D-5L - to assess the overall state of health 
HCRU - to assess migraine-specific healthcare resource utilization 
WPAI - to assess overall effect of health on productivity at work and daily activities
9.3.1.2
Headache Impact Test (HIT-6)
The HIT-6 (v1.0)43 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 


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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-Specific Quality of Life Questionnaire, version 2.1 (MSQ v2.1)
The MSQ v2.144 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 5-10 minutes to complete the MSQ v2.1.
9.3.1.4
Euroqol 5 Dimension – 5 Levels (EQ-5D-5L)
The EQ-5D-5L45 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 visual analogue scale (VAS) of the overall health state. Each 
descriptive item is rated on a 5-point index ranging from 1 (no problems) to 5 (extreme 
problems) 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.
9.3.1.5
Health Care Resource Utilization (HCRU)
Migraine-specific healthcare 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 
trial.
9.3.1.6
Work Productivity and Activity Impairment: Migraine (WPAI:M)
The WPAI46 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: 4 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.


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9.3.1.7
External COA Monitoring Oversight
See section 9.2.5
9.3.1.8
COA Training
See section 9.2.6
Safety Assessments
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 clinical safety 
laboratory tests, vital signs, and ECGs, 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.
Clinical Safety Laboratory Tests
The clinical safety laboratory tests are listed in Panel 5.


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Panel 5
Clinical Safety Laboratory Tests
Haematology
Liverb
Serologyc
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]
S-HBsAg [HBSAG]
S-anti HCV [HCAG]
Infectionc
S-C-reactive protein [CRP]
Electrolytesb
Kidneyb
Urined
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]
Endocrine and Metabolicb
Lipidsb,e
Pregnancyf
S-albumin [ALB]
B-glucosee [GLUC]
B-HbA1c [HBA1C]
P-creatine phosphokinase [CK]
S-thyroid-stimulating hormonec [TSH]
S-follicle-stimulating hormoneg [FSH]
S-low density lipoprotein [LDL]
S-high density lipoprotein [HDL]
S-triglycerides [TRIG]
S-cholesterol (total) [CHOL]
S-human chorionic gonado-
tropin [HCG]
Urine (dipstick)
B = blood; P = plasma; S = serum; U = urine; [ ] = CDISC term
a
Count and % of total leucocytes.
b
Clinical chemistry.
c
Performed at the Screening Visit only. In case of abnormal TSH, reflex testing of T3 and T4 will be 
conducted. In case of positive or indeterminate results for serology, confirmatory testing will be performed 
including viral load.
d
In case of a positive urine dipstick, a microscopic evaluation will be done.
e
Fasting, when possible.
f
Only for women of childbearing potential. Pregnancy test at the Screening Visit to be performed using serum 
β-HCG. At all other visits, urine pregnancy testing will be performed and in case of a positive finding, 
confirmatory testing will be performed via serum β-HCG.
g
Only for women at the Screening Visit.
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.
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 


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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).  A patient 
with a value that is out-of-range at the Completion or Withdrawal Visit and considered 
clinically significant must be followed in accordance with usual clinical practice until the 
value normalizes or stabilizes or a diagnosis or reasonable explanation has been established.  
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.
Vital Signs
The investigator may appoint a designee (for example, nurse or paramedic) to measure vital 
signs including body temperature, provided this is permitted according to local regulations 
and provided the investigator has trained the designee how to measure these.  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. Pulse rate will be recorded before 
each blood pressure measurement.
Vital signs including body temperature must be assessed prior to blood sampling.
Any out-of-range values considered clinically significant by the investigator must be recorded 
as an adverse event on an Adverse Event Form.
Height and Weight 
The patient’s height 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.
Electrocardiograms (ECGs)
A standard 12-lead ECG will be recorded using digital ECG recording equipment provided to 
the investigator or, upon agreement, to an external cardiology centre.  The ECGs will be 
transferred digitally to a central ECG laboratory for evaluation.


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The investigator will be provided with the results and a cardiological interpretation of the 
ECG from the central ECG laboratory.
The results from the central ECG laboratory will include the RR, PR, QRS, QT, and QTc
intervals.
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.
Physical Examination
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 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 
physician assistant.  
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.
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.47 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 1year assessment) and the “Since last 
visit” version (for all subsequent visits). It takes approximately 5 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 clinician, such as a neurologist, 
geriatrician, psychiatrist, or (neuro-) psychologist involved in clinical practice or regularly 
evaluating patients. Any exceptions must be discussed and approved by Lundbeck and/or its 
designee. For each individual patient, the same certified rater should preferably rate the 
patient throughout the study. In case of unforeseen circumstances, certified back-up raters 
should be available throughout the study.


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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 trial 
master file (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.
Anti-Drug Antibody (ADA) including Neutralizing Antibody (NAb)
Assessments
Blood samples for the ADA including NAb assessments will be collected as outlined in 
Panel 2.
Patients who test positive for ADA at the Completion Visit will be asked to provide up to two 
additional blood samples for immunogenicity testing at 12-week intervals for up to 24 weeks.
Blood samples (2 mL per occasion) for ADA including NAb analysis will be collected in
silica clot activator tubes.  The blood sampling and handling procedures are described in the 
study-specific Laboratory Specification Manual.
The blood samples will be analysed by Charles River under the responsibility of Department 
of Bioanalysis, H. Lundbeck A/S, according to a protocol approved by Lundbeck before the 
serum samples are analysed.
Other Assessments
Exit Interview (subset)
At the Week 24 Visit/Withdrawal Visit (for patients who withdraw prior to Week 24), the site 
personnel should remind patients of the exit interview, which is to be conducted shortly after 
the last assessment of the Week 24 Visit and no later than 2 weeks after the Week 24 
Visit/Withdrawal Visit (for patients who withdraw prior to Week 24). The interviews will be 
conducted by an external designated qualitative study interviewer. The investigator will 
schedule the patient exit interview at the patient’s convenience. The patient exit interview will 
take up to 60 minutes in total and collect qualitative information on the patient’s experiences 
with migraine related to disease impact on daily activities, social and professional life. Exit 
interviews will help better understand experiences with disease, gain additional insight into 
trial data, support interpretation of quantitative assessments and endpoints to discuss 
meaningfulness of change. Additional aspects identified by a focused literature review and 
pilot exit interviews, may also be discussed to collect the patient´s treatment experience. 
Details will be provided in separate Exit Interview Guidelines. 


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The data will not be included in the CSR. The coding, analysis and reporting of exit interview 
data will be performed by the CRO based on a separate analysis plan.
Biobanking
General Considerations
This study includes collection of blood samples for long term storage and use in a possible 
future explorative biomarker research study, that may help to increase our understanding of 
the aetiology of psychiatric or neurological diseases, such as migraine and the molecular basis 
of the drug response.
Although the potential future exploratory biomarker analyses will help to increase our 
understanding of the aetiology of migraine and the molecular basis of the drug response, the 
efforts described in this protocol are strictly research based.  Therefore, as the complex 
interactions between genes, biomarkers and disease are currently not characterized to a level 
that translates to a meaningful clinical advantage, individual results from the exploratory 
biomarker analyses will as per usual not be given to either the study participants or the 
investigator.  For the same reasons, individual results will not be added to the patients’ 
medical records.
The patients will have no direct benefit from the exploratory biomarker analyses.
To ensure privacy protection, the blood samples for RNA gene expression profiling, 
proteomics/metabolomics analysis and future ADA assessments will be single-coded using 
the patient’s screening number. The blood samples for the pharmacogenetic biomarker 
analysis will be double-coded, that is one code key will be stored at the site and the other at 
Lundbeck.  To link a DNA sample to a specific subject, both code keys are needed.
The blood samples collected for the possible future exploratory biomarker analysis may be 
shared with academic and public institutions and other companies. However, Lundbeck will 
retain full control of the samples and their use in accordance with the information in the 
Patient Information Sheet and a Material Transfer Agreement. Furthermore, the results based 
on the analysis of the samples may be pooled across studies to increase the statistical power of 
the analyses.
Blood Sampling for Gene Expression Profiling
Blood samples for gene expression profiling will be collected in two PAXgene RNA tubes
(2.5 mL) in accordance with Panel 2. The maximum volume of blood to be collected during 
the study for this purpose will be 25 mL. 
Samples for gene expression profiling will be shipped to Lundbeck Biobank (at Brooks Life 
Sciences, Indianapolis, IN, USA) for storage. Sample preparation and analysis may be 
performed by CRO or by a bona fide research collaborator.


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Blood Sampling for Metabolomics and/or Proteomics
Blood samples for plasma separation and metabolomics and/or proteomics will be collected in 
one 10 mL K2 EDTA tube in accordance with Panel 2. The maximum volume of blood to be 
collected during the study for this purpose will be 50 mL. 
Samples for metabolomics and/or proteomics will be shipped to Lundbeck Biobank (at 
Brooks Life Sciences, Indianapolis, IN, USA) for storage. Sample preparation and analysis 
may be performed by CRO or by a bona fide research collaborator.
Blood Sampling for Pharmacogenetics
It is optional for the patient to donate a blood sample for exploratory pharmacogenetic 
analysis.
Blood samples for subsequent DNA extraction and aliquoting will be collected in 9 mL K3
EDTA tube in accordance with Panel 2. The maximum volume of blood to be collected 
during the study for this purpose will be 9 mL.
The extracted DNA aliquots will be shipped to Lundbeck Biobank (at Brooks Life Sciences, 
Indianapolis, IN, USA) for storage. Sample preparation and analysis may be performed by 
CRO or by a bona fide research collaborator.
The genetic variants to be analysed may include single nucleotide polymorphisms (SNPs) and 
copy number variations (CNVs). The analytical methods may be polymerase chain reaction 
(PCR), qPCR quantitative PCR), sequencing, or whole genome scans on microarrays.
Blood sampling for possible future anti-drug antibody assessments
Whole blood samples for serum separation and potential future anti-eptinezumab antibody 
analyses will be collected in 2 mL silica clot activator (SST) tube in accordance with Panel 2. 
The maximum volume of blood to be collected during the study for this purpose will be 4 mL.
The samples for future anti-drug antibody assessments will be shipped to Lundbeck Biobank 
(at Brooks Life Sciences, Indianapolis, IN, USA) for storage. Sample preparation and analysis 
may be performed by CRO or by a bona fide research collaborator. 
Order of Assessments
The assessments should preferably be administered in the following order:
No study related activities must be conducted until after the applicable Informed Consent 
Form is signed. 
Screening Visit:
Blood and urine sampling for clinical safety laboratory tests must be scheduled and 
results reviewed prior to the Baseline Visit.


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At the Screening Visit the “Baseline/Screening” version of the Columbia-Suicide 
Severity Rating Scale will be used. At each following visit, the “Since Last Visit” 
version of the C-SSRS will be used. 
Clinic Visits:
PROs must be completed at the patient’s convenience before or after blood and urine 
sampling.
On clinic visit days, patients must complete the daily eDiary entries prior to infusion.  
PROs completed in the clinic must be done before the infusion. HIT-6 should preferably 
be the first PRO completed, followed by the PGIC, MBS, MSQ v2.1, EQ-5D-5L, 
HCRU, WPAI. Alternatively, PROs that are scheduled in alignment with a clinic visit 
can be completed in the remote setting within 3 days prior to the scheduled clinic visit 
date. It is also 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. 
Infusion must be preceded by the assessment of vital signs including body temperature, 
concomitant medications, AEs, physical examination, ECG, blood sampling and urine 
sampling and C-SSRS administration. Vital signs must be assessed prior to blood 
sampling. 
Vital signs including body temperature, IRRs and AEs will be checked after infusion 
and before the patient is discharged from the site. IRRs must be assessed after the AE 
collection. For procedures preceding and following IMP administration, see section 8.5. 
Clinic Visits and Phone Contacts:
A compliance check of the eDiary must be conducted and the patient must be assisted 
with re-training if necessary. See section 9.2.2 for further details on the eDiary.
Phone Contacts: 
The patient will be contacted via phone every 4 weeks between infusion visits for 
eDiary compliance check, to ensure that selected assessments (PGIC (at Week 4 only), 
HIT-6, EQ-5D-5L, HCRU, WPAI) have been completed and for collection of relevant 
information such as AEs and concomitant medication.
Exit Interview subset: The exit interview will be conducted shortly (no later than 2 weeks)
after Visit 8 (Week 24 Visit or at the Withdrawal Visit for patients who withdraw prior to 
Week 24). The exit interview must be conducted after all visit assessments are completed. 
A visit window of 2 weeks is allowed for the exit interview from the last assessment 
conducted for Visit 8/Withdrawal Visit (for patients who withdraw prior to Week 24). See 
section 9.5.1 for further details on the exit interview.
Total Volume of Blood Drawn and Destruction of Biological Material
The total volume of blood drawn from each patient will be approximately 300 mL during the 
study.
Additional blood samples may be required if the original blood samples are not viable or if re-
testing is required.


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The biobank blood samples and any derived material for potential future exploratory gene 
expression profiling, metabolic or proteomic biomarker analyses or anti-drug antibody 
assessments will be destroyed ≤10 years after the end of the study (see definition in 
section 8.11).
The biobank blood samples and any derived material for potential future exploratory 
pharmacogenetic analyses will be destroyed ≤15 years after the end of the study (see 
definition in section 8.11).
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
Definitions
Adverse Event Definitions48
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 Lundbeck policy to collect and record all adverse events, including pre-treatment adverse 
events, that is, those that start after the patient has signed the Informed Consent Form and 
prior to the first dose of IMP.
Serious adverse event (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


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results in persistent or significant disability/incapacity
is a congenital anomaly/birth defect
is medically important (this refers to an event that may not be immediately life-threatening 
or result in death or hospitalization, but may jeopardize the patient or may require 
intervention to prevent any of the SAEs defined above)
Examples of medically important events are intensive treatment for allergic bronchospasm; 
blood dyscrasia or convulsions that do not result in hospitalization; or development of drug 
dependency or drug abuse.
Planned hospitalizations or surgical interventions for a condition that existed before the 
patient signed the Informed Consent Form and that did not change in intensity are not adverse 
events.  Emergency room visits that do not result in admission to the hospital are not 
necessarily SAEs; however, they must be evaluated to determine whether they meet any of the 
SAE definitions (for example, life-threatening or other serious [medically important] event).
Non-serious adverse event – is any adverse event that does not meet the definition of an SAE.
If there is any doubt as to whether an adverse event meets the definition of an SAE, a 
conservative viewpoint must be taken, and the adverse event must be reported as an SAE.
Suspected unexpected serious adverse reaction (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 Brochure29), and related to a medicinal product by either the 
investigator or Lundbeck.
Overdose – is a dose taken by a patient that exceeds the dose prescribed to that patient.  Any 
overdose (and associated symptoms) must, at a minimum, be recorded as a non-serious 
adverse event.
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
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 Lundbeck 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.


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The investigator must follow up on the outcome of the pregnancy and report it on a 
Pregnancy Form (paper).  The follow-up must include information on the neonate at least up 
until the age of 1 month.
Recording Adverse Events
Adverse events (including pre-treatment adverse events) 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 
AE 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 Lundbeck immediately (within 24 hours) after becoming aware of it (see section 10.4).
If individual adverse events are later linked to a specific diagnosis, the diagnosis should be 
reported and linked to the previously reported adverse events.
Reporting Serious Adverse Events (SAEs)
The investigator must report SAEs to Lundbeck 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
Lundbeck will assume responsibility for reporting SAEs to the authorities in accordance with 
local requirements.
It is the investigator’s responsibility to be familiar with local requirements regarding reporting 
SAEs to the EC or IRB and to act accordingly.
Lundbeck 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 Directive49 and in Norway, Liechtenstein, 


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and Iceland, that is, in the countries where unblinded expedited safety reporting is required, 
Lundbeck will also assume responsibility for reporting SUSARs to the ECs.
Lundbeck will assess the expectedness of SAEs and inform the investigator(s) about SUSARs 
in the blinded SUSAR listings.
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 
Completion/Withdrawal Visit, whichever comes first.  At the Completion/Withdrawal Visit, 
information on new AEs, if any, and stop dates for previously reported adverse events must 
be recorded.
The investigator must follow up on all SAEs until the patient has recovered, stabilized, or 
recovered with sequelae, and report to Lundbeck all relevant new information using the same 
procedures and timelines as those for the initial Serious Adverse Event Form.
SAEs that are spontaneously reported by a patient to the investigator after the 
Completion/Withdrawal Visit must be handled in the same manner as SAEs that occur during 
the study. These SAEs will be recorded in the Lundbeck safety database.
Patients with a clinically significant out-of-range clinical safety laboratory test value at the
Completion or Withdrawal Visit must be followed in accordance with usual clinical practice.  
If the clinically significant out-of-range clinical safety laboratory test value has not 
normalized or stabilized or a diagnosis or a reasonable explanation has not been established 
by the Safety Follow-up at the Completion/Withdrawal Visit, the investigator must decide 
whether further follow-up visits are required (this may include an additional medical 
examination and/or additional blood sampling).  If further follow-up visits are made, these 
must be documented in the patient’s medical records and not in the eCRF.
Patients who withdraw due to an elevated AST or ALT value (see section 5.4) must be 
followed until the values normalize or stabilize or a diagnosis or a reasonable explanation has 
been established.  Additional medical examinations (for example, ultrasound scanning and/or 
sampling for serology, conjugated bilirubin, prothrombin time) should be considered.  
A gastroenterology or hepatology consultation should also be considered.
Management of Reactions to Study Drug
There are no specific antidotes to eptinezumab. A medical emergency should be treated 
appropriately by the Investigator using proper standard of care and according to local
guidelines for that emergency condition. Emergency equipment and medication for the 
treatment of these potential adverse events must be available for immediate use.


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Should a medical condition arise that the investigator believes is related to the study drug, 
clinical judgment should be used to provide the 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 therapy instituted. Any events believed to be allergic reactions should be 
discussed with the medical monitor.
The site will have the possibility to collect, at the time of the event, additional blood 
specimens using the immune response lab kit, per the laboratory manual. This assessment 
includes serum histamine, serum tryptase, immunoglobulin E, and complement components. 
Data Monitoring Committee (DMC)
The DMC will consist of medical doctors with speciality relevant to the fields of neurology 
and cardiology, as well as a biostatistician. The DMC will monitor safety data on an ongoing 
basis in addition to cumulative safety data. The DMC will be informed to what extent the data 
and analyses provided to them have been quality controlled.  Members of the DMC will not 
be involved in other study-related tasks. The DMC procedures are described in the Data 
Monitoring Committee Charter.
11 Data Handling and Record Keeping
Data Collection
Electronic Case Report Forms (eCRFs)
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.


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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.
External Data
All electronic data will be transferred using a secure method accepted by Lundbeck.
The following electronic data will be transferred by the vendor and kept in a secure 
designated storage area outside the eCRF:
eDiary data
Exit Interview results
ECG results
Clinical Safety Laboratory data
Biobanking data: RNA, Metabolomics/Proteomics, ADA including NAb, DNA (optional)
Blood ADA including NAb data
In case of any electronic Assessment(s) COA(s)/PRO(s) the results will be transferred by 
designated vendor.
Retention of Study Documents at the Site
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.


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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.  Lundbeck will remind the investigator in writing 
of this obligation when the Clinical Study Report Synopsis is distributed to the site.
If off-site storage is used, a study-specific binder will remain at the site after the other study-
specific documents have been shipped for off-site storage.  This binder is considered part of 
the investigator TMF and must be kept in a secure place by the site for the required period of 
time.  The binder must contain, at a minimum, the following documents:  a copy of the
Investigator TMF Index, a certified copy of the Patient Identification Code List, and a 
Retrieval Form.
When the required storage period has expired, the documents may be destroyed in accordance 
with regulations.
12 Monitoring Procedures
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/designee 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/designee must obtain general medical history 
prior to the study and acceptable documented evidence of previous treatment failures <10 
years prior to the Screening Visit (see below).
Acceptable documented evidence of previous treatment failures.
Confirmation must be specific to each treatment failure. Treatment failure corresponds to the 
first documented failure for each medication:
Medical record with medication’s name, treatment duration, dose level and reasons for 
discontinuation, OR,
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 the treating physician in the patient’s medical notes, OR,
If the investigator is not the treating physician, the investigator can request a written note 
from the treating physician with the above information signed and dated by the treating 
physician.


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If none of the above can be obtained the patient is not eligible for the study.
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. If it is not possible to perform an on-site visit,
medical records may be remotely accessed by the CRA in accordance with local and national 
regulations.
13 Audits and Inspections
Authorized personnel from Medical, Regulatory and Clinical Quality Assurance, 
H. Lundbeck A/S, and quality assurance personnel from business partners may audit the study 
at any time to assess compliance with the protocol and the principles of Good Clinical 
Practice and all other relevant regulations.
The investigator must be aware that representatives from regulatory authorities may also wish 
to inspect source data, such as medical records.  The investigator must notify Lundbeck, 
without delay, of an announced inspection by a regulatory authority.
During audits and inspections, the investigator must permit direct access to all the source 
documents, including medical records and other documents pertinent to the study.
During audits and inspections, the auditors and inspectors may request relevant parts of 
medical records.  No personal identification apart from the screening 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
Lundbeck has a “no-waiver” policy, which means that permission will not be given to deviate 
from the protocol.
If a deviation occurs, the investigator must inform the CRA and they must review, discuss, 
and document the implications of the deviation.


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15 Study Termination
Lundbeck or a pertinent regulatory authority may terminate the study or part of the study at 
any time.  The reasons for such action may include, but are not limited to:
safety concerns
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 
who participated in the study.  If so, the actions needed to protect the patients must be 
described.
16 Statistical Methodology
Responsibilities
Biostatistics, H. Lundbeck A/S, will perform the statistical analyses for the clinical study 
report.
Analysis Sets
The following analysis sets will be used to analyse and present the data:
all-patients-randomized set (APRS) - all randomized patients
all-patients-treated (APTS) - all patients in the APRS who received at least one infusion of 
double-blind IMP 
full-analysis set (FAS) - all patients in the APTS who had a valid baseline assessment and 
at least one post-baseline 4-week assessment of MMDs in Weeks 1-12
all-patients-treated long-term set (APTS_LT) - all patients in the APRS who received at 
least one infusion of IMP and had a visit in the Extension Period
full-analysis long-term set (FAS_LT) - all patients in the APTS_LT who had a valid 
baseline assessment and a valid assessment of monthly migraine days in the Extension 
period 
The patients and data will be classified into the analysis sets according to these definitions at 
separate Classification Meetings:

For the reporting of the Placebo-controlled Period, the Classification Meeting will be held 
after the data base release for the reporting of the Placebo-controlled Period but before the 
blind has been broken and will concern the classification into APTS and FAS.


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
For the addendum to the CSR, the Classification Meeting will be held after the data base 
release for the reporting of the Extension Period and will concern the classification into 
APTS_LT and FAS_LT.
If not otherwise stated, TFLs in the Placebo-controlled Period will be summarized by 
randomized treatment group and TFLs in the Extension Period will be summarized by 
treatment group in the extension (eptinezumab 300 mg or 100 mg).
Efficacy analyses of the Placebo-controlled Period will be based on FAS, and efficacy 
analyses in the Extension Period will be based on FAS_LT.
Safety tables (including exposure and medications) will be based on APTS in the Placebo-
controlled Period and APTS_LT in the Extension Period.
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.
Unless otherwise specified, data listings for the Placebo-controlled Period will include site, 
treatment group, patient screening number, sex, age, race, and baseline weight. For the 
Extension Period, the listings will include both treatment group in the Placebo-controlled 
Period and treatment group in the Extension Period in addition to the variables included in 
listings for the Placebo-controlled Period.
Patient Disposition
Patient disposition will be summarized based on the APRS and will include the analysis sets 
defined. The number of completed or withdrawn patients within each all-patient-treated set
will also be included. 
The number of patients who withdrew from treatment will be summarized for the Placebo-
controlled Period and for the Extension Period by primary reason for withdrawal as well as by 
all reasons for withdrawal.
Demographics and Baseline Characteristics
Demographics (sex, age, and race), baseline characteristics (height, weight, and BMI), 
baseline efficacy variables, and other disease characteristics will be summarized based on the 
FAS.  


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Recent and Concomitant Medication
Recent and concomitant medication will be summarized by anatomical therapeutic chemical 
(ATC) code and generic drug name in the Placebo-controlled Period and the Extension 
Period.
Exposure 
Number of infusions in the Placebo-controlled Period (infusions at Visit 2 and visit 5), and 
number of infusions in the Extension Period (infusions at Visit 8, Visit 11, Visit 14, and 
Visit 17) will be summarized.
Efficacy Analyses
General Efficacy Analysis Methodology
All the statistical tests of the efficacy endpoints will be two-sided tests based on a 5% 
significance level and all confidence intervals (CIs) will be two-sided 95% CIs, unless 
otherwise specified.
Primary Analysis of the Primary Endpoint
The number of monthly migraine days (MMDs) Week 1-12 summarises diary data across 
Weeks 1 to 12. Details on derivation and imputations of days with missing or incomplete 
eDiary data will be described in the SAP. 
Changes from baseline in MMDs at the 6 first 4-week intervals will be analysed using a 
restricted maximum likelihood (REML)-based mixed model for repeated measures (MMRM) 
approach. The analysis will be performed using all available monthly change scores for the 
first 6 months in the study. The model will include the following fixed effects: month (Weeks 
1-4, Weeks 5-8, Weeks 9-12, Weeks 13-16, Weeks 17-20, and Weeks 21-24), country, 
stratification factor (MHDs at baseline: ≤14/>14) and treatment as factors, baseline MMDs as 
a continuous covariate, treatment-by-month interaction, baseline score-by-month interaction, 
and stratum-by-month interaction. An unstructured variance structure will be used to model 
the within-patient errors. The mean differences between each dose of eptinezumab and 
placebo will be estimated based on the least squares means for the treatment-by-visit 
interaction in the MMRM model. The primary comparisons will be the contrasts between 
each dose of eptinezumab and placebo averaged across Weeks 1-12.
Sensitivity Analyses of the Primary Endpoints
The impact of missing data in the derivation of the primary endpoint (days with missing or 
incomplete information in the eDiary) will be evaluated by applying different methods of 
imputation. Details will be specified in the SAP.


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Analysis of the Key Secondary Endpoints
For the key secondary endpoints based on response rates, treatment effects compared to 
placebo will be analysed using logistic regression. The model will include baseline MMDs 
as a continuous covariate, and treatment and stratification (MHDs at baseline: ≤14 />14) as 
factors. 
The change from baseline in HIT-6 score for the Placebo-controlled Period will be 
analysed using a mixed model repeated measures (MMRM) including baseline HIT score 
as covariate, treatment, country, stratification factor (MHDs at baseline: ≤14 />14), and 
week as fixed factors. In addition, the model will include treatment-by-week interaction, 
baseline HIT-6 score-by-week interaction, and stratum-by-week interaction. An 
unstructured covariance structure will be used to model the within-patient errors. The 
Kenward-Roger approximation will be used to estimate denominator degrees of freedom. 
Treatment effects will be calculated based on least squares means for the treatment-by-
week interaction estimated at Week 12.
Change from baseline in the number of MMDs (Weeks 13-24), will be analysed using the 
same MMRM methodology as for the primary endpoint. The comparisons will be the 
contrasts between each dose of eptinezumab and placebo averaged across Weeks 13-24.
Sensitivity Analyses of the Key Secondary Endpoints
Endpoints where data imputation is used, the impact of the imputations will be assessed in 
sensitivity analyses, applying different methods of imputation. Details will be specified in the 
SAP.
Testing Strategy
The testing strategy will be a sequence of tests, either testing one endpoint at a time or using 
Bonferroni-Holm to test a group of endpoints. Only if one step has shown a statistically 
significant effect will the formal testing continue with the next step, thus ensuring protection 
of the type 1 error. The steps are described below.
A significance level of 0.05 will be used. The significance level is denoted by α below.
Step1
Test the primary endpoint change from baseline in MMDs (Weeks 1-12) for the 300 mg dose 
compared to placebo on a significance level of α. Only if the p-value <α in favour of the 
300 mg dose is the effect considered statistically significant and the testing continues with the 
next step.
Step 2
Test the key secondary endpoint 50% responders for MMD (Weeks 1-12) for the 300 mg dose 
compared to placebo, using a significance level of α. Only if the p-value <α in favour of the 


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300 mg dose is the effect considered statistically significant and the testing continues with the 
next step.
Step 3
Test the primary endpoint change from baseline in MMDs (Weeks 1-12) for the 100 mg dose 
compared to placebo on a significance level of α. Only if the p-value <α in favour of the 100 
mg dose is the effect considered statistically significant and the testing continues with the next 
step.
Step 4
Test the key secondary endpoint 50% responders for MMD (Weeks 1-12) for the 100 mg dose 
compared to placebo, using a significance level of α. Only if the p-value <α in favour of the 
100 mg dose is the effect considered statistically significant and the testing continues with the 
next step.
Step 5
Uses Bonferroni-Holm to test the 3 key secondary endpoints: Change from baseline in MMDs 
(Weeks 13-24), 75% responders for MMD (Weeks 1-12), Change from baseline to Week 12 
in HIT-6. All comparisons are of the 300 mg dose compared to placebo. If the smallest of the 
3 p-values is <α /3 in favour of the 300 mg dose then the effect seen on this endpoint is 
considered statistically significant, and the testing continues. Next, if the second smallest 
p-value is <α/2 in favour of the 300 mg dose, then the effect seen on this endpoint is 
considered statistically significant, and the testing continues. If the largest p-value is <α in 
favour of the 300 mg dose then the effect seen on this endpoint is considered statistically 
significant, and the testing continues.
Step 6
Uses Bonferroni-Holm to test the 3 key secondary endpoints: Change from baseline in MMDs 
(Weeks 13-24), 75% responders for MMD (Weeks 1-12), Change from baseline to Week 12 
in HIT-6. All comparisons are of the 100 mg dose compared to placebo. If the smallest of the 
3 p-values is <α /3 in favour of the 100 mg dose, then the effect seen on this endpoint is 
considered statistically significant, and the testing continues. Next, if the second smallest 
p--value is <α/2 in favour of the 100 mg dose, then the effect seen on this endpoint is 
considered statistically significant, and the testing continues. If the largest p-value is <α in 
favour of the 100 mg dose then, the effect seen on this endpoint is considered statistically 
significant.
Analysis of the Secondary Endpoints
Analyses of continuous data based on diary data will use a similar model to the primary 
analysis, and continuous scale endpoints will be analysed by the same MMRM methodology 
as for HIT-6. Response variables will use similar analyses as the key secondary response 


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endpoints. The endpoints; patients with a migraine on the day after first dosing and 100% 
responders for MMDs and MHDs (Weeks 1-12) will be analysed using an extended Cochran-
Mantel-Haenszel (CMH) test, adjusting for the stratification factor (MHDs at 
baseline: ≤14 />14). 
Analysis of the Exploratory Endpoints
Analyses of continuous data based on diary data will use a similar model to the primary 
analysis, and continuous scale endpoints will be analysed by the same MMRM methodology 
as for HIT-6. Response variables will use similar analyses as the key secondary response 
endpoints.
Analysis of Subgroups
Details of subgroup analyses will be specified in the SAP.
Safety Analyses
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 and time of first infusion of IMP
treatment-emergent adverse event (TEAE) – an adverse event that starts or increases in 
intensity during or after administration of the first dose of IMP. Adverse events, sorted by 
system organ class (SOC) and preferred term, will be summarized.
Allocation of TEAEs to Study Periods
TEAEs will be allocated to study periods (these will be defined in the Statistical Analysis 
Plan).
Analysis of Other Safety Endpoints
The clinical safety laboratory test values, vital signs, and ECG parameter values will be 
summarized.  Potentially clinically significant (PCS) values will be flagged and summarized.
Non-suicidal self-injury behaviour (considered separately) and no suicidal ideation or 
behaviour or the worst suicidal ideation or behaviour will be summarised for the double-blind 
treatment Period and the extension Period.


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Sample Size and Power
The two prior eptinezumab Phase III studies, PROMISE-1 performed in an EM population 
and PROMISE-2 performed in a CM population, had the following effect sizes for the 
primary endpoint when compared to placebo (standard deviations):
EM: 100 mg 0.69 (3.1), 300 mg 1.11 (3.1)
CM: 100 mg 2.03 (5.8), 300 mg 2.60 (5.8)
The power was determined by simulating the testing strategy (10000 simulations) assuming 
normal distributions with similar mean and SD for continuous endpoints and similar success 
rates as the response variables in the Phase III studies for the corresponding population (EM 
or CM) without assuming the variables to be correlated. With 280 patients per treatment 
group, assuming that 40% of the patients will be from the EM population and 60% from the 
CM population, and that 2% of the patients do not have a post-baseline assessment of the 
primary endpoint, simulations show that the power for the test of the primary endpoint is 
approximately 94% for the comparison of 100 mg to placebo and 99% power for the 
comparison of 300 mg to placebo. The individual key secondary endpoints had a power of at 
least 68% for showing an effect, with a combined power of 58% for seeing an effect for all 
primary and key secondary endpoints and both doses in the testing strategy. 
Statistical Analysis Plan
A Statistical Analysis Plan describing the handling of data issues and the planned statistical 
analyses in more detail will be prepared by Biostatistics, H. Lundbeck A/S before the study is 
unblinded.
17 Clinical Study Report and Publications
Data Ownership
The data collected in this study are the property of Lundbeck.
Clinical Study Report
For data collected in the Placebo-controlled Period a Clinical Study Report will be prepared 
by Regulatory Medical Writing, H. Lundbeck A/S.  Upon completion of the study, an 
addendum to the Clinical Study Report, including the results from the Extension Period, will 
be produced.
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.


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Publications
The results of this study will be submitted for publication.
Lundbeck 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 
International Committee of Medical Journal Editors (ICMJE).50
18 Indemnity and Insurance
In the event of study-related injuries or deaths, insurance for the patients and indemnity of the 
investigators and those of their employees, servants, or agents whose participation in this 
study has been documented are provided.  Insurance and liability will be in accordance with 
applicable laws and Good Clinical Practice.
19 Finance
Site Agreements
The financial agreements with each site are addressed in one or more documents.  Both 
parties must sign the agreements before each site is initiated.
Financial Disclosure
All the investigators, including sub-investigators, and raters participating in the study must 
complete a Financial Disclosure Form.
Equipment
Equipment owned or rented by Lundbeck 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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tolerability of erenumab in patients with episodic migraine in whom two-to-four previous 
preventive treatments were unsuccessful: a randomised, double-blind, placebo-controlled, phase 
3b study. Lancet. 2018; 392: 2280–2287.
26. Ferrari MD, Diener HC, Ning X, Galic M, Cohen JM, Yang R, et al. Fremanezumab versus 
placebo for migraine prevention in patients with documented failure to up to four migraine 
preventive medication classes (FOCUS): a randomised, double-blind, placebo-controlled, phase 
3b trial. Lancet. 2019; 394: 1030–1040.
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double-blind, placebo-controlled study to evaluate the efficacy and safety of eptinezumab in 
frequent episodic migraine prevention: primary results of the PROMISE 1 (PRevention Of 
Migraine via Intravenous eptinezumab Safety and Efficacy 1) Trial. Cephalagia. 2017; 37: 337.
28. Kudrow D, Lipton R, Silberstein S, Cady R, Schaeffler B, Biondi D, et al. Eptinezumab for 
Prevention of Chronic Migraine: Results of 2 Infusions in the Phase 3 PROMISE-2 (Prevention 
of Migraine via Intravenous Eptinezumab Safety and Efficacy–2) Trial (P2.10-006). Neurology.
2019; 92(15 Suppl).
29. H. Lundbeck A/S. Investigator’s Brochure: eptinezumab, current edition.
30. Zeller J, Poulsen KT, Sutton JE, Abdiche YN, Collier S, Chopra R, et al. CGRP function-
blocking antibodies inhibit neurogenic vasodilatation without affecting heart rate or arterial blood 
pressure in the rat. Br J Pharmacol. 2008; 155(7): 1093-1103.
31. Lipton RB, Bigal ME. The epidemiology of migraine. Am J Med. 2005; 118 Suppl 1: 3S-10S.
32. Dodick DW, Goadsby PJ, Silberstein SD, Lipton RB, Olesen J, Ashina M, et al. Safety and 
efficacy of ALD403, an antibody to calcitonin gene-related peptide, for the prevention of frequent 
episodic migraine: a randomised, double-blind, placebo-controlled, exploratory phase 2 trial. 
Lancet Neurol. 2014; 13(11): 1100-1107.


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33. Dodick DW, Lipton RB, Silberstein S, Goadsby PJ, Biondi D, Hirman J, et al. Eptinezumab for 
prevention of chronic migraine: A randomized phase 2b clinical trial. Cephalalgia. 2019; 39(9):
1075–1085.
34. Spierings E, Biondi D, Hirman J, Horblyuk R, Cady R. Reduced impact of headaches after 
migraine preventive treatment with eptinezumab in patients with chronic migraine: Results from 
the PREVAIL open-label safety study. Presented at: 2019 American Headache Society Annual 
Meeting. July 11-14, 2019; Philadelphia, PA. Poster 16. 
35. Kudrow D, Berman G, Kassel E, et al. Eptinezumab treatment for migraine prevention reduces 
migraine disability in patients with chronic migraine: An analysis from the PREVIAL open-label 
safety study. Presented at: 2019 American Headache Society Annual Meeting. July 11-14, 2019; 
Philadelphia, PA. Poster 17.
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Good Clinical Practice. November 2016.
39. Puledda F, Messina R, and Goadsby PJ. An update on migraine: current understanding and future 
directions. J Neurol. 2017 Sep;264(9):2031-2039.
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perspective review. Ther Adv Drug Saf. 2016 Aug;7(4):147-158.
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Official Journal of the European Union L119, 4 May 2016.
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the International Headache. Society for controlled trials of preventive treatment of chronic 
migraine in adults. Cephalalgia. 2018; Vol. 38(5): 815–832. 
43. Kosinski M, Bayliss MS, Bjorner JB, Ware JE, Garber WH, Cady R, et al. A six-item short-form 
survey for measuring headache impact: the HIT-6. Qual Life Res. 2003; 12(8): 963–974.
44. Jhingran P, Osterhaus JT, Miller DW, Lee JT, Kirchdoerfer L. Development and validation of the 
Migraine-Specific Quality of Life Questionnaire. Headache. 1998; 38(4): 295–302.
45. Herdman M, Gudex C, Lloyd A, Janssen M, Kind P, Parkin D, et al. Development and 
preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). Quality of Life 
Research. 2011; 20: 1727–1736.
46. Reilly MC, Zbrozek AS, Dukes, EM. The validity and reproducibility of a work productivity and 
activity impairment instrument. Pharmacoeconomics. 1993; 4(5): 353–365.
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Suicide Severity Rating Scale: initial validity and internal consistency findings from three 
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49. European Parliament and Council of the European Union. Directive 2001/20/EC: Approximation 
of the laws, regulations and administrative provisions of the Member States relating to the 
implementation of Good Clinical Practice in the conduct of clinical trials on medicinal products 
for human use. 4 April 2001. Official Journal of the European Communities L 121, 1 May 2001.
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reporting, editing, and publication of scholarly work in medical journals. [Internet] 
icmje.org/icmje-recommendations.pdf. December 2017.


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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 
with an extension period to evaluate the efficacy and safety of eptinezumab for the 
prevention of migraine in patients with unsuccessful prior preventive treatments
Study No.:
18898A
Edition No.:
3.0
Date of edition:
30 November 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.
Authorization
I hereby confirm that I am of the opinion that the ethical and scientific basis of this study is sound.


H. Lundbeck A/S
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Study 18898A – Clinical Study Protocol
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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 anti-migraine agents. Other medication in 
the same class is allowed if prescribed for non-migraine indications.
Antihypertensives
See restrictions in use under anti-migraine 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.
Anti-inflammatory agents
Allowed if prescribed for non-migraine indications, for example, low 
dose NSAIDs (acetylsalicylic acid) for cardiovascular disease 
prevention.
Antimigraine agents
Acute treatment of migraine (prescription or over-the-counter 
medication recommended by a healthcare professional) is allowed 
provided the dose has been stable for at least 12 weeks prior to the 
Screening Visit.
Do not use preventive migraine treatments <1week prior to the 
Screening Visit and during the study. This includes daily use of:

beta-blockers: propranolol, metoprolol 

anticonvulsants: topiramate, valproate or divalproex

tricyclics: amytriptyline 

calcium channel blocker: flunarizine 

angiotensin II receptor antagonist: candesartan 

medication locally approved for prevention of migraine
Other medications in the same classes above but not included in this list 
are allowed.
Do not use oral anti-CGRPs for acute treatment <4 weeks prior to the 
Screening Visit and during the study.
Do not use eptinezumab or other monoclonal antibody targeting the 
CGRP pathway <24 weeks prior to the Screening Visit and during the 
study.
Patients who experienced failure on a previous treatment targeting the 
CGRP pathway are disallowed in the study.
Do not use CNS- and migraine-related devices (neuromodulation, 
neurostimulation) or injectable therapy (trigger point injections, 
extracranial nerve blocks, or facet joint injections) <8 weeks prior to the 
Screening Visit and during the study.
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 during the study.
Do not use monoamine oxidase inhibitors, ketamine, methysergide, 
methylergonovine, or nimesulide <12 weeks prior to the Screening Visit
and during the study.


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Drug Class
Details
Hormones
Hormonal therapy (for example, contraceptives, hormone replacement 
therapy) is allowed provided the dose has been stable for at least 12
weeks prior to the Screening Visit.
Other interventions and devices
See restrictions for CNS- and migraine-related devices under anti-
migraine agents.
Non-pharmacological interventions (including CBT) are allowed 
provided the use has been stable for at least 12 weeks prior to the 
Screening Visit.
Sedatives/hypnotics
Limited use of the following is allowed provided a stable regimen 
(<4 days per month) has been maintained for at least 12 weeks prior to 
the Screening visit. These agents may be prescribed when considered 
medically indicated by the investigator during the study (including the 
screening period) providing its use does not exceed 4 days per month:

barbiturates (including Fiorinal®, Fioricet®, or any other 
combination containing butalbital).

prescription opiates (including single-ingredient or combination 
medications containing opiates, opioids, tramadol, or tapentadol).
Vaccinations
COVID-19 vaccinations are allowed during the study with the following 
guidance:

COVID -19 vaccination should not be given within ±3 days of the 
IMP administration.

If the patient has recently received a COVID-19 vaccine, the 
investigator should judge if the patient can be administered the IMP 
infusion at the scheduled visit based upon the patient’s individual 
response to the COVID-19 vaccine.
Other vaccination are allowed.

SAP_001.pdf: 
H. Lundbeck A/S
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Study 18898A – Statistical Analysis Plan
Page 1 of 80
Statistical Analysis Plan
Interventional, randomized, double-blind, parallel-group, 
placebo-controlled study with an extension period to evaluate the 
efficacy and safety of eptinezumab for the prevention of migraine 
in patients with unsuccessful prior preventive treatments
Eptinezumab
Study No.:
18898A
Sponsor:
H. Lundbeck A/S (Lundbeck)
2500 Valby (Copenhagen), Denmark
SAP date (v.1.0):
8 March 2021
SAP date (v.2.0):
13 October 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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Study 18898A – Statistical Analysis Plan
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Table of Contents
List of Panels and Tables.......................................................................................................... 6
List of Abbreviations and Definitions of Terms....................................................................... 7
1
Objectives and Endpoints................................................................................................. 8
2
Study Design................................................................................................................... 10
2.1
Clinical Study Report............................................................................................ 12
3
COVID-19....................................................................................................................... 12
4
Definitions....................................................................................................................... 12
4.1
Definition of Periods............................................................................................. 12
4.2
Definition of Baseline ........................................................................................... 13
4.3
Definition of Withdrawal ...................................................................................... 13
4.4
Definition of Planned versus Actual Treatment...................................................... 13
4.5
Definition of Migraine and Headache Days ........................................................... 14
4.5.1
Migraine Day ......................................................................................... 15
4.5.2
Headache Day ........................................................................................ 15
5
Analysis Sets ................................................................................................................... 16
6
Descriptive Statistics....................................................................................................... 16
7
Patient Disposition.......................................................................................................... 17
7.1
Summary of Patient Disposition ............................................................................ 17
7.2
Withdrawals.......................................................................................................... 17
8
Demographics and Baseline Characteristics.................................................................. 18
9
Recent and Concomitant Medication............................................................................. 19
9.1
Documented Evidence of Treatment Failure.......................................................... 20
10
Exposure......................................................................................................................... 20
11
eDiary Compliance......................................................................................................... 20
12
Efficacy ........................................................................................................................... 21
12.1
General Efficacy Analysis Methodology ............................................................... 21
12.2
Testing Strategy .................................................................................................... 21
12.3
Analysis Methodology for the Primary Endpoint................................................... 23
12.3.1
Primary Estimand................................................................................... 23
12.3.2
Primary Analysis of the Primary Endpoint.............................................. 24
12.3.3
Strategies for Addressing Intercurrent Events in Primary Estimand......... 25
12.3.4
Rationale for Selected Analysis Method for the Primary Endpoint.......... 26
12.3.5
Sensitivity Analyses of the Primary Endpoint ......................................... 27
12.3.6
Supplementary Analyses of the Primary Endpoint .................................. 27
12.3.7
Covariate Investigation and Subgroup Analyses of the Primary Endpoint 27
12.4
Analysis Methodology for the Key Secondary Endpoints....................................... 28
12.4.1
Key Secondary Estimands...................................................................... 28
12.4.2
Analysis of the Key Secondary Endpoints............................................... 29
12.4.3
Rationale for Selected Analysis Method for the Key Secondary Endpoints
.............................................................................................................. 30


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12.4.4
Sensitivity Analyses of the Key Secondary Endpoints............................. 31
12.5
Analysis of the Secondary Endpoints..................................................................... 31
12.6
Analysis of the Exploratory Endpoints................................................................... 33
13
Safety .............................................................................................................................. 34
13.1
Adverse Events ..................................................................................................... 34
13.1.1
General Methodology for Adverse Events .............................................. 34
13.1.2
Coding of Adverse Events...................................................................... 34
13.1.3
Classification of Adverse Events ............................................................ 34
13.1.4
Allocation of TEAEs to Treatment Periods............................................. 35
13.1.5
Presentation of Adverse Events .............................................................. 35
13.1.6
Presentation of Treatment-emergent Adverse Events .............................. 35
13.1.7
Presentation of Deaths............................................................................ 36
13.1.8
Presentation of Serious Adverse Events.................................................. 36
13.1.9
Presentation of Adverse Events Leading to Withdrawal.......................... 36
13.1.10
Presentation of Adverse Events Leading to Study Drug Infusion 
Interruption ............................................................................................ 37
13.1.11
Presentation of Adverse Events of Special Interest.................................. 37
13.2
General Methodology for Other Safety Data.......................................................... 37
13.3
Clinical Safety Laboratory Test Data..................................................................... 38
13.3.1
Data Presentation ................................................................................... 38
13.3.2
Anti-Drug Antibody (ADA) including Neutralizing Antibody (NAb) 
assessments............................................................................................ 39
13.3.3
Potential Drug-induced Liver Injury (DILI)............................................ 39
13.4
Vital Signs and Weight.......................................................................................... 40
13.5
ECGs .................................................................................................................... 40
13.6
Other Safety Endpoints ......................................................................................... 41
13.6.1
Columbia-Suicide Severity Rating Scale (C-SSRS) Scores ..................... 41
14
Blinded Data Reviews..................................................................................................... 42
15
Interim Analyses............................................................................................................. 42
16
Sample Size Considerations ........................................................................................... 42
17
Statistical Software......................................................................................................... 43
18
Changes to Analyses Specified in the Protocol .............................................................. 43
19
Details on Data Handling ............................................................................................... 44
19.1
Derived Variables ................................................................................................. 44
19.1.1
eDiary .................................................................................................... 44
19.1.1.1
Monthly Migraine Days (MMDs)/Monthly Headache Days 
(MHDs).................................................................................. 44
19.1.1.2
Migraine/Headache Responder Rates...................................... 46
19.1.1.3
Percentage of Patients with Migraines..................................... 47
19.1.1.4
Migraines/Headaches With Severe Pain Intensity and Headache 
Episodes/Migraine Attacks ..................................................... 47
19.1.1.5
Monthly Days with Acute Migraine Medication Usage and 
MMDs/MHDs with Acute Medication Usage.......................... 48
19.1.2
Patient Global Impression of Change (PGIC).......................................... 49
19.1.3
Most Bothersome Symptom (MBS)........................................................ 49
19.1.4
Headache Impact Test (HIT-6) ............................................................... 49


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19.1.5
Migraine-Specific Quality of Life Questionnaire Version 2.1 (MSQ v2.1)
.............................................................................................................. 49
19.1.6
Euroqol 5 Dimension – 5 Levels (EQ-5D-5L)......................................... 51
19.1.7
Health Care Resource Utilization (HCRU).............................................. 51
19.1.8
Work Productivity and Activity Impairment: Migraine (WPAI:M) ......... 51
19.2
Assigning Data to Visits........................................................................................ 52
19.2.1
Clinical Outcome Assessments (COAs) - Scales..................................... 52
19.2.2
Safety Variables ..................................................................................... 52
19.3
Handling Missing or Incomplete Dates/Times ....................................................... 55
19.3.1
Missing Headache End Date and Time ................................................... 55
19.3.2
Withdrawal Date .................................................................................... 55
19.3.3
Medical Disorder Start and Stop Dates ................................................... 55
19.3.4
Medication Start and Stop Dates............................................................. 55
19.3.5
Adverse Event Start and Stop Dates........................................................ 56
19.4
Data with Multiple Records................................................................................... 57
19.4.1
Dose Changes in Medication .................................................................. 57
19.4.2
Changes in Intensity or Seriousness of Adverse Events........................... 57
References ............................................................................................................................... 59


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Appendices
Appendix I
Statistical Analysis Plan Authentication and Authorization ............................ 60
Appendix II
Study Procedures and Assessments................................................................ 62
Appendix III
PDS Migraine Event Definition ..................................................................... 68
Appendix IV
SAS® Code.................................................................................................... 70
Appendix V
PCS Criteria .................................................................................................. 74
Appendix VI
Adverse Events of Special Interest................................................................. 78


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List of Panels and Tables
Panel 1
Objectives and Endpoints........................................................................................8
Panel 2
Study Design.........................................................................................................11
Panel 3
Testing Strategy ....................................................................................................23
Panel 4
C-SSRS Scores .....................................................................................................41
Panel 5
Overview of Imputation Rules for 4-Week Periods for eDiary Data.......................45
Panel 6
MSQ v.2.1 Domains..............................................................................................50
Panel 7
MSQ v.2.1 Item Values.........................................................................................50
Panel 8
Derivation of MSQ v.2.1 Domain Scores...............................................................50
Panel 9
Derivation of WPAI:M sub-scores.........................................................................52
Panel 10
Visit Windows for Placebo-Controlled Period – Laboratory tests, ECG.................53
Panel 11
Visit Windows for Extension Period – Laboratory tests, ECG................................53
Panel 12
Visit Windows for Placebo-Controlled Period – Vital Signs ..................................54
Panel 13
Visit Windows for Extension Period – Vital Signs.................................................54
Table 1
Study Procedures and Assessments........................................................................63
Table 2
PDS Migraine Event Definition.............................................................................69
Table 3
PCS Criteria for Clinical Safety Laboratory Tests..................................................75
Table 4
PCS Criteria for Vital Signs, Weight/BMI, and Waist Circumference....................77
Table 5
PCS Criteria for ECG Parameters..........................................................................77
Table 6
Adverse Events of Special Interest ........................................................................79


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List of Abbreviations and Definitions of Terms
ANCOVA
analysis of covariance
APRS
all-patients-randomized set
APTS
all-patients-treated set
APTS_LT
all-patients-treated-long-term set
CI
confidence interval
CM
chronic migraine
CMH
Cochran-Mantel-Haenszel
DILI
drug-induced liver injury
DMC
Data Monitoring Committee
EM
episodic migraine
EQ-5D-5L
Euroqol 5 Dimensions
FAS
full-analysis set
FAS_LT
full-analysis-long-term set
HCRU
health care resource utilization
HIT-6
headache impact test
IMP
investigational medicinal product
MAR
missing at random
MBS
most bothersome symptom
MedDRA
Medical Dictionary for Regulatory Activities 
MHDs
monthly headache days
ML
maximum likelihood
MMDs
monthly migraine days
MMRM
mixed model for repeated measurements
MNAR
missing not at random
MOH
medication overuse headache
MSQ v2.1
Migraine-Specific Quality of Life Questionnaire Version 2.1
PCS
potentially clinically significant
REML
restricted maximum likelihood
SAE
serious adverse event
SAS®
statistical software package from the SAS® Institute
SD
standard deviation
SE
standard error 
SOC
system organ class
TEAE
treatment-emergent adverse event
WPAI:M
Work Productivity and Activity Impairment: Migraine


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1
Objectives and Endpoints
The study objectives and endpoints are summarized in Panel 1.
Panel 1
Objectives and Endpoints
Objectives
Endpoints
Primary Objective

To evaluate the efficacy of 
eptinezumab for the 
prevention of migraine in 
patients with unsuccessful 
prior preventive treatments
Primary endpoint:
- Change from baseline in the number of monthly migraine days 
(Weeks 1-12)
Key secondary endpoints:
- Response: patients with 50% reduction from baseline in monthly 
migraine days (Weeks 1-12)
- Response: patients with 75% reduction from baseline in monthly 
migraine days (Weeks 1-12) 
- Change from baseline in the number of monthly migraine days 
(Weeks 13-24)
Secondary endpoints:
- Response: patients with 50% reduction from baseline in monthly 
migraine days (Weeks 13-24)
- Response: patients with 75% reduction from baseline in monthly 
migraine days (Weeks 13-24)
- Response: patients with 100% reduction from baseline in monthly 
migraine days (Weeks 1-12) 
- Response: patients with 50% reduction from baseline in monthly 
headache days (Weeks 1-12)
- Response: patients with 75% reduction from baseline in monthly 
headache days (Weeks 1-12)
- Response: patients with 100% reduction from baseline in monthly 
headache days (Weeks 1-12)
- Change from baseline in the number of monthly headache days 
(Weeks 1-12)
- Change from baseline in percentage of migraines/headaches with 
severe pain intensity (Weeks 1- 12)
- Change from baseline in the number of monthly days with use of 
acute migraine medication (Weeks 1-12)
- Change from baseline in the number of monthly days with use of 
acute migraine medication (Weeks 13-24)
- Change from baseline in the number of monthly migraine days with 
use of acute medication (Weeks 1- 12)
- Change from baseline in number of monthly migraine days with use 
of acute medication (Weeks 13-24)
- Patient Global Impression of Change (PGIC) score at Week 12
- PGIC score at Week 24
- Change from baseline in the number of monthly migraine days in 
patients with Medication Overuse Headache (MOH) (Weeks 1-12)
- Patients with a migraine on the day after first dosing
- Most Bothersome Symptom (MBS) score at Week 12, as measured 
relative to Baseline


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Study 18898A – Statistical Analysis Plan
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Objectives
Endpoints
Exploratory endpoints:
- Change from baseline in the number of monthly headache episodes
for each 12-week period
- Change from baseline in the number of monthly migraine attacks for 
each 12-week period
Secondary Objectives
To evaluate the health-related 
quality of life and work 
productivity impact of 
eptinezumab 
To evaluate the effect of long-
term treatment with eptinezumab
Key secondary endpoints:
- Change from baseline to Week 12 in the Headache Impact Test (HIT-
6) score
Secondary endpoints:
- Change from baseline to Week 24 in the HIT-6 score
- Change from baseline to Week 12 in the Migraine-Specific Quality 
of Life (MSQ v2.1) sub-scores (Role Function-Restrictive, Role 
Function-Preventive, Emotional Function)
- Change from baseline to Week 12 in the Health-Related Quality of 
Life (EQ-5D-5L) Visual Analogue Scale (VAS) score
- Health Care Resources Utilization (HCRU) at Week 12 
- 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
- HCRU at Week 24 
- Change from baseline to Week 12 in the Work Productivity and 
Activity Impairment questionnaire (WPAI) sub-scores (Absenteeism, 
Presenteeism, Work productivity loss, Activity impairment)
- Change from baseline to Week 24 in the WPAI sub-scores
- Response: Patients with a 5-point reduction from baseline to Week 
12 in HIT-6 score
- Response: Patients with a 5-point reduction from baseline to Week 
24 in HIT-6 score
Secondary endpoints:
- Change from baseline in the number of monthly migraine days 
(Weeks 25-36, 37-48, 49-60, 61-72)
- Response: patients with 50% reduction from baseline in monthly 
migraine days (Weeks 25-36, 37-48, 49-60, 61-72)
- Response: patients with 75% reduction from baseline in monthly 
migraine days (Weeks 25-36, 37-48, 49-60, 61-72)
- Change from baseline in the HIT-6 score (at Weeks 36, 48, 60, and 
72)
Exploratory endpoints:
- Response: patients with 100% reduction from baseline in monthly 
migraine days
- Response: patients with 50% reduction from baseline in monthly 
headache days
- Response: patients with 75% reduction from baseline in monthly 
headache days 
- Response: patients with 100% reduction from baseline in monthly 
headache days
- Change from baseline in percentage of migraines/headaches with 
severe pain intensity


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Objectives
Endpoints
- Change from baseline in the number of monthly days with use of 
acute migraine medication 
- Change from baseline in the number of monthly migraine days with 
use of acute migraine medication
- PGIC score 
- Change from baseline in the number of monthly migraine days in 
patients with MOH 
- MBS score 
- Change from baseline in monthly number of Migraine attacks for 
each 12-week period 
- Change from baseline in monthly number of Headache episodes for 
each 12-week period 
- Change from baseline in the MSQ v2.1 sub-scores 
- Change from baseline in the EQ-5D-5L VAS score 
- HCRU 
- Change from baseline in the WPAI sub-scores
Safety Objective
To evaluate the safety and 
tolerability of eptinezumab
To evaluate the long-term safety 
and tolerability of eptinezumab
Safety Endpoints
- Adverse events
- Absolute values and changes from baseline in clinical safety 
laboratory test values, vital signs, weight, and ECG parameter values
- Potentially clinically significant clinical safety laboratory test values, 
vital signs, weight changes, and ECG parameter values
- Development of specific anti-eptinezumab antibodies (ADA) 
including neutralizing antibodies (NAbs)
- Columbia-Suicide Severity Rating Scale (C-SSRS) score
2
Study Design
This is an interventional, multi-national, multi-site, randomized, double-blind, placebo-
controlled Phase IIIb study designed to demonstrate efficacy and safety of eptinezumab for 
migraine prevention in patients with unsuccessful prior preventive treatments. The placebo-
controlled period will be followed by an extension period where all patients will receive 
active treatment to assess the long-term safety, tolerability and effect of eptinezumab.
The target population for this study is defined as patients with chronic migraine (CM) or 
episodic migraine (EM), as outlined in the IHS ICHD-3 guidelines1 with documented 
evidence of migraine occurring on ≥4 days per month prior to screening as confirmed via 
prospectively collected information in the eDiary during the Screening Period, and with 
documented evidence of failure to 2-4 different preventive migraine medications in the past 
10 years. The aim is that approximately 40% of the randomized patients are patients with EM.
It is planned that 840 patients will be randomly allocated to one of three treatment groups: 
eptinezumab 300 mg, eptinezumab 100 mg, or placebo, in a ratio of 1:1:1.
Randomization will be stratified by country and monthly headache days (MHDs) at baseline 
(≤14 MHDs/ >14 MHDs). 


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The patient will receive IMP starting from the Baseline Visit to follow a dosing schedule with 
IV infusions every 12 weeks with either eptinezumab or placebo over 30 minutes (+15). 
At Visit 8 patients will enter the Extension Period. Patients who were assigned to placebo in 
the Placebo-controlled Period will be randomly allocated to one of two treatment groups: 
eptinezumab 300 mg or eptinezumab 100 mg with a ratio of 1:1. Patients assigned to 
eptinezumab 300 mg or eptinezumab 100 mg in the Placebo-controlled Period will continue 
on their original assignments. 
An overview of the study is presented in Panel 2 and the scheduled study procedures and 
assessments are summarized in Appendix II. See also the Clinical Study Protocol for further 
details on the study design.
Panel 2
Study Design
For patients who withdraw, except for those who withdraw their consent, a Withdrawal Visit 
will be scheduled 12 weeks after the last dose of IMP. The withdrawal visit will include 
Safety Follow-up evaluations and will therefore also serve as a Safety Follow-up Visit. 
For patients who withdraw prior to Week 24 the Withdrawal Visit will allow for eDiary
closeout and for a final assessment of scales not based on the eDiary. Patients are expected to 
complete their eDiary until this Withdrawal Visit unless the patient withdraws consent. 


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2.1
Clinical Study Report
The data collected in the Placebo-controlled Period will be used for generating the output to 
be included in the Clinical Study Report (CSR). Upon completion of the study, an addendum 
to the Clinical Study Report, including the results from the Extension Period, will be 
produced.
This means that all tables, listings, and figures that are related to the Extension Period or
cover the full study period will be prepared after the Clinical Study Report for the study is 
final. This Statistical Analysis Plan describes both the output that will be prepared for the 
Clinical Study Report and for the addendum.
Throughout this document, the term CSR will be used to refer to the Clinical Study Report
including the output from the Placebo-controlled Period and the term addendum to CSR will 
be used to refer to the addendum that includes the results from the Extension Period.
3
COVID-19
For this study, all patients are considered to have been enrolled after the beginning of the 
COVID-19 outbreak.
The following information is collected with regards to COVID-19:
Whether a visit was done remotely due to COVID-19 including which assessments 
were/were not performed
If a visit was not done, whether it was not done due to COVID-19
Whether patients withdrew due to the COVID-19 situation
Whether patients got diagnosed with COVID-19
Specific output addressing the impact of COVID-19 for this trial is specified in Sections 7.1
and 7.2.
4
Definitions
4.1
Definition of Periods
The study consists of the following periods:
Screening Period (28-30 days): Starts at the Screening Visit and continues up to start of 
Visit 2 IMP infusion
Placebo-Controlled Period: Starts at start of Visit 2 IMP infusion and continues up to start 
of Visit 8 IMP infusion
Extension Period: Starts at start of Visit 8 IMP infusion and continues up to and including 
Visit 20  


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4.2
Definition of Baseline
For migraine and headache endpoints, the baseline value will be based upon the data recorded 
in the headache eDiary during the first 28 days following screening. 
For other endpoints, the baseline assessment will be the latest available valid measurement 
taken prior to the administration of IMP.
4.3
Definition of Withdrawal
The group of patients who withdrew in the Placebo-controlled Period before receiving any 
IMP in the Extension period will be described as withdrawn in the Placebo-controlled Period.
The complementary group will be described as completed in the Placebo-controlled Period.
Similarly, for the Extension Period the group of patients who withdrew after receiving IMP in 
the Extension Period will be described as withdrawn in the Extension Period and the 
complementary group will be described as completed in the Extension Period. 
4.4
Definition of Planned versus Actual Treatment
Every 12 weeks, patients will receive either eptinezumab 300 mg, eptinezumab 100 mg, or 
placebo in the Placebo-controlled Period and either eptinezumab 300 mg or eptinezumab 100 
mg in the Extension Period.
Planned treatment is defined as the treatment a patient was randomized to. 
Actual treatment is defined as the treatment a patient actually received during the study. If a 
patient received a different dose than what was planned at a given visit, the actual treatment in 
the relevant Period will equal the highest dose received. The actual treatment group will be 
determined separately for the Placebo-controlled Period and the Extension Period. 
The term treatment sequence will be used to denote the treatment groups arising by 
combining the treatments received in the Placebo-controlled Period and the treatments 
received in the Extension Period, i.e. if all patients receive their treatment as planned the 4 
groups are: Placebo-eptinezumab 100 mg, placebo-eptinezumab 300 mg, eptinezumab 100 
mg-eptinezumab 100 mg, and eptinezumab 300 mg-eptinezumab 300 mg.
For reporting purposes, the following will be summarized by planned treatment:
Efficacy
Demographics and baseline characteristics
Disposition
eDiary compliance
Concomitant medication


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And the following will be summarized by actual treatment:
Adverse events
Exposure
Disposition
Laboratory parameters, vital signs, ECG, and C-SSRS
Unless otherwise specified, data listings will display actual treatment. 
4.5
Definition of Migraine and Headache Days
For the purpose of endpoint derivations, the following definitions of migraine and headache 
days will be used. The definition of a migraine day reflects the strategy chosen to handle the 
intercurrent event of using acute migraine medication in the primary estimand, as outlined in 
Sections 12.3.1 and 12.3.3.
In this document, the term headache will encompass both headaches and migraine headaches.
Migraine headaches (henceforth simply referred to as “migraines”) are a subgroup of 
headaches with characteristics outlined below (Section 4.5.1). Using this definition, we have 
that all migraines are headaches but not all headaches are migraines. 
Headaches will be self-reported by the patient using an electronic headache diary (eDiary). 
The eDiary is split into two parts, the headache diary and the evening diary. The headache 
diary is the part of the eDiary where the start and stop date and times of experienced
headaches are recorded along with headache characteristics used for classifying headaches as 
migraines, and the evening diary is the part of the eDiary that patients are expected to 
complete each day during the study regardless of whether or not they experienced a headache 
on that day.
Randomization is stratified by Monthly Headache Days (MHDs) at baseline (≤14 MHDs/ >14 
MHDs). The stratum is based on a calculation performed directly in the eDiary at Baseline. 
The eDiary uses an algorithm described in the Project Design Specification (PDS), a 
document providing the technical specifications for the set-up of the eDiary, for determining 
whether a day in the screening period classifies as a day with a headache or a day with a 
migraine. Patients are deemed eligible if, according to this algorithm, they fall into the criteria 
for CM or EM as defined in inclusion criterion 10 in the Clinical Study Protocol (ed. 1.0 and 
2.0), i.e:
For patients with CM: Migraine occurring on ≥8 days and headache occurring on >14 
days.
For patients with EM: Migraine occurring on ≥4 days and headache occurring on ≤14 
days
In this document, whenever stratum or stratification factor is mentioned, the reference is to 
this classification into EM and CM that was used for randomization.
The PDS definition of a migraine day can be seen in Appendix III.  


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4.5.1
Migraine Day
A migraine day is defined as any day with a headache that meets criteria A, B, C or D listed 
below:
A. All of the following criteria:
1.
Lasted 4 hours or more
2.
Had at least 2 of the following:
a. Unilateral location
b. Pulsating quality
c. Moderate or severe pain intensity
d. Aggravation by or causing avoidance of routine physical activity
3.
Had at least 1 of the following:
a. Nausea
b. Vomiting
c. Photophobia and phonophobia
B. A headache that lasted 30 minutes or more and patient had an aura with the headache
C. A headache that lasted 30 minutes or more and met 2 of the 3 following criteria:
1.
Lasted 4 hours or more
2.
Had at least 2 of the following:
a.
Unilateral location
b. Pulsating quality
c.
Moderate or severe pain intensity
d. Aggravation by or causing avoidance of routine physical activity
3.
Had at least 1 of the following:
a.
Nausea
b. Vomiting
c.
Photophobia and phonophobia
D. Patient took medication to treat the headache because they believed they were having a
migraine
4.5.2
Headache Day
A headache day is defined as any day with a headache that meets one of the following criteria:
Lasted 30 minutes or more
Meets the criteria for being a migraine, i.e. fulfils either criteria A, B, C or D above (see 
Section 4.5.1)


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5
Analysis Sets
The following analysis sets will be used to analyse and present the data:
all-patients-randomized set (APRS) – all randomized patients
all-patients-treated set (APTS) – all patients in the APRS who received at least one 
infusion of the double-blind IMP
full-analysis set (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
all-patients-treated-long-term set (APTS_LT) – all patients in the APRS who received at 
least one infusion of IMP and had a visit in the Extension Period
full-analysis-long-term set (FAS_LT) – all patients in the APTS_LT who had a valid 
baseline assessment and a valid assessment of monthly migraine days in the Extension 
Period
The patients and data will be classified into the analysis sets according to these definitions at 
separate Classification Meetings:
For the reporting of the Placebo-controlled Period, the Classification meeting will be held 
after the data base release for the reporting of the Placebo-controlled Period but before the 
blind has been broken and will concern the classification into APTS and FAS. 
For the addendum to CSR, the Classification meeting will be held after the data base 
release for the reporting of the Extension Period and will concern the classification into 
APTS_LT and FAS_LT.
Efficacy analyses of the Placebo-controlled Period will be based on FAS, and efficacy 
analyses in the Extension Period will be based on FAS_LT.
Safety tables (including exposure and concomitant medications) will be based on APTS in the 
Placebo-controlled Period and APTS_LT in the Extension Period.
6
Descriptive Statistics
Unless otherwise specified, summary statistics (n, arithmetic mean, standard deviation [SD], 
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.
Unless otherwise specified, data listings for the Placebo-controlled Period will include site, 
treatment group, patient screening number, sex, age, race, and baseline weight. For the 
Extension Period, the listings will include both treatment group in the Placebo-controlled 
Period and treatment group in the Extension Period in addition to the variables included in 
listings for the Placebo-controlled Period. 


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7
Patient Disposition
7.1
Summary of Patient Disposition
Patient disposition will be summarized separately for the Placebo-controlled Period and the 
Extension Period and will present patient disposition overall and by treatment group. If 
needed, further tables summarizing disposition by country or site and treatment group can be 
added.
The summaries for the Placebo-controlled Period will include the number of patients included 
in APRS, APTS, and FAS, and the number of patients within APTS, who completed or 
withdrew, as well as the number of screened patients and number of screening failures.
The summaries for the Extension Period will include the number of patients included in 
APTS_LT and FAS_LT and the number of patients within APTS_LT, who completed or 
withdrew.
To assess the potential impact of COVID-19 on the visit structure, a table will be provided by 
type of visit (on site or remote) and treatment group separately for each period, for the visits 
that are changed from on site to remote. The summary will be based on APTS for the 
Placebo-controlled Period and on APTS_LT for the Extension Period.
7.2
Withdrawals
For each period, the number of patients who withdrew from treatment, which also implies that 
they withdrew from the study, will be summarized by treatment group, and primary reason for 
withdrawal, and by treatment group and all reasons for withdrawal.
Patients who withdrew will be listed for each period. The listings will include the number of 
days in the study until withdrawal, the date of first IMP infusion, the date of the latest IMP 
infusion prior to withdrawal, the number of days since latest IMP infusion, the primary reason 
for withdrawal, all reasons for withdrawal, specification of ‘Other’ reason, and a flag if the 
drug code was broken. For the listing for the Extension Period both date of first IMP in the 
Placebo-controlled Period and date of first IMP in the Extension Period will be included. 
If needed, a listing of patients who withdrew due to COVID-19 situation (as the primary 
reason) will be provided for each period as well as a listing of patients withdrawing due to 
falling ill of COVID-19 (as the primary reason). The latter is defined as patients withdrawing 
due to an adverse event, which is then specified to be COVID-19.
If relevant, Kaplan-Meier failure plots of time to withdrawal in each period will be presented 
by treatment group. The time will be calculated from the date of first dose of IMP in the 
period to the date of completion or withdrawal. Patients who completed the period will be 
regarded as censored. For the Extension Period, the plot will be by treatment sequence group.


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All tables, graphs, and listings will be based on the APTS for the Placebo-controlled Period 
and on APTS_LT for the Extension Period.
8
Demographics and Baseline Characteristics
Demographics (sex, age, age group, race, ethnicity, region, country); baseline characteristics 
(height, weight, and BMI); baseline disease characteristics; and baseline efficacy variables 
will be summarized for the Placebo-controlled Period by treatment group.
The disease characteristics comprise of age and age group (≤ 21 years, > 21 years) at first 
diagnosis of migraine, duration and duration group (≤ 15 years, > 15 years) of first migraine 
diagnosis at baseline, whether the current diagnosis is a CM or EM diagnosis, duration of 
current CM/EM diagnosis, whether the patient suffers from fully reversible aura symptoms
and if yes, which aura symptoms, whether the patient experiences aura symptoms without 
headache and if yes, which aura symptoms, whether the patient has an MOH diagnosis, for 
women whether migraines started before or after menarche and for men whether migraines 
started before or after puberty, and whether the start of migraine was related to any event. 
The baseline efficacy variables that will be summarized will be split into eDiary reported 
baseline migraine characteristics and other efficacy variables. 
The eDiary reported baseline migraine characteristics that will be summarized are the number
of baseline MMDs, number of baseline MHDs, number of monthly migraine attacks and 
headache episodes at baseline, percentage of headaches and migraines with severe pain
intensity, baseline average length of migraine attacks and headache episodes, number of 
baseline MMDs with use of acute medication, and number of monthly days with use of acute 
medication, which are all collected during the screening period. The number of patients in 
each stratum based on the definition in Appendix III will also be included, as well as the 
number of EM/CM patients and low/high frequency EM patients (see Section 12.3.7) based 
on baseline MMDs and MHDs derived according to the definitions in Section 4.5 and the 
descriptions in Section 19.1.1.1.
The other baseline efficacy variables that will be summarized are HIT-6 total score – both 
summarized as a continuous variable and as a categorical displaying the percentage and 
counts of the life impact categories (see Section 19.1.4) – MSQ v2.1 sub-scores, EQ-5D-5L 
VAS score, WPAI sub-scores, and counts and percentages of MBS symptom chosen at 
screening. 
Concurrent as well as relevant past medical, neurological, and psychiatric disorders will be 
coded using the Medical Dictionary for Regulatory Activities (MedDRA , Version 23.0 or 
later) and summarized by treatment group. Social history will be summarized by treatment 
group.
A concurrent medical, neurological, or psychiatric disorder is a disorder that is ongoing at the 
Screening Visit. A past medical, neurological, or psychiatric disorder is a disorder that ended 
prior to the Screening Visit.


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Demographics, baseline characteristics and baseline efficacy variables will be summarized 
based on the FAS.
9
Recent and Concomitant Medication
Recent and concomitant medication will be coded using the WHO Drug Dictionary
(WHO-DDE).
Medications will be classified according to the start and stop dates and summarized by 
anatomical therapeutic chemical (ATC) code level 4, generic drug name, treatment group, and 
period. Handling of missing or incomplete dates is specified in Section 19.3.4.
The following categories will be used:
Prior: Medications with a stop date before first IMP infusion.
Concomitant Placebo-controlled Period: Medications with a start date at or after the date of 
first IMP infusion and prior to the date of V8 IMP infusion, medications with a stop date at 
or after the date of first IMP infusion that also have a start date prior to the date of V8 IMP 
infusion, and medications where both start and stop date are completely missing. Ongoing 
medications with a start date prior to the date of V8 IMP infusion are also included, as well 
as medications with a start date prior to the date of V8 IMP infusion with a completely 
missing stop date.  
Concomitant Extension Period: Medications with a start or stop date at or after the date of 
V8 IMP infusion and medications where both start and stop date are completely missing. 
Ongoing medications are also included, as well as medications with a completely missing 
stop date.
The tables for the Placebo-controlled Period will be based on the APTS and the tables for the 
Extension Period will be based on APTS_LT.
The summaries will be repeated for prophylactic and acute migraine medications, which will 
be identified via a clinical review of the coded medication data.
All disallowed medications will be listed for the Placebo-controlled Period based on the 
APRS. The listing will include the generic drug name, the duration, the start and end dates, 
and dosing information. 
A similar listing will be provided for the patients taking disallowed concomitant medications 
in the Extension Period based on the APTS_LT for inclusion in the addendum to CSR.
The eDiary reported medications will be handled separately. In the evening eDiary, patients 
are asked each day to fill out whether they used any of the following medications during that 
day: Ergotamine, triptan, analgesic, opioid, or combination analgesic. The number of patients 
taking each of the medication types will be presented for each 4-week interval in the study by 
treatment group, separately for the Placebo-controlled Period and the Extension Period.


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9.1
Documented Evidence of Treatment Failure
Summaries of prior preventive treatment failure medications will be presented for the 
Placebo-controlled Period by treatment group. The number and percentage of patients, who 
experienced each type of treatment failure (lack of efficacy, safety/tolerability, or 
contraindication) will also be presented by treatment group, as well as the number of prior 
preventive treatment failures. 
The number and percentage of patients fulfilling criteria for inclusion into AMNOG 
subpopulation B (defined October 2020), henceforth referred to as subpopulation B, will be 
summarized.
Patients fulfilling criteria for subpopulation B will be defined as patients who have at least 2 
documented treatment failures due to inadequate efficacy or poor tolerability of either:
metoprolol or propranolol
flunarizine
topiramate
amitriptyline
The summaries will be based on the APTS.
10 Exposure
For each period, the total number of infusions received and total number of infusions 
completed as planned will be summarized by treatment group. 
Furthermore, for each infusion visit, the number of infusions received, completed as planned, 
temporarily interrupted, and lasted longer than 30(+15) minutes, as well as descriptive 
statistics for the duration of infusions and duration of temporary interruptions will be 
summarized by treatment group.
Patients, who at any point during the study received a different dose than what was planned, 
will be listed for each period. The listing will include all infusion visits for the period, dates of 
infusion visits, planned dose for the patient and actual dose received for the patient. 
In addition, all infusion data will be listed for each period separately.
For the Placebo-controlled Period, the tables and listings will be made based on APTS and for 
the Extension Period, the tables and listings will be made based on APTS_LT. For the 
Extension Period, the summaries will be by treatment sequence group.
11 eDiary Compliance
For each period, the rate of days where the eDiary has been missed within each 4-week 
interval will be summarized and presented by 4-week interval and treatment group.


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Furthermore, the number of patients missing 7 days or more and 14 days or more in a 28-day 
period will be presented by 4-week interval and treatment group, separately for each period.
A day where the eDiary has been missed is defined as a day where the subject did not fill out 
anything in the evening eDiary and did not have a headache reported in the headache eDiary. 
The summaries will be based on the APTS for the Placebo-controlled Period and on the 
APTS_LT for the Extension Period.
12 Efficacy
12.1
General Efficacy Analysis Methodology
Unless otherwise specified, all the efficacy analyses for the Placebo-controlled Period will be 
based on the FAS and all the efficacy analyses for the Extension Period will be based on the 
FAS_LT.
All the tables and graphs will be presented by treatment group for the Placebo-controlled 
Period and both by treatment group and treatment sequence group for the Extension Period.
All the p-values will be based on two-sided tests; the confidence intervals (CIs) will be two-
sided; and the endpoints not included in the testing strategy will be presented with nominal p-
values and 95% CIs. 
12.2
Testing Strategy
The testing strategy will be a sequence of tests, either testing one endpoint at a time or using
Bonferroni-Holm to test a group of endpoints. Only if one step has shown a statistically
significant effect will the formal testing continue with the next step, thus ensuring protection
of the type 1 error. The steps are described below. A graphical representation of the testing 
strategy can be found in Panel 3.
A significance level of 0.05 will be used. The significance level is denoted by α below.
Step 1
Test the primary endpoint change from baseline in MMDs (Weeks 1-12) for the 300 mg dose
compared to placebo on a significance level of α. Only if the p-value <α in favour of the 300
mg dose is the effect considered statistically significant and the testing continues with the next
step.
Step 2
Test the key secondary endpoint 50% responders for MMD (Weeks 1-12) for the 300 mg dose
compared to placebo, using a significance level of α. Only if the p-value <α in favour of the
300 mg dose is the effect considered statistically significant and the testing continues with the
next step.


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Step 3
Test the primary endpoint change from baseline in MMDs (Weeks 1-12) for the 100 mg dose
compared to placebo on a significance level of α. Only if the p-value <α in favour of the 100
mg dose is the effect considered statistically significant and the testing continues with the next
step.
Step 4
Test the key secondary endpoint 50% responders for MMD (Weeks 1-12) for the 100 mg dose
compared to placebo, using a significance level of α. Only if the p-value <α in favour of the
100 mg dose is the effect considered statistically significant and the testing continues with the
next step.
Step 5
Uses Bonferroni-Holm to test the 3 key secondary endpoints: Change from baseline in MMDs
(Weeks 13-24), 75% responders for MMD (Weeks 1-12), Change from baseline to Week 12
in HIT-6. All comparisons are of the 300 mg dose compared to placebo. If the smallest of the
3 p-values is <α /3 in favour of the 300 mg dose then the effect seen on this endpoint is
considered statistically significant, and the testing continues. Next, if the second smallest p-
value is <α/2 in favour of the 300 mg dose, then the effect seen on this endpoint is considered 
statistically significant, and the testing continues. If the largest p-value is <α in favour of the 
300 mg dose then the effect seen on this endpoint is considered statistically significant, and 
the testing continues.
Step 6
Uses Bonferroni-Holm to test the 3 key secondary endpoints: Change from baseline in MMDs
(Weeks 13-24), 75% responders for MMD (Weeks 1-12), Change from baseline to Week 12
in HIT-6. All comparisons are of the 100 mg dose compared to placebo. If the smallest of the
3 p-values is <α /3 in favour of the 100 mg dose, then the effect seen on this endpoint is
considered statistically significant, and the testing continues. Next, if the second smallest p-
value is <α/2 in favour of the 100 mg dose, then the effect seen on this endpoint is considered 
statistically significant, and the testing continues. If the largest p-value is <α in favour of the 
100 mg dose then, the effect seen on this endpoint is considered statistically significant.


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Panel 3
Testing Strategy
12.3
Analysis Methodology for the Primary Endpoint
12.3.1
Primary Estimand
A summary of the intercurrent events that will be addressed and the estimand attributes can be 
found below. Further details on the intercurrent events and the strategies used to address them 
are given in Section 12.3.3. 
The primary estimand will be the effect of eptinezumab on number of monthly migraine days
that would be seen in the hypothetical case where no acute medication was available, if 
patients withdrawing due to lack of efficacy remained on their current trajectory, if patients
withdrawing due to adverse events at an early stage were considered as obtaining only limited 
improvement to their baseline disease level, and if the effect was considered regardless of use 
of preventive medication and infusion interruptions or terminations.
Intercurrent events that will be addressed:
Use of acute medication to treat a headache
Use of preventive migraine medication
Withdrawal due to lack of efficacy
Withdrawal due to adverse event
Withdrawal due to other reasons
Interruption/termination of infusions
Attributes of the primary estimand:
The treatment condition of interest is eptinezumab (both 300 mg and 100 mg) compared 
to placebo


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The population is all patients that fulfil the inclusion and none of the exclusion criteria for 
the study
The endpoint to be considered is the change from baseline in MMDs across weeks 1-12
The population-level summary is the least squares mean difference between eptinezumab 
and placebo for the endpoint
12.3.2
Primary Analysis of the Primary Endpoint
Changes from Baseline in MMDs at the 6 first 4-week intervals will be analysed using a 
restricted maximum likelihood (REML)-based mixed model for repeated measures (MMRM) 
approach. The analysis will be performed using all available monthly scores for the first 6
months in the study derived as specified in Section 19.1.1. Below, the term “month” refers to 
4-week periods.
The model will include the following fixed effects: month (Weeks 1-4, Weeks 5-8, Weeks 9-
12, Weeks 13-16, Weeks 17-20, and Weeks 21-24), country, stratification factor (MHDs at 
baseline: ≤14/>14) and treatment as factors, baseline MMDs as a continuous covariate, 
treatment-by-month interaction, baseline score-by-month interaction, and stratum-by-month
interaction. An unstructured variance structure will be used to model the within-patient errors. 
If, unexpectedly, this analysis fails to converge, the following variance structures will be tried 
out, in the following order: first-order ante-dependence, heterogenous compound symmetry, 
compound symmetry, and the first to converge will be applied. The Kenward-Roger 
approximation will be used to estimate denominator degrees of freedom. The SAS® code for 
the primary analysis is shown in Appendix IV.
The mean differences between each dose of eptinezumab and placebo will be estimated based 
on the least squares means for the treatment-by-month interaction in the MMRM model. The 
estimates will be presented with p-values and 95% CIs. The primary comparisons will be the 
contrasts between each dose of eptinezumab and placebo averaged across Weeks 1-12. These 
averaged contrasts are obtained by weighting together the first 3 monthly least squares mean 
estimates for each dose. More specifically, they are computed via the matrix product: , 
where L is the 18×p coefficient matrix used for computing the least squares mean estimates 
for the treatment-by-month interaction effects,  is the p×1 vector of parameter estimates, and 
k is a 1×18 vector of coefficients, which for the comparison between eptinezumab 100 mg and 
placebo is defined as: 
 = 	1
3, 1
3 , 1
3 , 0, −1
3 , −1
3 , −1
3 , 0,
and for the comparison between eptinezumab 300 mg and placebo is defined as:
 = 	 0, 1
3 , 1
3 , 1
3 , 0, −1
3 , −1
3 , −1
3 , 0,
where 0x is used to represent a vector consisting of x 0’es, and it is assumed that the ordering 
of the levels of the treatment factor is: 100 mg, 300 mg, placebo and the ordering of the levels 


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of the month factor is: Weeks 1-4, Weeks 5-8, Weeks 9-12, Weeks 13-16, Weeks 17-20, and
Weeks 21-24.
The primary comparisons will be part of the testing strategy described in section 12.2.
12.3.3
Strategies for Addressing Intercurrent Events in Primary Estimand
Use of acute medication to treat a headache
When patients complete a headache in the headache eDiary they are asked whether they took 
any medications to treat the headache. In case of an affirmative answer, they are asked the 
question “Did you take this medication because you believed that you were having a 
migraine?”. In a hypothetical scenario where medication is not available, it is hypothesised 
that patients that answer this question with a “Yes” would have experienced a migraine.
Thereby, a hypothetical strategy is used to address the intercurrent event of use of acute 
medication by counting a day where patients took medication because they believed they were 
experiencing a migraine as a migraine day, using the definition given in Section 4.5.1. 
Use of preventive migraine medication
Initiating a new preventive migraine treatment and concomitant use of preventive migraine 
treatment at study entry is generally disallowed in the study, see the Clinical Study Protocol, 
Appendix II.
A treatment policy strategy is used to address the intercurrent event of use of preventive 
migraine medication by using the data collected regardless of whether or not the patient uses
preventive migraine treatment. 
Withdrawal due to lack of efficacy
It is hypothesised that patients withdrawing due to lack of efficacy will remain on their 
current level of MMDs after withdrawing at least until 12 weeks after their first dose. 
Therefore, the intercurrent event of experiencing lack of efficacy resulting in a patient 
withdrawing, will be addressed using a hypothetical strategy. In the hypothetical world where 
patients would not drop out due to lack of efficacy, it is hypothesised that the patients would
continue on their current unsatisfactory symptom level, so imputation of missing data in this 
situation aim to ensure that the current symptom level is used for the analysis even if very 
little data is available. See details of the implementation in the rules for handling missing data 
described in Section 19.1.1.
Withdrawal due to adverse event
It is hypothesised that patients withdrawing very early in the study (during the first 4 weeks 
after first IMP infusion) due to adverse events have not been successfully treated. Therefore, 
in a situation where a patient withdraws during the first 4 weeks after first IMP infusion and 
the amount of data collected through the eDiary is not sufficient to derive a monthly score
using the general derivation rules, the missing data is penalized to reflect that the symptom 
level will be close to the expected higher level of MMDs that was experienced at Baseline. 


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Patients withdrawing due to adverse events later in the study are hypothesised to behave 
similarly to the study population as a whole.
Details of the imputations used can be seen in the rules for handling missing data described in 
Section 19.1.1.
Withdrawal due to other reasons
Withdrawals due to other reasons than lack of efficacy or adverse events will be handled with
a treatment policy strategy using the data collected regardless of the intercurrent event and 
using the imputation rules specified in Section 19.1.1.
Interruption/termination of infusions
If interruption or termination of infusion leads to withdrawal, it is handled according to the 
rules above.
Temporary interruption of infusion is not expected to impact the efficacy data. Premature 
termination of infusion (that is, only receiving a partial infusion) could impact the efficacy. 
However, it is expected that the implications of a partial infusion will be reflected in the 
collected eDiary data.
Hence, the intercurrent events of temporary infusion interruptions, premature terminations of 
infusions, and complete termination of infusions not leading to withdrawal will be addressed 
using a treatment policy strategy by using the data collected regardless of these intercurrent 
events.
12.3.4
Rationale for Selected Analysis Method for the Primary Endpoint
The MMDs are considered continuous data, and they are analysed using methods based on 
observations following a normal distribution. Given the repeated observation of normally 
distributed data, an MMRM analysis using all available data has been chosen for the primary 
analysis. Covariates are included in the model based on an approach including key factors 
representing study design features (month, treatment, MHD stratum, country), and baseline 
MMD score to account for differences in baseline MMDs and its predictive ability. When the 
MMRM analysis includes the individual factors mentioned as well as interaction of month
and treatment, month and baseline score, and month and stratum, and applies an unstructured 
covariance, as described in Section 12.3.1, it allows for flexibility in modelling the 
development over time and similarly provides robust estimation, even under some deviation 
from the assumption of normality.
The use of MMRM combined with the rules for handling missing data in this set-up allows 
for inclusion of the majority of the patients, even if they only have limited data observed.


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12.3.5
Sensitivity Analyses of the Primary Endpoint
Imputations for Withdrawals Due to Adverse Event or Lack of Efficacy
To explore the assumptions related to how patients withdrawing due to adverse events or lack 
of efficacy are behaving, an analysis similar to the primary analysis will be conducted, where 
monthly values for all patients are calculated using the prorating imputation rule described in 
Section 19.1.1.1 without penalization for early withdrawal due to adverse events or lack of 
efficacy as was done for the primary estimand. This means that the number of MMDs for all
patients will be calculated according to rows 1-3 in Panel 5, even if patients are withdrawing 
due to lack of efficacy or adverse events.
Imputation for Weeks 1-4
To explore the robustness of the results to missing eDiary data in the first 4 weeks after 
infusion, an analysis similar to the primary analysis will be conducted, where monthly values 
in the first 4 weeks after first infusion are calculated using the weighting rule described in 
Section 19.1.1.1 if patients have less than 14 days with eDiary reporting in this period. This 
means that baseline values will be used in the calculation of Weeks 1-4 values for patients 
with less than 14 days of eDiary data in the 4 weeks after first infusion. 
12.3.6
Supplementary Analyses of the Primary Endpoint
To provide additional insight into the understanding of the treatment effect, a supplementary 
analysis for the primary estimand will be conducted. 
The supplementary analysis will be a repetition of the primary analysis for the change from 
baseline in number of MMDs but without differentiating between headaches where patients 
took medication to treat their headache and headaches where patients took medication to treat 
their headache because they believed they were having a migraine. This means that a day will 
be counted as a migraine day by changing criterion D in Section 4.5.1 to:
Patient took medication to treat the headache.
12.3.7
Covariate Investigation and Subgroup Analyses of the Primary Endpoint
Subgroup analyses will be performed, where relevant, using the model specified in 
Section 12.3.2 on the set of patients included in the subgroup. For EM/CM and low/high 
frequency EM and CM (see below), the terms with stratum will be excluded from the model.
The subgroups that will be investigated are
Sex
Race: White and other
EM (MMDs ≥ 4, MHDs ≤ 14) and CM (MMDs ≥ 8, MHDs >14) (based on baseline 
MMDs and MHDs derived according to the definitions in Section 4.5 and the descriptions 
in Section 19.1.1.1)
Age group: ≤35 years and >35 years


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Medication overuse headache diagnosis
Number of failed previous treatments (2 and > 2)
Low frequency EM (4 ≤MMDs < 8), high frequency EM (8 ≤ MMDs ≤ 14), and CM
(MMDs ≥ 8) based on baseline MMDs and MHDs derived according to the definitions in 
Section 4.5 and the descriptions in Section 19.1.1.1.
The assumption of equal treatment effect across subgroups will be investigated on an 
exploratory basis for all subgroups listed above by adding the three-way interaction term 
subgroup-by-treatment-by-week to the model. A test for whether the 3-way interaction term 
and the 2-way interaction (subgroup-by-treatment) term can be removed from the model will 
be performed by comparing the model without both the 3-way interaction term and the 
subgroup-by-treatment 2-way interaction term to the model with the 3-way interaction term. 
This will be done by fitting both models using (maximum likelihood) ML and making a
likelihood ratio test comparing -2*log(Q) to the asymptotic Χ2 distribution, where Q is the 
quotient of the maximised likelihood functions. The p-value for this test will be reported.
12.4
Analysis Methodology for the Key Secondary Endpoints
12.4.1
Key Secondary Estimands
The key secondary endpoints 50% response (Weeks 1-12), 75% response (Weeks 1-12), and 
change from baseline in MMDs (Weeks 13-24) are all derived based on the number of MMDs 
for the relevant intervals.
Therefore, the key secondary estimands can be formulated similarly to the primary estimand 
described in Section 12.3.1, with the following modifications in regards to endpoint and 
population-level summary attributes. The binary 50% and 75% response variables across 
three 4-week intervals are calculated based on the available monthly values. Further details on 
the derivation of the endpoints can be found in Section 19.1.1.
50% response (Weeks 1-12)
The endpoint to be obtained is a binary response variable indicating a successful response
if a patient has achieved a 50% reduction or more in number of MMDs across weeks 1-12
The population-level summary is the odds ratio of a successful response between 
eptinezumab and placebo
75% response (Weeks 1-12)
The endpoint to be obtained is a binary response variable indicating a successful response
if a patient has achieved a 75% reduction or more in number of MMDs across weeks 1-12
The population-level summary is the odds ratio of a successful response between 
eptinezumab and placebo
Change from baseline in MMDs (Weeks 13-24)
The endpoint to be obtained is the change from baseline in MMDs across weeks 13-24


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The population-level summary is the least squares mean difference between eptinezumab 
and placebo for the endpoint
Change from Baseline in HIT-6
For HIT-6, some of the intercurrent events will be addressed using different strategies than 
what is described for the primary and other key secondary estimands. Therefore, the phrasing 
of the key secondary estimand related to this endpoint is also a little different.
The differences to the strategies used for the primary and other key secondary estimands in 
the handling of intercurrent events are as follows:
Use of acute medication to treat a headache: Instead of a hypothetical strategy, this 
intercurrent event will be handled using a treatment policy strategy, i.e. the values of HIT-
6 are used regardless of whether the patient took any acute medication because they 
believed they were experiencing a migraine
Withdrawal due to lack of efficacy: Will be addressed using a treatment policy strategy 
where the available values of HIT-6 are used regardless of patients withdrawing due to 
lack of efficacy
Withdrawal due to adverse event: Will be addressed using a treatment policy strategy 
where the available values of HIT-6 are used regardless of patients withdrawing due to 
adverse events
Based on this, the key secondary estimand for evaluating the health-related quality of life and 
work productivity impact objective of the study will be the effect of eptinezumab on change 
from baseline in HIT-6 score regardless of patients withdrawing due to lack of efficacy or 
adverse events and regardless of use of acute or preventive migraine medication and infusion 
interruptions or terminations.
In addition, the following two attributes differ from the primary and other key secondary 
estimands:
The endpoint to be obtained is the change from baseline in HIT-6 at Week 12
The population-level summary is the least squares mean difference between eptinezumab 
and placebo for the endpoint
12.4.2
Analysis of the Key Secondary Endpoints
50% and 75% response
The two key secondary endpoints, 50% response (Weeks 1-12) and 75% response (Weeks 1-
12) will be analysed using logistic regression. The model will include baseline MMDs as a 
continuous covariate, and treatment and stratification factor (MHDs at baseline: ≤14 />14) as
factors. The SAS® code for these key secondary analyses is shown in Appendix IV.
The logistic regression model will be fitted using the maximum likelihood (ML) method and 
the logit link function.


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The odds ratios for eptinezumab 300 mg and eptinezumab 100 mg compared to placebo will 
be estimated from the model and presented with p-values based on the likelihood ratio test 
and 95% CIs based on the profile likelihood.
The nominal p-values comparing each dose of eptinezumab to placebo will be presented. The 
comparisons will be part of the testing strategy described in Section 12.2.
In addition, the differences in response proportions between each dose of eptinezumab and 
placebo will be presented.
Change from Baseline in the number of MMDs (Weeks 13-24)
Changes from Baseline in MMDs at Weeks 1-4, Weeks 5-8, Weeks 9-12, Weeks 13-16, 
Weeks 17-20, and Weeks 21-24 will be analysed using the same methodology as described in 
Section 12.3.2 for the primary endpoint. 
The mean differences between each dose of eptinezumab and placebo will be estimated based 
on the least squares means for the treatment-by-visit interaction in the MMRM model. The 
estimates will be presented with nominal p-values and 95% CIs. The comparisons will be the 
contrasts between each dose of eptinezumab and placebo averaged across Weeks 13-24. The 
comparisons will be part of the testing strategy described in Section 12.2.
Change from Baseline in HIT-6
Changes from Baseline in HIT-6 total score at weeks 4, 8, 12, 16, 20, and 24 will be analysed 
using the same methodology as described in Section 12.3.2 for the primary endpoint,
replacing baseline MMD score with baseline HIT-6 score in the model.
The mean differences between each dose of eptinezumab and placebo will be estimated based 
on the least squares means for the treatment-by-visit interaction in the MMRM model. The 
estimates will be presented with nominal p-values and 95% CIs. The comparisons will be the 
contrasts between each dose of eptinezumab and placebo at Week 12. The comparisons will 
be part of the testing strategy described in Section 12.2.
12.4.3
Rationale for Selected Analysis Method for the Key Secondary Endpoints
The rationale for the selected analysis method for change from Baseline in the number of 
MMDs (Weeks 13-24) and change from Baseline in HIT-6 is covered by Section 12.3.4.
The logistic regression model has been chosen for its ability to provide estimates of treatment 
effects, as well as adjust for the effects of strata and covariates. Covariates are included in the 
model based on an approach including key factors representing study design features/strata 
(stratum and treatment), and baseline MMDs to account for its predictive ability for the 
response.
Although it is recognized that adjustment for predictive covariates will always, in contrast to 
classical linear regression models, result in a loss of precision (or no change) of the estimates, 
the adjustment for predictive covariates will result in greater efficiency/higher power when
testing for a treatment effect in a randomized study.2,3 The chosen covariate is considered to 


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be highly predictive for the response, and thus the logistic regression model is considered 
valid as a key secondary analysis model.
12.4.4
Sensitivity Analyses of the Key Secondary Endpoints
For the two key secondary endpoints, 50% response (Weeks 1-12) and 75% response (Weeks 
1-12), a sensitivity analysis will be performed, where any patient that does not have a value of 
MMDs for all 3 post-baseline 4-week periods included in Weeks 1-12 will be imputed with a 
non-response. 
For the key secondary endpoint, change from baseline in the number of MMDs (Weeks 13-
24), a sensitivity analysis will be conducted similarly to the one described for the primary 
endpoint under Imputation for Weeks 1-4 (Section 12.3.5), i.e. where monthly values in the 
first 4 weeks after first infusion are calculated using the weighting rule described in Section 
19.1.1.1 if patients have less than 14 days with eDiary reporting in this period.
For the key secondary endpoint, change from baseline in HIT-6 total score, a sensitivity 
analysis using the placebo-based multiple imputation method to assess the robustness of the 
conclusions for this endpoint to the type of missing data will be conducted.
An analysis will be performed using a pattern-mixture model (PMM), in which missing HIT-6
total scores will be imputed using a sequential regression-based multiple imputation method, 
based on the imputation models established from the placebo group.4
200 simulations will be performed to generate the datasets that will be analysed using the 
model described in section 12.4.2.These analyses will be combined using Rubin’s rule to form 
a unique point estimate and standard error, taking into account the uncertainty of the 
imputation.5 The SAS® code for this sensitivity analysis is shown in Appendix IV.
12.5
Analysis of the Secondary Endpoints
The following endpoints will be derived according to the descriptions given in Section 19.1
and analysed using the same methodology as that described for the primary endpoint (see 
Section 12.3.2) with a few exceptions, which are highlighted below the list:
Change from baseline in the number of MHDs (Weeks 1-12)
Change from baseline in percentage of migraine/headaches with severe pain intensity 
(Weeks 1- 12)
Change from baseline in the number of MMDs with use of acute medication (Weeks 1- 12 
and Weeks 13-24)
Change from baseline in the number of monthly days with use of acute migraine 
medication (Weeks 1-12 and Weeks 13-24)
PGIC score at Week 12 and at Week 24
Change from baseline in the number of MMDs in patients with MOH (Weeks 1-12)
MBS score at Week 12
Change from baseline to Week 24 in the HIT-6 score


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Change from baseline to Week 12 and to Week 24 in MSQ v2.1 sub-scores (Role 
Function-Restrictive, Role Function-Preventive, Emotional Function)
Change from baseline to Week 12 and to Week 24 in EQ-5D-5L VAS score
Change from baseline to Week 12 and to Week 24 in WPAI sub-scores (Absenteeism, 
Presenteeism, Work productivity loss, Activity impairment)
For the endpoints listed above, the baseline MMD score will be replaced with the baseline 
score for the endpoint in question in the model except for analysis of PGIC and MBS, which 
will exclude the baseline score terms, since the rating of the scales in themselves represent a 
change from baseline so no baseline score exists. 
In the analysis of MHDs, the model will include following fixed effects: month, country, and 
treatment as factors, baseline MHDs as a continuous covariate, treatment-by-month
interaction, and baseline score-by-month interaction.
The analysis of MMDs in patients with MOH will only be performed if the number of patients 
with MOH constitutes a sufficiently large part of the study population.
For HIT-6, in addition to summary tables presenting descriptive statistics for the total score, 
tables presenting the counts and percentages of patient in each life impact category as defined 
in Section 19.1.4 will be produced by visit and treatment group.
The following endpoints will be analysed using the same methodology as that described for 
the key secondary response endpoints (see Section 12.4.2):
Response: Patients with 50% reduction from baseline in MMDs (Weeks 13-24)
Response: Patients with 75% reduction from baseline in MMDs (Weeks 13-24)
Response: Patients with 50% reduction from baseline in MHDs (Weeks 1-12)
Response: Patients with 75% reduction from baseline in MHDs (Weeks 1-12)
Response: Patients with a 5-point reduction from baseline to Week 12 and from baseline to 
Week 24 in HIT-6
For the HIT-6 response endpoints, LOCF will be used to impute a potentially missing value at 
Week 12 or Week 24. Baseline values will not be carried forward.
The following endpoints:
Response: Patients with 100% reduction from baseline in MMDs (Weeks 1-12)
Response: Patients with 100% reduction from baseline in MHDs (Weeks 1-12)
Patients with a migraine on the day after first dosing
Will be derived according to the descriptions in Section 19.1.1.2 and 19.1.1.3 and analysed
using an extended Cochran-Mantel-Haenszel (CMH) test, adjusting for one of the 
stratification factors (MHDs at baseline: ≤14 />14). The rates for each dose of eptinezumab 
and placebo will be presented. The SAS® code for performing the extended CMH test is 
shown in Appendix IV.


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Descriptive tables displaying the distribution of answers to the items in HCRU at each visit 
will be provided by treatment group.
Tables displaying the counts and percentage of answers to each category of response options 
for each item of EQ-5D-5L will be presented by visit and treatment group. Furthermore, shift 
tables displaying for each item in EQ-5D-5L the number and percentage of patients who 
decreased, increased or had no change from baseline in the item score will be provided by 
visit and treatment group.
For inclusion into the addendum CSR, the endpoints listed below will be derived according to 
the descriptions given in Section 19.1 and the absolute values will be analysed using an 
MMRM similar to the one described for the primary endpoint (see Section 12.3.2) but using 
treatment sequence group instead of treatment group. 
No treatment comparisons will be performed for any of the efficacy endpoints after Week 24. 
Instead, the estimated mean values will be reported with two-sided 95% confidence intervals 
by treatment sequence for:
Number of MMDs (at Weeks 1-4, Weeks 5-8, Weeks 9-12, Weeks 13-16, Weeks 17-20, 
Weeks 21-24, Weeks 25-36, 37-48, 49-60, and 61-72)
HIT-6 score (at week 4, 8, 12, 16, 20, 24, 36, 48, 60, and 72)
The absolute values and changes from baseline in MMDs at Weeks 25-36, 37-48, 49-60, and 
61-72 will be summarized descriptively by treatment sequence group and by treatment group 
in the Extension Period. 
Similarly, the absolute values and changes from baseline in HIT-6 total score at Weeks 36, 
48, 60, and 72 will be summarized descriptively by treatment sequence group and by 
treatment group in the Extension Period.
Tables displaying the counts and proportion of patients achieving a 50% and 75% reduction 
from baseline in MMDs across Weeks 25-36, 37-48, 49-60, and 61-72 will be presented by 
treatment sequence group and by treatment group in the Extension Period.
12.6
Analysis of the Exploratory Endpoints
The exploratory endpoints change from baseline in number of monthly headache episodes and 
migraine attacks for Weeks 1-12 and Weeks 13-24 will be evaluated similarly to the primary 
endpoint (see Section 12.3.2). 
All the exploratory endpoints related to the eDiary or scales endpoints after Week 24 will be 
analysed similarly to what is described in Section 12.5, for inclusion into the addendum CSR.


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13 Safety
13.1
Adverse Events
13.1.1
General Methodology for Adverse Events
Unless otherwise specified, tables, graphs, and listings will be based on the APTS for the 
Placebo-controlled Period and the APTS_LT for the Extension Period.
All the tables and graphs will be presented by treatment group for the Placebo-controlled 
Period and by treatment sequence group for the Extension Period, unless otherwise specified.
Tables by preferred term and tables by system organ class (SOC) and preferred term will be 
sorted in descending order based on the percentages of patients with these adverse events in 
the eptinezumab 300 mg dose group.
Unless otherwise specified, the summaries of adverse events will include the number and 
percentage of patients with an adverse event. In tables displaying SOC or preferred terms,
patients are counted only once within each SOC or preferred term.
Listings of adverse events will be sorted by site, treatment group, patient screening number, 
and adverse event start date, and include preferred term, investigator term, adverse event start 
date, the date of first IMP infusion, the date and time of the latest IMP infusion prior to the 
adverse event, the time since latest IMP infusion, duration of the adverse event, date of death, 
action taken, causality, intensity, seriousness, and outcome. For adverse events that change in 
intensity, each intensity will be included. In listings of adverse events, start or stop dates will 
be displayed as collected also in case of partially or completely missing dates.
13.1.2
Coding of Adverse Events
Adverse events will be coded using MedDRA, Version 23.0 or later.
13.1.3
Classification 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 and time of first dose of IMP
treatment-emergent adverse event (TEAE) – an adverse event that starts or increases in 
intensity during or after administration of the first dose of IMP
For handling of adverse events with incomplete start dates to facilitate this classification, see 
Section 19.3.5. Note that adverse events with incomplete start dates will be classified as 
treatment-emergent simply if the imputed start date is on or after the date of first IMP 
infusion, since the start time of the adverse event will not be imputed, unless the investigator 
in such a case has assessed that the causality to IMP is “Not Related - Prior to IMP”.


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An adverse event is considered causally related to the use of the IMP when the causality 
assessment by the investigator is probable or possible. If the causality assessment is missing,
the adverse event is considered causally related.
13.1.4
Allocation of TEAEs to Treatment Periods
TEAEs will be allocated to treatment periods according to the time of onset of the adverse 
event:
TEAE in the Placebo-controlled Period – a TEAE that starts before the date and time of 
the start of Visit 8 IMP infusion
TEAE in the Extension Period – a TEAE that starts during or after administration of Visit 8 
IMP infusion
For allocation of TEAEs to treatment periods, the same rule for imputed dates as specified 
above (in Section 13.1.3) applies, i.e. for incomplete start dates, only the imputed start date 
and not the time (which will not be imputed) of the adverse event will be taken into account in 
the allocation of the TEAE to periods.
If an adverse event starts on the day of the Visit 8 IMP infusion but with an unknown start 
time, the adverse event will be classified as treatment-emergent in the Placebo-controlled 
period.
13.1.5
Presentation of Adverse Events
A listing of all adverse events starting at or after entering the Extension Period, including a 
flag for TEAEs will be included in the addendum to CSR based on the APTS_LT.
A similar listing of all adverse events occurring before entering the Extension Period will be 
produced for the CSR based on APRS.
For each period, an overview of the numbers and percentages of patients with TEAEs, serious 
adverse events (SAEs), TEAEs leading to infusion interruption, TEAEs leading to 
withdrawal, and of patients who died will be provided based on the APTS/APTS_LT. For 
TEAEs, SAEs, and TEAEs leading to withdrawal, the total number of events will be included.
13.1.6
Presentation of Treatment-emergent Adverse Events
The following summaries will be provided for the Placebo-controlled Period and for the 
Extension Period:
TEAEs by SOC and preferred term
TEAEs by preferred term
TEAEs by sex and preferred term
TEAEs with an incidence ≥2% in any treatment group by preferred term
causally related TEAEs by SOC and preferred term
TEAEs by intensity (mild/moderate/severe), SOC, and preferred term


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causally related TEAEs by intensity, SOC, and preferred term
TEAEs occurring on the day of dosing after infusion start by SOC and preferred term (this 
includes day of V2 and V5 infusion for the Placebo-controlled Period and day of V8, V11, 
V14, and V17 infusion for the Extension Period)
The summaries will be provided for the APTS for the Placebo-controlled Period and for 
APTS_LT for the Extension Period.
For the Extension Period, the two tables summarizing all TEAEs by SOC and preferred term 
and all TEAEs by preferred term will include two additional columns displaying the totals for 
eptinezumab 100 mg and eptinezumab 300 mg.
For TEAEs occurring on the day of dosing after infusion start, TEAEs with missing start 
times will also be included.
13.1.7
Presentation of Deaths
All the adverse events in patients who died before entering the Extension Period will be listed 
for the APRS for inclusion in the CSR.
All the adverse events in patients who died after entering the Extension Period will be listed 
for the APTS_LT for inclusion in the addendum to CSR.
13.1.8
Presentation of Serious Adverse Events
All SAEs occurring before entering the Extension Period will be listed for the APRS for 
inclusion in the CSR.
All SAEs occurring at or after entering the Extension Period will be listed for the APTS_LT 
for inclusion in the addendum to CSR.
Treatment-emergent SAEs will be summarized for the Placebo-controlled Period based on 
APTS and for the Extension Period based on APTS_LT by:
SOC and preferred term
preferred term
13.1.9
Presentation of Adverse Events Leading to Withdrawal
All AEs leading to withdrawal before entering the Extension Period will be listed for the 
APRS for inclusion in the CSR.
All AEs leading to withdrawal occurring at or after entering the Extension Period will be 
listed for the APTS_LT for inclusion in the addendum to CSR.


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TEAEs leading to withdrawal will be summarized for the Placebo-controlled Period based on 
APTS and for the Extension Period based on APTS_LT by:
SOC and preferred term
preferred term
13.1.10 Presentation of Adverse Events Leading to Study Drug Infusion Interruption
All AEs leading to study drug infusion interruption before entering the Extension Period will 
be listed for the APRS for inclusion in the CSR. 
All AEs leading to study drug infusion interruption occurring at or after entering the 
Extension Period will be listed for the APTS_LT for inclusion in the addendum to CSR. 
TEAEs leading to study drug infusion interruption will be summarized for the Placebo-
controlled Period based on APTS and for the Extension Period based on APTS_LT by:
SOC and preferred term
preferred term
13.1.11 Presentation of Adverse Events of Special Interest
Treatment-emergent adverse events of special interest (AESI) will consist of the preferred 
terms defined by the SMQs/HLTs/HLGTs listed in Table 6.
All AESIs occurring before entering the Extension Period will be listed for the APRS for 
inclusion in the CSR. 
All AESIs occurring at or after entering the Extension Period will be listed for the APTS_LT 
for inclusion in the addendum to CSR.
The listings will be repeated for all AEs belonging to the Hypersensitivity and Anaphylactic 
Reactions event category only, see Table 6.
The following summaries of treatment-emergent AESIs will be provided for the Placebo-
controlled Period and for the Extension Period:
AESIs by SOC and preferred term
AESIs by SOC and preferred term, separately for each individual event category 
The summaries will be provided for the APTS for the Placebo-controlled Period and for 
APTS_LT for the Extension Period.
13.2
General Methodology for Other Safety Data
Unless otherwise specified, tables, graphs, and listings will be based on the APTS for the 
Placebo-controlled Period and APTS_LT for the Extension Period.


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All tables and graphs will be presented by treatment group for the Placebo-controlled Period 
and by treatment sequence group for the Extension Period.
The denominators for the summaries of a given variable will be based on the number of 
patients with non-missing values at a given visit or during the assessment period.
Descriptive statistics for the safety variables, both absolute values and changes from baseline, 
will be presented by visit, separately for each period.
The number and percentage of patients with at least one PCS value at any post-baseline
assessment time point will be summarized by variable, separately for each period. All 
available assessments in each period will be included in the evaluation of PCS values. 
For patients with post-baseline PCS values in the Placebo-controlled Period, listings will be 
provided including all the values for those patients for the variable prior to entering the 
Extension Period, with flagging of PCS values and out-of-reference-range values for inclusion 
in the CSR.
For patients with PCS values occurring after start of V8 IMP infusion, similar listings will be 
provided including all the values for those patients for the variable for inclusion in the 
addendum to CSR.
For inclusion in the CSR, all the adverse events occurring before entering the Extension 
Period in patients with post-baseline PCS values in the Placebo-controlled Period will be 
listed by treatment group and patient screening number; the listing will include the PCS value, 
the assessment date, the change from baseline in PCS value, the preferred term for the adverse 
event, and start date and stop date of the adverse event. The PCS values and adverse events 
will be listed in chronological order according to assessment date and the start date of the 
adverse event.
Similar listings will be provided for patients with PCS values occurring after start of V8 IMP 
infusion, including all the adverse events for the patients, for inclusion in the addendum to
CSR.
For urine dipsticks, for which the results are categorical values (for example, negative, trace, 
1+, 2+), the number and percentage of patients will be summarized by visit for each test, 
separately for each period. The microscopy results will be listed by assessment time point for 
patients with findings.
13.3
Clinical Safety Laboratory Test Data
13.3.1
Data Presentation
The PCS criteria used for the clinical safety laboratory tests can be found in Table 3.
The clinical safety laboratory test values will be presented both in conventional and Système 
International (SI) units.


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13.3.2
Anti-Drug Antibody (ADA) including Neutralizing Antibody (NAb) assessments
Analysis of specific anti-eptinezumab antibodies is restricted to subjects who are randomized
to eptinezumab.
For subjects with pre-existing antibodies at Baseline, the number and percent of subjects who 
are positive for anti-eptinezumab antibody will be summarized. In addition, the number and 
percent of subjects who develop anti-drug antibodies to eptinezumab during the trial will be 
summarized at each scheduled visit. Denominators for percentages will be the total number of 
samples taken for the specified visit. For patients with ADA, neutralizing properties of anti-
eptinezumab antibodies will also be summarized.
All the immunogenicity data will be listed by period.
Subjects with a positive anti-eptinezumab antibody result will be listed by period.
For inclusion in the CSR, all the adverse events occurring before entering the Extension
Period in patients with positive anti-eptinezumab antibody results in the Placebo-controlled 
Period or with pre-existing antibodies at Baseline, will be listed. The listing will include the 
ADA result, the assessment date, the preferred term for the adverse event, and start date and 
stop date of the adverse event. The ADA results and adverse events will be listed in 
chronological order according to assessment date and the start date of the adverse event.
Similar listings will be provided for patients with ADA-positive results occurring after start of 
V8 IMP infusion, including all the adverse events for the patients, for inclusion in the 
addendum to CSR.
In addition, summaries of TEAEs by SOC and preferred term will be provided for the 
Placebo-controlled Period and for the Extension Period for patients who are ADA-positive.
13.3.3
Potential Drug-induced Liver Injury (DILI)
Signals of DILI will be assessed according to the FDA guideline6 using the following criteria:
ALT or AST >2×, >3×, >5×, >10×, or >20×ULN
total bilirubin (BILI) >2×ULN
alkaline phosphatase (ALP) >1.5×ULN
ALT or AST >3×ULN AND total bilirubin >1.5× or >2×ULN
Patients fulfilling any of the criteria in the Placebo-controlled Period will be listed for 
inclusion in the CSR, and the listing will include all the ALT, AST, BILI, and ALP values for 
those patients prior to entering the Extension Period, sorted by assessment date and time in 
ascending order. If a criterion for a test is fulfilled, the value will be flagged with the highest 
criterion fulfilled (for example, AST >3×ULN, >5×ULN, >10×ULN, or >20×ULN).


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A similar listing will be provided including all the ALT, AST, BILI and ALP values for the 
patients fulfilling any of the criteria in the Extension Period for inclusion in the addendum to
CSR.
In addition, assessment time points for patients for whom Hy’s Law is potentially fulfilled 
will also be flagged in the listings (pHYL):
ALT or AST >3×ULN AND
alkaline phosphatase <2×ULN AND
total bilirubin ≥2×ULN
The number of patients who met any of the criteria specified above at any post-baseline visit 
will be summarized by treatment group and period. In the summaries, each patient will be 
counted only once using the maximum assessment, or the most severe for the combined 
criteria. The summaries will also include the number of potential Hy’s Law cases. 
13.4
Vital Signs and Weight
The PCS criteria used for vital signs and weight are the Lundbeck standard PCS criteria 
described in SOP_09978: GPV – PCS and standard reference values for laboratory 
investigations, vital signs and ECGs in clinical studies, version 6, and are also included in
Table 4.
13.5
ECGs
The PCS criteria used for the ECG parameters are the Lundbeck standard PCS criteria 
described in SOP_09978: GPV – PCS and standard reference values for laboratory 
investigations, vital signs and ECGs in clinical studies, version 6, and are also included in
Table 5.
In addition to the tables and listings specified in Section 13.2, absolute values and changes 
from Baseline in QTcF will also be summarized categorically by visit and treatment, 
separately for the Placebo-controlled Period and the Extension Period. The categories that will 
be used are as follows for the absolute QTcF values:
QTcF interval < 450 msec
QTcF interval 450 - 480 msec
QTcF interval > 480 - 500 msec
QTcF interval > 500 msec
The categories that will be used for the change from baseline QTcF values are:
QTcF interval increase from baseline > 30 msec
QTcF interval increase from baseline > 60 msec
Furthermore, the number and percentage of patients being classified as having either a 
normal, abnormal but not clinically significant, abnormal and clinically significant ECG result


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based on the overall interpretation of the ECG from the investigator will be summarized by 
visit and treatment group, separately for each period.
13.6
Other Safety Endpoints
13.6.1
Columbia-Suicide Severity Rating Scale (C-SSRS) Scores
The C-SSRS was administered:
for lifetime (using the Baseline/Screening Version) – the C-SSRS assessment at screening 
that collects a lifetime recall
for the past 12 months at screening (using the Baseline/Screening Version) – the C-SSRS 
assessment at screening that focuses on the last 12 months
at baseline (using the Since Last Visit Version) – the C-SSRS assessment at baseline that 
collects information since the previous visit
post-baseline (using the Since Last Visit Version) – the C-SSRS assessments after baseline
The numbers and percentages of patients with lifetime, past 12 months, baseline, or post-
baseline suicide-related events based on the C-SSRS will be summarized by treatment group.
For each summary, the most severe item with an answer “Yes” for each patient according to 
the ordering given in Panel 4 is displayed. For the post-baseline assessments, the summaries 
will be by treatment group and period and the most severe item with an answer “Yes” for the 
whole period for each patient related to suicidal ideation and/or behaviour will be 
summarized.
The number and percentage of patients with no suicidal ideation or behaviour will be 
included in the summaries.
Panel 4
C-SSRS Scores
C-SSRS Score
Related to:
1
Wish to be dead
Suicidal ideation
2
Non-specific active suicidal thoughts
3
Active suicidal ideation with any methods (not plan) without intent to act
4
Active suicidal ideation with some intent to act, without specific plan
5
Active suicidal ideation with specific plan and intent
6
Preparatory acts or behaviour
Suicidal behaviour
7
Aborted attempt
8
Interrupted attempt
9
Non-fatal suicide attempt
10
Completed suicide (only applicable for the post-baseline assessments)
The C-SSRS scores will be summarized based on the APTS for the lifetime, past 12 months, 
baseline and Placebo-controlled Period summaries and based on the APTS_LT for the 


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Extension Period summary. Patients with at least one C-SSRS assessment in the period will 
be included, regardless of whether they had a baseline C-SSRS assessment.
Missing C-SSRS scores will not be imputed.
Positive responses to non-suicidal self-injurious behaviour will be summarized separately.
For patients with any post-baseline suicidal ideation or behaviour in the Placebo-controlled 
Period (C-SSRS scores of 1 to 10), listings will be provided based on APRS including all C-
SSRS scores prior to entering the Extension Period for those patients for inclusion in the CSR.
A similar listing will be provided for patients with any post-baseline suicidal ideation or
behaviour in the Extension Period including all the C-SSRS scores for those patients for 
inclusion in the addendum to CSR.
14 Blinded Data Reviews
The quality of the study will be overseen by performing blinded data reviews during the 
conduct of the study. The reviews may include, but are not limited to, data quality, protocol 
adherence, and the appropriateness of design assumptions, including the sample size 
assumptions.
An independent Safety Data Monitoring Committee (DMC) will regularly monitor the 
patients' safety data according to the DMC Charter. The DMC will have access to unblinded 
information for the double-blind treatment for each patient. Members of the DMC will not be 
involved in other study-related tasks.
15 Interim Analyses
See Section 18.
16 Sample Size Considerations
The two prior eptinezumab Phase III studies, PROMISE-1 performed in an EM population 
and PROMISE-2 performed in a CM population, had the following effect sizes for the 
primary endpoint when compared to placebo (standard deviations):
EM: 100 mg 0.69 (3.1), 300 mg 1.11 (3.1)
CM: 100 mg 2.03 (5.8), 300 mg 2.60 (5.8)
The power was determined by simulating the testing strategy (10000 simulations) assuming 
normal distributions with similar mean and SD for continuous endpoints and similar success 
rates as the response variables in the Phase III studies for the corresponding population (EM 
or CM) without assuming the variables to be correlated. With 280 patients per treatment 
group, assuming that 40% of the patients will be from the EM population and 60% from the 


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CM population, and that 2% of the patients not having a post-baseline assessment of the 
primary endpoint, simulations show that the power for the test of the primary endpoint is 
approximately 94% for the comparison of 100 mg to placebo and 99% power for the 
comparison of 300 mg to placebo.  The individual key secondary endpoints had a power of at 
least 68% for showing an effect, with a combined power of 58% for seeing an effect for all 
primary and key secondary endpoints and both doses in the testing strategy. 
17 Statistical Software
The statistical software used will be SAS®, Version 9.4 or later.
18 Changes to Analyses Specified in the Protocol
In the Clinical Study Protocol (ed. 1.0 and 2.0), it is described that an unblinded interim 
analysis for efficacy will be performed, when 345 patients have been randomized and 
received the first infusion of IMP and have had the opportunity to complete the Primary 
Outcome Visit (Week 12). The analysis was intended to allow for stopping the study for 
efficacy if the results fulfilled the interim criteria. Based on the result of the interim analysis, 
Lundbeck could decide to stop the study for efficacy or continue the enrolment. Due to 
recruitment being faster than expected, it has been decided not to conduct the interim analysis 
after all. Therefore, any references to the interim analysis have been removed from the 
Statistical Analysis Plan, and the significance level to be used in the testing strategy has been 
updated to 0.05. 
The wording of endpoints related to HCRU has been updated since it is not the changes from 
baseline but the frequency of responses in each category that will be summarized for the 
study.
The wording of endpoints related to MBS has been updated to reflect that the MBS score in 
itself reflects a change from baseline.
HIT-6 responder endpoints have been added to the list of secondary endpoints.
In relation to the addition of HIT-6 response endpoints, responder analyses using logistic 
regression have been added to the list of secondary analyses.
According to the original Clinical Study Protocol ed. 1.0, the primary analysis of the primary 
endpoint has been updated from an ANCOVA using the average values of MMDs over 
Weeks 1-12 to an MMRM using the available monthly values of MMDs. This update is 
included in an amendment of the Clinical Study Protocol, resulting in a Clinical Study 
Protocol ed. 2.0, dated 22 January 2021. 
According to the original Clinical Study Protocol ed. 1.0, the key secondary analyses of key 
secondary responder endpoints (50% response (Weeks 1-12) and 75% response (Weeks 1-
12)) have been updated to logistic regressions instead of the CMH tests specified in the 


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protocol. This update is included in an amendment of the Clinical Study Protocol, resulting in 
a Clinical Study Protocol ed. 2.0, dated 22 January 2021.
The definition of a treatment-emergent adverse event (TEAE) has been updated to clarify that 
the time of infusion is also taken into account in the classification.
For the numerical representation of PGIC scores, the score 1 is used to represent a score of 
“very much improved” and a score of 7 to represent a score of “very much worse”. This is the 
opposite of what is described in the protocol, where it is stated that a high score indicates 
improvement.  
19 Details on Data Handling
19.1
Derived Variables
19.1.1
eDiary
19.1.1.1
Monthly Migraine Days (MMDs)/Monthly Headache Days (MHDs)
The following describes the derivation of MMDs. The derivation of MHDs follows the same 
principles.
4-Week Intervals
For Baseline and each 4-week period post-baseline in the study, the number of MMDs will be
derived as the number of migraine days within each 28-day interval using the imputation rules
described below. The 4-week periods post-baseline that are considered are the following: 
Weeks 1-4, Weeks 5-8, Weeks 9-12, Weeks 13-16, Weeks 17-20, Weeks 21-24, Weeks 25-
28, Weeks 29-32, Weeks 33-36, Weeks 37-40, Weeks 41-44, Weeks 45-48, Weeks 49-52, 
Weeks 53-56, Weeks 57-60, Weeks 61-64, Weeks 65-68, Weeks 69-72.
In general, for 4-week periods where the eDiary is completed on at least 14 days out of the 28 
days, prorating will be used to calculate the MMDs, and for 4-week periods where the eDiary 
is completed on less than 14 days out of the 28 days, the MMDs will be set to missing. 
However, there are cases where weighting will be used when less than 14 days have been 
completed, and an overview is given in Panel 5. 
Prorating
Intended to be used for 4-week periods where the eDiary is completed on at least 14 out of the 
28 days, the prorating procedure consists of imputing days with missing information with the 
observed mean number of migraine days in the period as follows:
28*(Reported Migraine Days/Reported eDiary Days)


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This imputation rule will also be used for the Baseline value regardless of the number of 
reported eDiary days in the screening period. Patients are, however, required to demonstrate 
compliance with the eDiary and fill it out for at least 24 out of the 28 days in the screening 
period in order to be eligible for randomization. 
Weighting
Intended to be used in special cases for the first 4-week period post-baseline, where the 
eDiary is completed on less than 14 days out of the 28 days due to withdrawal. When 
weighting is used, the number of MMDs is derived as a weighted sum of the observed mean 
number of migraine days in the period and the mean MMDs for the preceding period as 
follows:
28*(W*X + (1 – W)*Xp),
where W = Reported eDiary Days/13, X = Reported Migraine Days/Reported eDiary Days, 
and Xp = preceding MMDs/28.
Patients who withdraw due to lack of efficacy so early that they only have post-baseline data 
from Weeks 1-4 will have their MMDs calculated using weighting for Weeks 1-4 if they have 
less than 14 days of eDiary reporting during the first 4 weeks of the study. If they have 14
days or more in this period, their MMDs for Weeks 1-4 will be calculated using prorating.
Patients who withdraw due to adverse events so early that they only have post-baseline data 
from Weeks 1-4 will have their MMDs calculated using weighting for Weeks 1-4 if they have 
less than 14 days of eDiary reporting during the first 4 weeks of the study. If they have 14
days or more in this period, their MMDs for Weeks 1-4 will be calculated using prorating.
Panel 5
Overview of Imputation Rules for 4-Week Periods for eDiary Data
Number of Reported eDiary Days in Period
Description
4-Week Period
0-13
14-28
All patients randomized
Baseline
Prorating*
Prorating
Patients not withdrawing due to 
lack of efficacy/adverse event
Weeks 1-4
None (missing)
Prorating
Patients not withdrawing due to 
lack of efficacy/adverse event
4-week periods after 
week 4 
None (missing)
Prorating
Patients withdrawing due to lack 
of efficacy
Weeks 1- 4
Weighting
Prorating
Patients withdrawing due to lack 
of efficacy
4-week periods after 
week 4 
None (missing)
Prorating
Patients withdrawing due to 
adverse event
Weeks 1-4
Weighting
Prorating
Patients withdrawing due to 
adverse event
4-week periods after 
week 4 
None (missing)
Prorating
*Patients are required to complete the eDiary for at least 24 days during the first 28 days of screening to be 
eligible


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In case of a reporting day where a patient answers in the evening diary that they experienced a 
headache on that day but then never fills out an actual headache in the headache diary, the day 
will be assigned as a no headache and no migraine day.
When the number of MMDs have been calculated for a given 4-week period, the result will be 
rounded to two decimals.
19.1.1.2
Migraine/Headache Responder Rates
The following describes the derivation for monthly migraine days. The derivation for monthly 
headache days is similar.
The following responder rates will be derived: 50%, 75%, and 100%. A responder is a patient, 
who achieves a ≥50% reduction, ≥75% reduction, or 100% reduction in MMDs, respectively, 
compared to the baseline number of MMDs. The derivation of these responder endpoints will 
be based on the number of MMDs resulting from the imputations described in Section 
19.1.1.1.
For each 4-week period post-baseline in the study, the responder status of a patient will be 
derived based on the percentage change from baseline in MMDs. If the MMDs value is 
missing for the month in question, the response status will also be missing.
For the 12-week and 24-week intervals, the 50% and 75% responder status will be derived as 
follows, using 50% response for Weeks 1-12 as an example:
50% Responder Status(Weeks 1 −12) = &
1,
if ave(∆+,, ∆+-, ∆+)
./012341
≤−0.5
0,
if ave(∆+,, ∆+-, ∆+)
./012341
> −0.5,
where  ∆+8 is the change from baseline value for month i. For 12-week intervals, if any of the 
months included in the calculation have a missing value of MMDs, the responder status will 
be derived based on the available values. For 24-week intervals, the responder status will only 
be calculated if at least one observation from each 12-week period is available, i.e. it will be 
non-missing if there is one observation from one of Weeks 1-4, Weeks 5-8, or Weeks 9-12 
and one of Weeks 13-16, Weeks 17-20, or Weeks 21-24. 
The 100% responder rate for the 12-week and 24-week intervals will be derived based on the 
average 100% responder status for the 4-week intervals included in the interval, i.e. if a 
patient has 100% response for Weeks 1-4 and Weeks 5-8 but not for Weeks 9-12, the 100% 
responder rate will be 0.67 (computed as (1 + 1 + 0)/3), since the responder status for the first 
and second month for the patient was 1 and the responder status for the third month was 0. If 
any of the months included have a missing value of MMDs, the patient will be imputed with a 
non-response, i.e. with the value 0, for the 12-week or 24-week interval.


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19.1.1.3
Percentage of Patients with Migraines
Day 1
The percentage of patients with a migraine on the day after first dosing will be derived based 
on whether the patient filled out the eDiary on Day 1 or not. If the patient filled out the eDiary 
on Day 1, the patient will have a rate of either 0 or 100 on Day 1 that is, 0 if the patient 
experienced no migraine on Day 1 and 100 if the patient did experience a migraine on Day 1.
If the patient did not fill out the eDiary on Day 1, the rate for the patient will be imputed as:
100*(Number of MMDs Weeks 1-4/28),
where the number of MMDs for Weeks 1-4 is derived as described in Section 19.1.1.1. Note 
that if the number of MMDs for Weeks 1-4 is missing for the patient and the patient did not 
fill out the eDiary on Day 1, the Day 1 rate will be missing.
Similarly, the rate for having a migraine on Day 1 after the Week 12 dosing will be imputed
using the MMDs for Weeks 13-16 in case of a missing eDiary report on that day.
19.1.1.4
Migraines/Headaches With Severe Pain Intensity and Headache
Episodes/Migraine Attacks
The percentage of migraines and headaches with severe pain intensity is derived based on the 
derived number of monthly migraine attacks and headache episodes. 
A migraine attack is defined as 1 continuously recorded migraine. One attack may result in 
multiple migraine days. Headache episodes are similarly defined. Headache severity is 
collected on a 3-point scale, Mild, Moderate and Severe. Migraines and headaches with 
severe pain intensity are defined as migraine attacks/headache episodes with a reported 
severity of “Severe”.
The following describes the derivation of number of monthly migraine attacks. The derivation 
of monthly headache episodes follows the same principles.
The derivation of the number of monthly migraine attacks will follow the imputation rules 
described in Section 19.1.1.1 for MMDs, replacing Reported Migraine Days with Reported 
Migraine Attacks everywhere. As an example, the number of monthly migraine attacks for a 
patient with 14 days or more of eDiary reporting in a 4-week period will be derived as:
28*(Reported Migraine Attacks/Reported eDiary Days)
And for a patient who withdraws due to an adverse event or lack of efficacy within the first 28 
days post baseline with less than 14 days of eDiary reporting in the first 4-week period, the 
number of monthly migraine attacks will be derived as:
28*(W*Xatt + (1 – W)*Xpatt),


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where W = Reported eDiary Days/13, Xatt = Reported Migraine Attacks/Reported eDiary 
Days, and Xpatt = preceding Number of Migraine Attacks/28.
The number of monthly migraines and headaches with severe pain intensity is derived in the 
same way using only migraine attacks/headache episodes with a reported severity of 
“Severe”.
The percentage of migraines and headaches with severe pain intensity is then calculated as the 
percentage of migraine attacks/headache episodes with severe pain intensity out of the 
number of migraine attacks/headache episodes. Patients with no migraine attacks/headache 
episodes are included with a rate of 0.
The average length of headache episodes and migraine attacks will also be derived and will be
based on the number of monthly migraine attacks and headache episodes. The number of 
monthly hours with headache and migraine will be derived similarly to how the number of 
monthly migraine attacks and headache episodes are derived, i.e. to derive the monthly 
number of migraine hours, Reported Migraine Attacks is replaced with Reported Migraine 
Hours in the calculations described above. From that, the average length of headache episodes 
and migraine attacks is calculated as the monthly hours with headache or migraine divided by 
the number of monthly headache episodes or migraine attacks, respectively. Patients with no 
migraine attacks/headache episodes are included with an average length of 0 for the month.
19.1.1.5
Monthly Days with Acute Migraine Medication Usage and MMDs/MHDs with 
Acute Medication Usage
In the evening eDiary, patients are asked each day to fill out whether they used any of the 
following medications during that day: Ergotamine, triptan, analgesic, opioid, or combination 
analgesic. A day where the patient answers that they took any of those in the evening eDiary
is considered a day with use of acute migraine medication.
The number of days with acute migraine medication usage is then derived for each 4-week
period using the imputations described in Section 19.1.1.1 and replacing Reported Migraine 
Days with Reported Acute Migraine Medication Days everywhere as well as replacing 
Reported eDiary Days with Reported Evening eDiary Days, where a “Reported Evening 
eDiary Day” is defined as any day where the evening eDiary has been filled out.
Similarly, the number of days with each of the medication types taken will be derived as well 
as the number of days with ergotamine and triptan use.
Additionally, the monthly migraine days/monthly headache days with acute medication usage 
will be derived. This is derived using the answer to “Did you take any medications to treat 
this headache?” in the headache diary. The question is asked when a patient is ending a 
headache. Thus, a migraine/headache day with acute medication usage is defined as a 
migraine/headache day with the extra condition that this question has been answered as 
“Yes”. In case of a migraine/headache with acute medication usage spanning multiple days,
all the days will be counted as a migraine/headache day with use of acute medication.


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19.1.2
Patient Global Impression of Change (PGIC)
The PGIC is a single patient-reported item reflecting the patient’s impression of change in 
their disease status since the start of the study (that is, in relation to activity limitations, 
symptoms, emotions, and overall quality of life). 
The item is rated on a 7-point scale ranging from 1 (very much improved) to 7 (very much 
worse).
19.1.3
Most Bothersome Symptom (MBS)
The Investigator will verbally obtain the most bothersome symptom associated with the 
patient’s migraines during the Screening Visit. 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, i.e. 
the scale ranges from 1 (very much improved) to 7 (very much worse). 
The MBS areas include: nausea, vomiting, sensitivity to light, sensitivity to sound, mental 
cloudiness, fatigue, pain with activity, mood changes, and other.
19.1.4
Headache Impact Test (HIT-6)
The HIT-6 (v1.0)7 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).
19.1.5
Migraine-Specific Quality of Life Questionnaire Version 2.1 (MSQ v2.1)
The MSQ v2.18 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). 
The items going into each domain9 are specified in Panel 6.
Each item score is mapped from the recorded value of the item as shown in Panel 7.10


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For each domain, the score is derived from the final item values by summing the scores from 
items within each domain and transforming the summed scores as shown in Panel 8.
Panel 6
MSQ v.2.1 Domains
Domain
Item number
Abbreviated content
Role function restrictive
1
. . . . . interfered with how well you dealt with
family, friends, and others
2
. . . . . interfered with your leisure time activities
such as reading or exercising
3
. . . . . had difficulty in performing work or daily
activities
4
. . . . . kept you from getting as much done at
work or at home
5
. . . . . limited your ability to concentrate on
work or daily activities
6
. . . . . left you too tired to do work or daily
activities
7
. . . . . limited the number of days you felt
energetic
Role function preventive
8
. . . . . canceled work or daily activities . . .
9
. . . . . needed help in handling routine tasks
10
. . . . . stopped work or daily activities . . .
11
. . . . . not able to go to social activities . . .
Emotional function
12
. . . . .felt fed up or frustrated
13
. . . . . felt like a burden on others
14
. . . . . afraid of letting others down
Panel 7
MSQ v.2.1 Item Values
Response categories
Precoded item value
Final item value
None of the time
1
6
A little bit of the time
2
5
Some of the time
3
4
A good bit of the time
4
3
Most of the time
5
2
All of the time
6
1
Panel 8
Derivation of MSQ v.2.1 Domain Scores
Domain
Sum of item scores range
Derivation
Role function restrictive
7 to 42
(Summed score – 7)*100/35
Role function preventive
4 to 24
(Summed score – 4)*100/20
Emotional function
3 to 18
(Summed score – 3)*100/15


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19.1.6
Euroqol 5 Dimension – 5 Levels (EQ-5D-5L)
The EQ-5D-5L11 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 visual analogue scale (VAS) of the overall health state. Each 
descriptive item is rated on a 5-point index ranging from 1 (no problems) to 5 (extreme 
problems) and a single summary index (from 0 to 1) can be calculated. 
The VAS is scored separately and ranges from 0 (worst imaginable health state) to 100 (best 
imaginable health state).
19.1.7
Health Care Resource Utilization (HCRU)
Migraine-specific healthcare resource utilization information will be collected in terms of 
outpatient health care professional visits (number of visits to doctor/genral practitioner and 
number of visits to a specialist), number of emergency room visits, number of hospital 
admissions, as well as number of overnight hospital stays during the past 4 weeks.
The items from the questionnaire will be analyzed separately.
19.1.8
Work Productivity and Activity Impairment: Migraine (WPAI:M)
The WPAI12 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: 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.


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The derivation of the WPAI:M sub-scores13 is given in Panel 9, where Q1-Q6 refers to 
question 1-6 in the questionnaire. If both Q2 and Q4 has a score of 0 then both the 
Absenteeism and the Work productivity loss sub-scores are set to missing.
Panel 9
Derivation of WPAI:M sub-scores
Sub-score
Description
Derivation
Absenteeism
Percent work time missed due to 
migraine
100*Q2/(Q2 + Q4)
Presenteeism
Percent impairment while 
working due to migraine
100*Q5/10
Work productivity loss
Percent overall work 
impairment due to migraine
100 ∗:
;-
;- <;= + :1 −
;-
;- < ;=? ∗
;@
,A?
Activity impairment
Percent activity impairment due 
to migraine
100*Q6/10
19.2
Assigning Data to Visits
See Section 4.2 for definition of Baseline values.
19.2.1
Clinical Outcome Assessments (COAs) - Scales
For treated patients withdrawing prior to Week 24, the withdrawal visit scheduled 12 weeks 
after the last IMP infusion will also include efficacy evaluations (PGIC, MBS, HIT-6, MSQ, 
EQ-5D-5L, HCRU, and WPAI:M). These assessments will be assigned to either Visit 5 or 
Visit 8 according to when the patient was withdrawn as follows:
For patients withdrawing prior to Visit 5, the assessments from the Withdrawal Visit will 
be assigned to nominal Visit 5
For patients withdrawing after Visit 5 (but prior to Visit 8), the assessments from the 
Withdrawal Visit will be assigned to nominal Visit 8.
Unscheduled visits will not contain assessments of the COAs mentioned above. In relation to 
the nominal visits post-Baseline, a patient can complete their COAs 3 days before the visit. In 
case of duplicate scale assessments in relation to a nominal visit, i.e. if a patient fills out the 
scales 3 days before the visit and the visit is postponed afterwards implying that the patient 
has to complete the COA again, the latest assessment will be used.
19.2.2
Safety Variables
Laboratory Tests and ECG
Assessments of laboratory tests and ECGs at unscheduled visits and withdrawal visits will be 
assigned to a nominal visit in the Placebo-controlled Period according to the visit windowing 
specified in Panel 10 for patients in the APTS. Assessments for patients not receiving any 
infusions of IMP will be assigned to Visit 2 (Baseline). For patients receiving an infusion of 


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IMP in the Extension Period, assessments of laboratory tests and ECGs at unscheduled visits
and withdrawal visits will be assigned to a nominal visit in the Extension Period according to 
the visit windowing specified in Panel 11.
Panel 10
Visit Windows for Placebo-Controlled Period – Laboratory tests, ECG
Nominal Visit Number
Nominal Visit Week
Nominal Visit Day
Time Window
V1 (Screening Visit)
-4
-28
NA
V2 (Baseline Visit)
0
0
NA
V5
12
84
After start of first IMP 
infusion to day 126
V8
24
168
Day 127 to start of Visit 8
IMP infusion
Panel 11
Visit Windows for Extension Period – Laboratory tests, ECG
Nominal Visit 
Number
Nominal Visit 
Week
Nominal Visit Day
Nominal Visit Day 
Relative to Visit 8 
IMP Infusion
Time Window 
Relative to Visit 8 
IMP Infusion
V11
36
252
84
After start of Visit 8
IMP infusion to day 
126
V14
48
336
168
Day 127 to day 210
V17
60
420
252
Day 211 to day 294
V20
72
504
336
> 294
Vital signs will be assessed before and after infusion at nominal visits. For unscheduled or 
withdrawal visit assessments of vital signs, the values will be assigned a nominal visit 
according to Panel 12 and Panel 13.


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Panel 12
Visit Windows for Placebo-Controlled Period – Vital Signs
Nominal Visit Number
Nominal Visit Week
Nominal Visit Day
Time Window
V1 (Screening Visit)
-4
-28
NA
V2 (Baseline Visit) pre-dose
0
0
NA
V2 (Baseline Visit) post-dose
0
0
After start of first IMP 
infusion to day 42
V5 pre-dose
12
84
Day 43 to start of V5 IMP 
infusion
V5 post-dose
12
84
After start of V5 IMP 
infusion to day 126 
V8 pre-dose
24
168
Day 127 to start of Visit 8 
IMP infusion
Panel 13
Visit Windows for Extension Period – Vital Signs
Nominal Visit 
Number
Nominal Visit 
Week
Nominal Visit Day
Nominal Visit Day 
Relative to Visit 8 
IMP Infusion
Time Window 
Relative to Visit 8 
IMP Infusion
V8 post-dose
24
168
0
After start of V8 
IMP infusion to day 
42
V11 pre-dose
36
252
84
Day 43 to start of 
V11 IMP infusion
V11 post-dose
36
252
84
After start of V11 
IMP infusion to day 
126
V14 pre-dose
48
336
168
Day 127 to start of
V14 IMP infusion
V14 post-dose
48
336
168
After start of V14 
IMP infusion to day 
210
V17 pre-dose
60
420
252
Day 211 to start of 
V17 IMP infusion
V17 post-dose
60
420
252
After start of V17 
IMP infusion to day 
294
V20
72
504
336
> 294
If there is more than one assessment at a visit (either due to multiple assessments or because 
an unscheduled or withdrawal visit assessment is mapped to a nominal visit with an already 
existing value) the value that will be used in summary tables by visit will be the one closest to 
the nominal day for the visit but prioritizing values from scheduled visits above values from 
withdrawal or unscheduled visits. In the ordering of multiple values, assessments without 
recorded time will come after assessments with recorded time and the first in the ordering will 
be picked.


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19.3
Handling Missing or Incomplete Dates/Times
19.3.1
Missing Headache End Date and Time
If the end date and time for a headache recorded in the eDiary is missing, the headache end 
date and time will be imputed as follows:
If there exists an entry in the evening eDiary at a date after the date of the start of the 
headache entered in the headache eDiary, the headache end date and time is imputed with the 
date and time of the last evening eDiary entry.
If there are no entries in the evening eDiary after the date of the start of the headache entered 
in the headache eDiary, the headache end date and time is imputed with the start date of the 
headache and the time 23:59.
Headaches that are not reported as stopped by the patient are missing the answers to the 
questions that allow for the determination of whether the headache was a migraine or not. 
Headaches with missing ‘end’ information will be classified as migraines (and thereby also as 
headaches).
Note that for each patient, it is only possible to have a missing end date and time for the last 
headache ever entered, since a patient needs to complete a headache in order to report a new 
one in the headache eDiary.
19.3.2
Withdrawal Date
Missing withdrawal dates will not be imputed and time to withdrawal from treatment will not 
be calculated for missing withdrawal dates.
19.3.3
Medical Disorder Start and Stop Dates
Incomplete dates will not be imputed. Classification of events into concurrent medical 
disorders or past disorders will be based on the reported ongoing status.
19.3.4
Medication Start and Stop Dates
Imputation of incomplete or partially missing dates will be performed in order to document 
the assigned categories specified in Section 9.
The algorithm for imputing the start dates will follow the one used for imputing adverse event 
start dates, see Section 19.3.5.
For imputing stop dates, the following will apply, where UK and UKN indicate unknown or 
missing day and month, respectively:
UK-MMM-YYYY: Medication end date is imputed with the last day of the month
UK-UKN-YYYY: Medication end date is imputed with 31-DEC-YYYY


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Medications marked as ongoing are considered concomitant medications in one or both of the 
periods (Placebo-controlled Period and Extension Period), depending on the (possibly 
imputed) start date, i.e. if the start date is at or after the date of V8 IMP infusion, the 
medication is only considered ongoing in the Extension Period.
19.3.5
Adverse Event Start and Stop Dates
Imputation of partially or completely missing dates will be included in data in order to 
document the classification of the treatment emergent status and assignment of the adverse 
event to a period. For an adverse event with an imputed start date, the classification of 
treatment emergent will depend only on whether the imputed date is the same as the date(s) of 
infusion and not the timepoint of the infusion, since start times for adverse events will not be 
imputed. No duration will be calculated for adverse events with incomplete start-or-stop dates 
or for ongoing adverse events.
Imputation will follow the algorithm below. If an imputed start date after this procedure is 
after the end date, the start date will be set to the end date.
Start Dates
Patients with no IMP infusion
For patients who have not been treated, the imputation of AE start date will be performed as 
follows, where UK and UKN indicate unknown or missing day and month, respectively:
UK-MMM-YYYY: The start date will be imputed with either the 1st of the month, or date 
of Visit 1. Date of Visit 1 will be used if that is the later of the two and if it is within the 
specified month and year
UK-UKN-YYYY: The start date will be imputed with either JAN 1, or date of Visit 1.
Date of Visit 1 will be used if it is within the specified year
If the AE start date is completely missing, it will be set equal to the date of Visit 1.
Patients who received at least one IMP infusion
For patients, who have been treated, the imputation of AE start dates will be performed as 
follows:
UK-MMM-YYYY:
o If the year and month are equal to the year and month of treatment start date, the 
adverse event start date is imputed with the date of first dose of IMP
o If the year is equal to the year of treatment start date: If the month is prior to the 
treatment start date, the adverse event start date is imputed with the last day of the 
month. If the month is equal to the month of the treatment start date, see above. If the 
month is after the month of the treatment start date, the adverse event start date is 
imputed with the first day of the month


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o If the year is prior to treatment start date, the adverse event start date is imputed with the 
last day of the month
o If the year is after the year of treatment start date, the adverse event start date is imputed 
with the first day of the month
UK-UKN-YYYY:
o If the year is equal to the year of treatment start date, the adverse event start date is 
imputed with treatment start date
o If the year is prior to the year of treatment start date, the adverse event start date is 
imputed with 31-DEC-YYYY
o If the year is after the year of treatment start date, the adverse event start date is imputed 
with 01-JAN-YYYY
If the AE start date is completely missing, it will be set equal to treatment start date.
End Dates
Missing AE end dates will not be imputed. 
Incomplete Intensity Change Dates
If the day is missing in a date of intensity change for an adverse event, the date will be 
imputed using the same algorithm as described above for incomplete adverse event start dates.
If this results in an imputed start date that is after the end date of the original event or after an 
intensity change that comes after the intensity change in question, the start date will be 
imputed with the end date of the original event or the date of the later intensity or change.
19.4
Data with Multiple Records
19.4.1
Dose Changes in Medication
Dose changes in medications are recorded on multiple rows in the dataset, with different start 
and stop dates. When classifying medications into categories (see Section 9), each dose is 
considered a separate medication, and the same medication can be assigned to several 
categories for the same patient. Within a category, multiple entries contribute as a single 
count.
19.4.2
Changes in Intensity or Seriousness of Adverse Events
An adverse event that changes in intensity in a period will contribute to the count of events as 
a single event.
In summaries of adverse events presented by intensity, the maximum intensity of the adverse 
event will be used. The maximum intensity is searched for in events with changes, as well as 
over repeated events based on the preferred term. Adverse events for which information on 
intensity is missing will be classified as severe.


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Adverse events with an update in seriousness will be included in ADaM with only one row. 
For such an event, the start date of the serious adverse event will be set to the start date of the 
original event. This means that an adverse event with a start date prior to first infusion of IMP 
(i.e. not classified as treatment-emergent) that is registered as serious after first IMP infusion 
will still not be classified as treatment-emergent, unless a change in intensity is taking place 
after first IMP infusion as well.
Adverse events for which information on seriousness is missing will be classified as serious.


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References
1.
International Headache Society (IHS), Headache Classification Committee. The International 
Classification of Headache Disorders, 3rd edition 2018 (ICHD-3 2018).
2.
Robinson LD and Jewell NP. Some surprising results about covariate adjustment in logistic 
regression models. International Statistical Review. 1991; 59: 227-240.
3.
Koch GG, Tangen CM, Jung J-W, Amara IA. Issues for covariance analysis of dichotomous and 
ordered categorical data from randomized clinical trials and non-parametric strategies for 
addressing them. Statist Med. 1998; 17: 1863-1892.
4.
Little R and Yau L. Intent-to-treat analysis for longitudinal studies with drop-outs. Biometrics. 
1996; 52: 1324-1333.
5.
Rubin, DB. Multiple imputation for nonresponse in surveys. New York: Wiley; 1997.
6.
United States Food and Drug Administration (US FDA). Guidance for Industry: Drug-induced 
liver injury: premarketing clinical evaluation. July 2009.
7.
Kosinski M, Bayliss MS, Bjorner JB, Ware JE, Garber WH, Cady R, et al. A six-item short-form 
survey for measuring headache impact: the HIT-6. Qual Life Res. 2003; 12(8): 963–974.  
8.
Jhingran P, Osterhaus JT, Miller DW, Lee JT, Kirchdoerfer L. Development and validation of the 
Migraine-Specific Quality of Life Questionnaire. Headache. 1998; 38(4): 295–302.
9.
Martin BC, Pathak DS, Sharfman MI, Adelman JU, Taylor F, Kwong WJ, Jhingran P. Validity 
and reliability of the migraine-specific quality of life questionnaire (MSQ Version 2.1). 
Headache. 2000 Mar; 40(3): 204-215.
10. Mapi Research Trust. Migraine specific quality of life questionnaire. Version 2.1. Scaling and 
scoring. Version 1.0. November 2017.
11. Herdman M, Gudex C, Lloyd A, Janssen M, Kind P, Parkin D, et al. Development and 
preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). Quality of Life 
Research. 2011; 20: 1727–1736.
12. Reilly MC, Zbrozek AS, Dukes, EM. The validity and reproducibility of a work productivity and 
activity impairment instrument. Pharmacoeconomics. 1993; 4(5): 353–365.
13. Reilly Associates. WPAI Scoring.[Internet] reillyassociates.net/WPAI_Scoring.html


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Appendix I
Statistical Analysis Plan
Authentication and Authorization


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Study 18898A – Statistical Analysis Plan
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Statistical Analysis Plan
Authentication and Authorization
Study title:
Interventional, randomized, double-blind, parallel-group, placebo-controlled study 
with an extension period to evaluate the efficacy and safety of eptinezumab for the 
prevention of migraine in patients with unsuccessful prior preventive treatments
Study No.:
18898A
SAP date (v.1.0): 8 March 2021
SAP date (v.2.0): 13 October 2021
This document has been signed electronically. The signatories are listed below.
Authentication
Authorization


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Appendix II
Study Procedures and Assessments


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Study Procedures and Assessments
Table 1
Study Procedures and Assessments
Visit Name
Screening
Baselinee + IMP
Phone Contactk
Phone Contactk
Primary Outcome + IMP 
Phone Contactk
Phone Contactk
IMP 
Phone Contactk
Phone Contactk
IMP
Phone Contactk
Phone Contactk
IMP
Phone Contactk
Phone Contactk
IMP
Phone Contactk
Phone Contactk
Completion
Withdrawalv
Placebo-controlled Period
Extension Period
Visit Number
1
2
3
4
5
6
7
8
z
9
z
10
z
11
z
12 13 14 15 16 17 18 19 20
End of Weeka
-4
0
4
8
12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72
Visit Windowb (days 
relative to nominal 
visit)
-2
-2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 +2 +2
Screening and Baseline Procedures and Assessments
Signed informed 
consents 

Demographics (age, 
sex, race)

Diagnosis

Documented evidence 
of previous failure of 
2-4 migraine 
preventive 
medicationsc

Disease-specific 
history

Relevant history 
(social, medical, 
psychiatric, 
neurological)

Recent medication


Smoking, alcohol 
consumption

Height

Blood sampling for 
serology (HIV, 
HBsAg, anti-HCV)





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Visit Name
Screening
Baselinee + IMP
Phone Contactk
Phone Contactk
Primary Outcome + IMP 
Phone Contactk
Phone Contactk
IMP 
Phone Contactk
Phone Contactk
IMP
Phone Contactk
Phone Contactk
IMP
Phone Contactk
Phone Contactk
IMP
Phone Contactk
Phone Contactk
Completion
Withdrawalv
Placebo-controlled Period
Extension Period
Visit Number
1
2
3
4
5
6
7
8
z
9
z
10
z
11
z
12 13 14 15 16 17 18 19 20
End of Weeka
-4
0
4
8
12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72
Visit Windowb (days 
relative to nominal 
visit)
-2
-2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 +2 +2
Blood and urine 
sampling for clinical 
safety laboratory tests 

n
n
n
n
n
n


Blood ADA
n
n
n
n
n
n
p

Vital signs body 
temperature including, 
weight, ECGs

n
n
n
n
n
n


Physical Examination

n
n
n
n
n
n


C-SSRSo









Biobanking
Blood sampling for 
gene expression 
profiling (RNA)w
n
n
n
n


Blood sampling for 
metabolomics/
proteomics (plasma)w
n
n
n
n


Blood sampling for 
pharmacogenetics 
(DNA) – optionalx
n
Blood sampling for 
possible future ADA 
assessmenty
n


Other Study Procedures and Assessments
IMP administeredr
q
q
q
q
q
q
IMP accountabilitys 






Concomitant 
medication 
(prescription and non-
prescription)




















eDiary trainingi



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Visit Name
Screening
Baselinee + IMP
Phone Contactk
Phone Contactk
Primary Outcome + IMP 
Phone Contactk
Phone Contactk
IMP 
Phone Contactk
Phone Contactk
IMP
Phone Contactk
Phone Contactk
IMP
Phone Contactk
Phone Contactk
IMP
Phone Contactk
Phone Contactk
Completion
Withdrawalv
Placebo-controlled Period
Extension Period
Visit Number
1
2
3
4
5
6
7
8
z
9
z
10
z
11
z
12 13 14 15 16 17 18 19 20
End of Weeka
-4
0
4
8
12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72
Visit Windowb (days 
relative to nominal 
visit)
-2
-2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 +2 +2
PRO trainingi

eDiary closeoutj


Pregnancy test
t








Exit Interview 
u
u
ADA = anti-drug antibody; C-SSRS = Columbia-Suicide Severity Rating Scale; ECG = electrocardiogram; 
EQ-5D-5L = Euroqol 5 Dimensions; HBsAg = hepatitis B surface antigen; FSH = follicle-stimulating 
hormone; HCRU = Health Care Resource Utilization; βhCG = beta-human chorionic gonadotropin; 
HCV = hepatitis C virus; HIT-6 = Headache Impact Test; HIV = human immunodeficiency virus; 
IMP = investigational medicinal product; MBS = Most Bothersome Symptom; MSQ v2.1 = Migraine-
Specific Quality of Life Questionnaire Version 2.1; PGIC = Patient Global Impression of Change; PRO = 
patient-reported outcome; WPAI = Work Productivity and Activity Impairment questionnaire
a
All assessments (except for the requirement of screening assessments prior to the Baseline Visit) may be 
completed over a maximum of 2 consecutive days with the exception of PROs (see footnote g below); if so, 
the first day is considered the “visit” day according to the schedule.
b
If the date of a clinic visit or phone contact does not conform to the schedule, subsequent visits should be 
planned to maintain the visit schedule relative to the Baseline Visit.
c
The patients must have documented evidence of failure in the past 10 years of 2-4 different pharmacological 
migraine preventive medications. Acceptable documentation of previous treatment failures includes medical 
or pharmacy record or physician’s confirmation specific to each treatment. 
d
Randomization will occur at the Baseline Visit 28-30 days after the Screening Visit and after eligibility 
criteria are confirmed by the investigator.
e
Dosing must occur at the Baseline Visit. 
f
Inclusion and exclusion criteria review must be done prior to dosing at the Baseline Visit.
g
Assessments involving interviews and scales must be done before the infusions. All efficacy and 
pharmacoeconomic assessments are PROs. PROs which are scheduled in alignment with a clinic visit can be 
completed in the clinic or in the remote setting within 3 days prior to the scheduled clinic visit date.
Additionally, PGIC (at Week 4 only), HIT-6, EQ-5D-5L, HCRU, WPAI which are scheduled in alignment 
with a phone contact 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. 
h
The eDiary assessments will be completed in the remote setting on a daily basis. 


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i
At the Screening Visit, the patient must be assisted with the provisioning and training of the eDiary and 
training of efficacy and pharmacoeconomic assessments (PROs). Details will be provided in a separate user 
manual.
j 
The eDiary closeout will take place at the Completion/Withdrawal Visit, while the patient is at site. Details 
will be provided in a separate user manual.
k
The patients will be contacted via phone every 4 weeks between infusion visits for eDiary data review and 
compliance check, to ensure that selected assessments have been completed and for collection of relevant 
information such as AEs and concomitant medication.
l
PGIC at Week 4 must be completed in the remote setting. 
m At infusion visits, IRRs must be checked as part of the overall AE collection, after infusion and before the 
patient is discharged from the site.
n
At infusion visits, physical examination, ECG, blood sampling (for clinical safety laboratory tests, ADA and 
biobank) and urine samples (for clinical safety laboratory tests and pregnancy) must be conducted before 
infusion. AEs, vital signs including  body temperature should be checked before and after infusion.
o
The C-SSRS will be administered by the authorized rater at the clinic and prior to infusion.
p
Patients who test positive for ADA at the Completion will be asked to provide up to two additional blood 
samples for immunogenicity testing at 12-week intervals for up to 24 weeks.
q
At infusion visits, patients must be monitored for a period of 1 hour from the end-of-infusion. Patients will be 
requested to stay longer should the investigator determine this is clinically warranted.
r 
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.
s A designated unblinded CRA is responsible for the IMP accountability.
t 
Pregnancy test at Screening to be conducted using serum β-HCG and at all other visits using urine testing.
u
Exit Interview subset: Patients undergoing the exit interviews must provide signed subset-specific Informed 
Consent. The exit interview will be conducted at the Week 24 Visit or at the Withdrawal Visit for patients 
withdrawing prior to Week 24. The exit interview must be conducted after all visit assessments are 
completed. Details will be provided in a separate exit interview guide.
v
Patients who withdraw, except for those who withdraw their consent, will be asked to attend a Withdrawal 
Visit 12 weeks after the last dose of IMP and undergo Safety Follow-Up evaluations. Patients who withdraw 
prior to Week 24 will undergo additional Efficacy Follow-Up evaluations.
w Exploratory gene expression profiling (RNA) and metabolomics/proteomics are an integrated part of the
study and are covered by the main Informed Consent.
x
Sampling for pharmacogenetics is optional and a separate signed Informed Consent must be in place to cover 
this analysis.
y
Whole blood samples for serum separation and potential future ADA analyses will be drawn at the Baseline 
Visit and at Week 24.
z
If a decision is made to end enrolment early, patients who have not yet completed their Week 12 Visit will 
immediately transfer to the Extension Period. Patients originally randomized to placebo will be scheduled for 
Visit 8 immediately and active treatment will be initiated. Patients originally randomized to eptinezumab will 
be scheduled for Visit 9 or 10 or 11. For these patients, the scheduling of Visit 9 or 10 or 11 should allow for 
the next dose of IMP to be received at Visit 11, that is 12 weeks after their first dose. Patients who have 
already completed their Week 12 Visit will continue to finalise 24 weeks of treatment in the Placebo-
controlled Period and enter the Extension Period at Visit 8. Patients must continue to complete the daily 
headache eDiary during the transfer to the Extension Period.


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Page 68 of 80
Appendix III
PDS Migraine Event Definition


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PDS Migraine Event Definition
The PDS definition of a migraine day, which was used at randomization for the classification 
into EM and CM stratum as defined in inclusion criterion 10, is a day with a migraine event 
defined as:
Table 2
PDS Migraine Event Definition
See PDS for details regarding the definitions and calculations used for eligibility.


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Study 18898A – Statistical Analysis Plan
Page 70 of 80
Appendix IV
SAS® Code


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SAS® Code
Primary Analysis
The SAS® code for the primary analysis of the primary endpoint described in Section 12.3.2
is given below. Here, it is assumed that the ordering of the levels of the treatment factor is:
100 mg, 300 mg, placebo.
proc mixed data = xxxx method = REML;
class USUBJID TRTP(ref = 'Placebo') STRATUM COUNTRY AVISITN;
      
model CHG = BASE TRTP AVISITN STRATUM COUNTRY BASE*AVISITN
     STRATUM*AVISITN TRTP*AVISITN / DDFM = KR;
repeated AVISITN / subject = USUBJID type = UN;
lsmestimate TRTP*AVISITN "100 mg vs. Placebo, Weeks 1-12"
[1, 1 1] [1, 1 2] [1, 1 3] [-1, 3 1] [-1, 3 2] [-1, 3 3]/
divisor = 3 cl;
lsmestimate TRTP*AVISITN "300 mg vs. Placebo, Weeks 1-12"
[1, 2 1] [1, 2 2] [1, 2 3] [-1, 3 1] [-1, 3 2] [-1, 3 3]/
divisor = 3 cl;
run;
Key Secondary Analysis
The SAS® code for conducting the key secondary analyses described in Section 12.4.2 is 
given below. Note that p-values to be included in the test strategy will be computed from a 
likelihood ratio test.
proc logistic data = xxxx;
       by AVISITN;
       class TRTP(ref = "Placebo") STRATUM / param = GLM;
       model RESPONSE(event = "1") = TRTP STRATUM BASE / 
                                                  clodds = PL alpha = 0.05;
run;
Secondary Analysis
The SAS® code for computing p-values from the extended CMH test for the secondary
endpoints described in Section 12.5 is given below. The p-values are computed separately for 
each active treatment group. In the code below the relevant p-value is stored in the p_value
output data set.
proc freq data = xxxx (where = (TRTP in ('EPTI xxx mg' 'PBO') and AVISIT = 
'xxxx'));
   output out = p_value CMHRMS;


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   tables STRATUM*TRTP*AVAL / cmh2;
run;
Sensitivity Analysis (placebo-based Multiple Imputation)
The SAS® code that will be the basis for the placebo-based multiple imputation (pMI)
sensitivity analysis for the key secondary endpoint, HIT-6, mentioned in Section 12.4.4, is 
given below. Note that data transformation steps are omitted and only the most crucial parts 
are shown.
The procedure for the pMI method will include the following steps:
1.
Impute missing intermittent data using Markov Chain Monte Carlo (MCMC) 
methodology by treatment group with the model for HIT-6 total score at baseline and 
at Week 4, 8, 12, 16, 20, and 24, using PROC MI from SAS®, with seed = 101990
and 200 imputations, to impute data to a monotone missing data pattern under a MAR
assumption.
2.
At time t, perform pMI according to the placebo-treated patients, where the monotone
missing values are assumed to follow an MNAR pattern. Only observations up to 
time t will be included for the placebo group. Based on the model established using 
only placebo data, observations up to but not beyond time t-1 in the eptinezumab
treatment groups will be used for imputing the missing data at time t. The regression 
model will include stratum and observed or imputed outcomes up to time t (including 
the baseline scores), and will use the MONOTON REG option in PROC MI with seed 
= 88775.
3.
Assemble a dataset containing data for all patients, including the imputed data from 
time t, to serve as predictors for the imputation of the next visit.
4.
Repeat steps 2 to 3 sequentially over all visits (t+1, t+2…).
5.
Analyse the 200 complete datasets using the same MMRM model as described in 
Section 12.4.2.
6.
Combine the estimated treatment effects obtained across the imputed datasets using 
PROC MIANALYZE from SAS®.
In the below, it is assumed that:
transposed_data: transposed analysis data with each AVISITN as a separate variable
mono_data: data with monotone missing data pattern
imputed_data: data with missing values imputed
mmrm_data: data with CHG calculated from imputed values and with additional variables to 
be used in the modelling added
diff_data: data with estimated treatment differences from the converged models fit on each of 
the 200 datasets
results_data: data with the combined estimated treatment effects
Code parts:
*Impute intermittent missing values;


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proc mi data = transposed_data out = mono_data nimpute = 200 seed = 101990;
   by TRTP;
   var BASE AVISITN 3 AVISITN_4 AVISITN_5 AVISITN_6 AVISITN_7 AVISITN_8;
   mcmc chain = multiple
   impute = monotone;
run;
*Impute monotone missing values;
proc mi data = mono_data seed = 88775 nimpute = 1 out = imputed_data;
by
IMPUTATION ;
class STRATUM TRTP;
monotone regression;
mnar model(AVISITN_3 AVISITN_4 AVISITN_5 AVISITN_6 AVISITN_7 AVISITN_8 /
     modelobs = (TRTP = "PBO"));
var STRATUM BASE AVISITN_3 AVISITN_4 AVISITN_5 AVISITN_6 AVISITN_7 
  
    AVISITN_8;
run;
*Execute model on imputed data;
ods output lsmeans = 
LS01 diffs = 
D01 ConvergenceStatus = __CONV01;
proc mixed data = mmrm_data method = REML;
by _IMPUTATION_;
class AVISITN COUNTRY STRATUM TRTP USUBJID;
model CHG = BASE TRTP AVISITN STRATUM COUNTRY BASE*AVISITN
  
     
  
            STRATUM*AVISITN TRTP*AVISITN / DDFM = KR;
lsmeans TRTP*AVISITN / diff cl alpha = 0.05;
repeated AVISITN / subject = USUBJID type = un;
run;
*Combine model estimates;
proc mianalyze parms(classvar = full) = diff_data;
by AVISITN;
class TRTP;
modeleffects TRTP*AVISITN;
ods output ParameterEstimates = results_data;
run;


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Appendix V
PCS Criteria


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PCS Criteria
Table 3
PCS Criteria for Clinical Safety Laboratory Tests
Laboratory Test
CDISC Term
Unit
PCS Low
PCS High
Haematology / Coagulation
B-haemoglobin
HGB
g/L
≤ 95 (women)
≥ 165 (women)
≤ 115 (men)
≥ 185 (men)
B-erythrocytes (red cell count)
RBC
x 10E12/L
≤ 3.5 (women)
≥ 6.0 (women)
≤ 3.8 (men)
≥ 7.0 (men)
B-haematocrit (packed cell 
volume)
HCT
V/V
≤ 0.32 (women)
≥ 0.50 (women)
≤ 0.37 (men)
≥ 0.55 (men)
B-MCV (mean cell volume)
MCV
fL
≤ 0.8 x LLN
≥ 1.2 x ULN
B-total leucocyte (white cell 
count)
WBC
x 10E9/L
≤ 2.8
≥ 16
B-neutrophils/leucocytes
NEUTLE
%
≤ 20
≥ 85
B-eosinophils/leucocytes
EOSLE
%
≥ 10
B-basophils/leucocytes
BASOLE
%
≥ 10
B-lymphocytes/leucocytes
LYMLE
%
≤ 10
≥ 75
B-monocytes/leucocytes
MONOLE
%
≥ 15
B-thrombocytes (platelet count)
PLAT
x 10E9/L
≤ 75
≥ 600
P-INR (prothrombin ratio)
INR
Ratio
≥ 2.0
B-prothrombin time
PT
Sec
≥ 18
Liver
S-aspartate aminotransferase
AST
U/L
≥ 3 × ULN
S-alanine aminotransferase
ALT
U/L
≥ 3 × ULN
S-bilirubin
BILI
μmol/L
≥ 34
S-bilirubin, direct
BILDIR
μmol/L
≥ 12
S-bilirubin, indirect
BILIND
μmol/L
≥ 22
S-alkaline phosphatase
ALP
U/L
≥ 3 × ULN
S-gamma glutamyl transferase
GGT
U/L
≥ 200
S-alpha-glutathione S-transferase 
(alpha-GST)
GSTAL
μg/L
≥ 20
Kidney
S-creatinine
CREAT
μmol/L
≥ 1.5 x ULN
B-urea nitrogen (BUN)
BUN
mmol/L
≥ 11
S-uric acid (urate)
URATE
μmol/L
≥ 510 (women)
≥ 630 (men)
Electrolytes
S-sodium (natrium)
SODIUM
mmol/L
≤ 125
≥ 155
S-potassium (kalium)
K
mmol/L
≤ 3.0
≥ 6.0


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Laboratory Test
CDISC Term
Unit
PCS Low
PCS High
S-calcium
CA
mmol/L
≤ 1.8
≥ 3.0
S-chloride
CL
mmol/L
≤ 90
≥ 117
S-magnesium
MG
mmol/L
≤ 0.6
≥ 1.3
S-phosphate (phosphorus, 
(inorganic)
PHOS
mmol/L
≤ 0.65
≥ 1.95
S-bicarbonate
BICARB
mmol/L
≤ 12
≥ 38
Endocrine / Metabolic
B-glucose, non-fasting/unknown
GLUC
mmol/L
≤ 3.4
≥ 9.4
B-glucose, fasting
GLUC
mmol/L
≤ 3.0
≥ 6.0
S-glucose, non-fasting/unknown
GLUC
mmol/L
≤ 3.9
≥ 11.1
S-glucose, fasting
GLUC
mmol/L
≤ 3.5
≥ 7.0
B-glycosylated haemoglobin, 
fasting
HBA1C
Hb fract.
≥ 0.065
S-prolactin
PROLCTN
mIU/L
≥ 1350
S-thyrotropin/TSH
TSH
mIU/L
≤ 0.3
≥ 5.5
S-protein (total)
PROT
g/L
≤ 45
≥ 95
S-albumin
ALB
g/L
≤ 27
Lipids
S-cholesterol total, non-
fasting/unknown
CHOL
mmol/L
≥ 7.8
S-cholesterol total, fasting
CHOL
mmol/L
≥ 6.2
S-triglycerides, non-
fasting/unknown
TRIG
mmol/L
≥ 5.65
S-triglycerides, fasting
TRIG
mmol/L
≥ 4.2
S-LDL cholesterol, non-
fasting/unknown
LDL
mmol/L
≥ 5.3
S-LDL cholesterol, fasting
LDL
mmol/L
≥ 4.9
S-HDL cholesterol, non-
fasting/unknown
HDL
mmol/L
≤ 0.8
S-HDL cholesterol, fasting
HDL
mmol/L
≤ 0.9
Cardiac/Skeletal/Muscle
S-creatine kinase (total)
CK
U/L
≥ 400 (women)
≥ 750 (men)
S-creatine kinase MB isoenzyme
CKMB
μg/L
≥ 8.5 or
CKMBCK
%
≥ 3.5% of total 
CK
S-lactate dehydrogenase (total)
LDH
IU/L
≥ 750
S-troponin I
TROPONI
μg/L
≥ 1.5
S-troponin T
TROPONT
μg/L
≥ 0.4
Infection
S-C-reactive protein
CRP
mg/L
≥ 25
S-globulin (total)
GLOBUL
g/L
≤ 15
≥ 55


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Laboratory Test
CDISC Term
Unit
PCS Low
PCS High
Urine
Urinary pH
PH
≤ 4
≥ 9
S=serum; B=whole blood; U=urine
Table 4
PCS Criteria for Vital Signs, Weight/BMI, and Waist Circumference
Variable
CDISC Term
Unit
PCS Low
PCS High
Waist circumference
WSTCIR
Cm
decrease ≥ 7%
increase ≥ 7%
Weight
WEIGHT
Kg
decrease ≥ 7%
increase ≥ 7%
Body Mass Index
BMI
kg/m2
decrease ≥ 7%
increase ≥ 7%
Pulse rate, 
supine/sitting/unknown
PULSE
beats/min
< 50 and
decrease ≥ 15
≥ 120 and
increase ≥ 15
Diastolic blood pressure,
supine/sitting/unknown
DIABP
mmHg
≤ 50 and
decrease ≥ 15
≥ 105 and
increase ≥ 15
Systolic blood pressure,
supine/sitting/unknown
SYSBP
mmHg
≤ 90 and
decrease ≥ 20
≥ 180 and
increase ≥ 20
Orthostatic systolic blood 
pressure
OBP
mmHg
≤ -30
Orthostatic pulse rate
OPR
beats/min
≥ 20
Temperature
TEMP
ºC
decrease ≥ 2
≥ 38.3 and
increase ≥ 2
Increase/decrease is relative to the baseline value.
Table 5
PCS Criteria for ECG Parameters
ECG Parameter
CDISC Term
Unit
PCS Low
PCS High
Absolute Time Interval
PR interval
PRAG
Msec
≥ 260
QRS interval
QRSAG
Msec
≥ 150
QT interval
QTAG
Msec
≥ 500
Derived Time Interval
Heart rate
EGHRMN
beats/min
< 50 and
decrease ≥ 15
≥ 120 and
increase ≥ 15
QTcB interval
QTCBAG
Msec
< 300
> 500 or
increase > 60
QTcF interval
QTCFAG
Msec
< 300
> 500 or
increase > 60
Increase/decrease is relative to the baseline value.


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Appendix VI
Adverse Events of Special Interest


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Adverse Events of Special Interest
Table 6
Adverse Events of Special Interest
Event types
SMQ/HLT/HLGT
Additional criteria
Cardio/cerebrovascular events
Cardiac arrhythmias (SMQ) 
(Narrow)
Cardiac failure (SMQ) (Narrow)
Cardiomyopathy (SMQ) (Narrow)
Central nervous system vascular 
disorders (SMQ) (Narrow)
Embolic and thrombotic events 
(SMQ) (Narrow)
Hypertension (SMQ) (Narrow)
Ischaemic heart disease (SMQ) 
(Narrow)
Pulmonary hypertension (SMQ) 
(Narrow)
Torsade de pointes/QT prolongation 
(SMQ) (Narrow)
Events associated with Suicide
Suicide/self-injury (SMQ) (Narrow)
Events potentially associated with 
Study Drug Infusion
Angioedema and urticaria (HLGT)
(primary PTs only)
TEAE on the day of dosing after the 
infusion was started or during the 7 
days after dosing
Bronchial disorders (excl 
neoplasms) (HLGT) (primary PTs 
only)
TEAE on the day of dosing after the 
infusion was started
Infusion site reactions (HLT)
(primary PTs only)
TEAE on the day of dosing after the 
infusion was started or during the 7 
days after dosing
Oral soft tissue signs and symptoms 
(HLT) (primary PTs only)
TEAE on the day of dosing after the 
infusion was started
Oral soft tissue swelling and 
oedema (HLT) (primary PTs only)
TEAE on the day of dosing after the 
infusion was started
Pruritus NEC (HLT) (primary PTs 
only)
TEAE on the day of dosing after the 
infusion was started or during the 7 
days after dosing
Rashes, eruptions and exanthems 
NEC (HLT) (primary PTs only)
TEAE on the day of dosing after the 
infusion was started or during the 7 
days after dosing
Respiratory disorders NEC (HLGT)
(primary PTs only)
TEAE on the day of dosing after the 
infusion was started
Respiratory tract signs and 
symptoms (HLGT) (primary PTs 
only)
TEAE on the day of dosing after the 
infusion was started
Upper respiratory tract disorders 
(excl infections) (HLGT) (primary 
PTs only)
TEAE on the day of dosing after the 
infusion was started


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Event types
SMQ/HLT/HLGT
Additional criteria
Hepatic events
Drug related hepatic disorders -
comprehensive search (SMQ) 
(Narrow)
Hypersensitivity and Anaphylactic 
Reactions
Anaphylactic reaction (SMQ) 
(Narrow)
Angioedema (SMQ) (Narrow)
Hypersensitivity (SMQ) (Narrow)
Seizures
Convulsions (SMQ) (Narrow)